| TheEgyptianJournalofMedicalHumanGenetics(2016)17,1–23 |
| HOSTED BY |
| Ain Shams University |
| The Egyptian Journal of Medical Human Genetics |
| www.ejmhg.eg.net |
| www.sciencedirect.com |
| REVIEW |
| Pathogenetics. An introductory review |
| Mohammad Saad Zaghloul Salem 1 |
| FacultyofMedicine, Ain-ShamsUniversity, Cairo, Egypt |
| Received 1July2015; accepted 7 July2015 |
| Available online27July2015 |
| KEYWORDS Abstract Pathogeneticsreferstostudyingthedifferentaspectsofinitiation/development/progres |
| sion and pathogenesis of genetic defects. It comprises the study of mutagens or factors capable |
| Pathogenetics; |
| Mutagens; of affecting the structural integrity of the genetic material leading to mutational changes that, in |
| Mutation; the majority of cases, result in harmful effects due to the resulting disturbances of functions of |
| Pathogeneticmechanisms; mutated components of the genome. The study of mutagens depicts different types of mutagenic |
| Anti-mutationmechanisms factors,theirnature,theirclassificationaccordingtotheireffectsonthegeneticmaterialandtheir |
| different modes of action. The study of mutation involves different types of mutations classified |
| according to various parameters, e.g. magnitude, severity, target of mutational event as well as |
| itsnature,whichcanbeclassified,inturn,accordingtowhetheritisspontaneousorinduced,static |
| ordynamic,somaticorgerminalmutationetc.Finally,pathogeneticscomprisesstudyinganddelin- |
| eatingthedifferentandinnumerablepathophysiologicalalterationsandpathogeneticmechanisms |
| that are directly and indirectly involved in, and leading to, the development of genetic disorders, |
| coupled with a parallel study of various anti-mutation mechanisms that play critical roles in |
| minimizing the drastic effects of mutational events on the genetic material and in effective |
| protectionagainstthedevelopmentofthesediseases. |
| (cid:2)2015ProductionandhostingbyElsevierB.V.onbehalfofAinShamsUniversity.Thisisanopenaccess |
| articleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Contents |
| 1. Definition.. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 2 |
| 2. Pathogenesis of geneticdiseases . . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 2 |
| 3. Mutagens.. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 3 |
| 4. Classificationof mutagens . .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 3 |
| 5. Factorsaffectingactions ofmutagens .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 3 |
| 6. Mutation .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 4 |
| 7. Classificationof mutation . .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 4 |
| 7.1. Inducedandspontaneousmutation . . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 5 |
| 7.2. Nuclearandmitochondrial mutation . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 5 |
| 7.3. Somaticandgerminal mutation.. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 5 |
| 7.4. Staticanddynamic mutation.. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 6 |
| 1 ProfessorofMedicalGenetics. |
| PeerreviewunderresponsibilityofAinShamsUniversity. |
| http://dx.doi.org/10.1016/j.ejmhg.2015.07.002 |
| 1110-8630(cid:2)2015ProductionandhostingbyElsevierB.V.onbehalfofAinShamsUniversity. |
| ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/). |
|
|
| 2 M.S.Z. Salem |
| 7.5. Pathological andnon-pathological mutation . .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 6 |
| 7.6. Point,small, gross andgenomic mutation. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. 6 |
| 7.6.1. Molecular mechanisms ofpointmutation.. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . 7 |
| 7.6.2. Types ofpoint mutations .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . 7 |
| 7.6.3. Small mutations. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . 9 |
| 7.6.4. Gross mutations. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 10 |
| 7.6.5. Genomic mutations .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 13 |
| 7.7. Base,sugar, phosphatemutation . .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 14 |
| 7.8. Persistent and reversible mutation .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 14 |
| 8. Pathogenetic mechanismsof geneticdiseases . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. . 15 |
| 9. Anti-mutationmechanisms ofthe human genome andhuman proteome .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. . 15 |
| 10. Anti-mutationmechanisms ofthe human genome. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. . 16 |
| 10.1. Structural organization of the humangenome. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 16 |
| 10.2. Structural features of DNA .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 16 |
| 10.3. Degeneracy of the geneticcode.. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 16 |
| 10.4. Nuclear localization of DNA. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 17 |
| 10.5. DNA-associated proteins. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 17 |
| 10.6. Replication proofreading system. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 17 |
| 10.7. Genetic repair systems. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 17 |
| 10.7.1. NuclearDNA repair. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 17 |
| 10.7.2. RNA repair/editing system .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 18 |
| 10.7.3. Mitochondrial DNA (mtDNA) repair . .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. 19 |
| 10.8. Protein repair systems. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 19 |
| 10.9. Silencing of transposonactivity duringdevelopment.. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 19 |
| 10.10. Antioxidant enzyme systems. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 19 |
| 10.11. Apoptosis ofheavily, lethally mutatedcells .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 20 |
| 10.12. Melatonin. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 20 |
| 11. Genetic imprinting. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. . 21 |
| 12. Biological consequences of mutation. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. . 21 |
| 12.1. Mutation andgeneticadaptations tostress . .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 21 |
| 12.2. Mutation andevolutionary variation . .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 22 |
| 12.3. Mutation andnatural selection.. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. . 22 |
| Conflict ofinterest. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. . 23 |
| References. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. .. .. .. . .. .. .. .. . 23 |
| 1. Definition ultimately to a deficient synthesis of proteins or synthesis of |
| defectiveproteinsnecessaryformediationofcellularactivities. |
| Pathogenetics encompasses studying the various factors and Thesefunctionalconsequencesarereflectedindisturbed/defec- |
| different mechanisms involved in the pathogenesis of genetic tiveconstructionofoneormoreofthemetabolicnetworksthat |
| diseases. It comprises the study of mutagens or factors that regulateeveryaspectofcellularfunctions.Asdepictedfromthe |
| can cause change and/or damage of the genetic material, the cardinaldogmaofmolecularbiology,mutatedgenomeresultsin |
| study of mutations or acquired structural/functional changes thetranscriptionofalteredtranscriptomewhich,inturn,causes |
| of the genetic components at any of its organizational levels synthesisofadefectiveproteome.Thedefectiveproteomeleads |
| that result secondary to the effects of mutagens, the study of towidespreadpathophysiologicalalterationsthatpavetheway |
| thevariousanti-mutationmechanismsofthehumangenome/ for the development of various pathogenetic mechanisms |
| transcriptome/proteomethatexertanessentialandpivotalrole responsibleforinitiationandpathogenesisofgeneticdisorders. |
| inmaintainingtheintegrity/stability/identityofthegenome,the The spectrum of pathophysiological alterations and patho- |
| studyofthedifferentandvaryingpathophysiologicalalterations geneticmechanismsisquitewideandissteadilyexpandingas |
| in cellular functions secondary to the ensuing disturbances of moreknowledgeofthestructure/function/behavior/regulation |
| the metabolic-regulatory networks that mediate and control ofthegeneticmaterialisrevealed.However,thebasicetiological |
| these functions, and the study of the different pathogenetic outlineofdevelopmentofgeneticdefects,asdepictedinFig.1, |
| mechanisms that mediate the development and pathogenesis canbesummarizedasfollows(Fig.1): |
| of genetic defects due to the ensuing changes of the normal |
| structure/functionframeworkofthegeneticmaterial. (1) Deletion or loss of part of a gene, one or many genes, |
| part of a chromosome, one ormore chromosomes, one |
| 2. Pathogenesisof genetic diseases ormoreofmitochondrialgenes,orevenawholegenome. |
| (2) Duplication/rearrangement ofthe geneticmaterial. |
| Genetic diseases are causedbyharmfulmutations. Mutations (3) Deficient/defective transcription of mRNA. |
| causestructuralchangesandconsequentfunctionalalterations (4) Deficient/defective post-transcriptionalmodificationsof |
| of the affected components of the genetic material, leading mRNA. |
|
|
| | Pathogenetics | | | | | | | | | | | | | | 3 | |
| | ------------- | --- | --- | --- | --- | ------- | --- | ------------------------------ | --- | --- | --- | --- | --- | --- | --- | |
| | | | | | | Figure1 | | Pathogenesisofgeneticdiseases. | | | | | | | | |
| (5) Deficient/defective translation of mRNA leading to (2) Physicalmutagens:theseincludeparticulateradi- |
| deficient/defectiveproduction ofgene products. ations like X ray,alpha particles,UVwaves at |
| 2800A˚ |
| (6) Deficient/defective post-translational modifications/ wavelength, solarradiation, thermal and |
| traffickingof synthesizedproteins. mechanical agitation ofnucleic acids [1]. |
| (7) Deficient/defective synthesis of genetic regulatory (3) Biologicalmutagens:theseincludelivingmicroor- |
| components that include transcription nucleoproteins, ganisms like someviruses: cytomegalovirus, rub- |
| transcription factors,microRNA, etc. ella virus andherpes virus. |
| | Irrespective | | of the | site, type, | nature | or magnitude | | of the | | | | | | | | |
| | ------------ | --- | ------ | ----------- | ------ | ------------ | --- | ------ | ------------- | --- | -------- | ------------ | --- | -------- | ------------ | |
| | | | | | | | | | (B) According | | to their | pathogenetic | | effects, | mutagens are | |
| mutationalevent(s)thatdrasticallyaffectthegeneticmaterial, |
| | | | | | | | | | classifiedinto | | fourmaincategories: | | | | | |
| | ------------- | ----------- | ------- | ----------------------- | ----------- | --------- | -------------- | ---- | -------------- | --------------- | ------------------- | ------------ | -------- | ----------- | --------- | |
| | the resultant | alterations | | in gene | function(s) | | trigger many | dis- | | | | | | | | |
| | | | | | | | | | (1) | Non-specific | | Mutagens. | | | | |
| | turbances | in one | or more | of the | cellular | metabolic | regulatory | | | | | | | | | |
| | | | | | | | | | (2) | Carcinogens | | are mutagens | | that induce | malignant | |
| | networks | mediated | by | the deficient/defective | | | gene products, | | | | | | | | | |
| | | | | | | | | | | transformations | | in | affected | cells. | | |
| thusleadingtoawideandvariedspectrumofpathophysiolog- |
| | | | | | | | | | (3) | Clastogens | | are mutagenic | | agents that | can induce | |
| | ------------ | -------------------- | ------------- | --------- | ------------------ | ----------- | ------------- | -------- | --- | ------------- | ------- | ------------------ | -------- | ----------- | ------------- | |
| | ical changes | in | cellular | functions | leading, | ultimately, | | to the | | | | | | | | |
| | | | | | | | | | | chromosome | | breaksin | affected | cells. | | |
| | development | of | genetic | diseases. | The | specific | pathognomonic | | | | | | | | | |
| | | | | | | | | | (4) | Teratogens | | are mutagens | | that cause | congenital | |
| | phenotype | that | characterizes | each | genetic | disease | is primarily | | | | | | | | | |
| | | | | | | | | | | malformations | | in exposedfetuses. | | (Fig. | 2) | |
| | determined | by the | spectrum | of | pathophysiological | | changes | in | | | | | | | | |
| | affected | subjects. | These, | in turn, | are | determined | by the | spec- | | | | | | | | |
| | trum of | the mutation-induced | | | damage | to the | genetic | material | | | | | | | | |
| | | | | | | | | | The | pathogenetic | effects | of | mutagens | and | the resulting | |
| | in affected | patients. | | | | | | | | | | | | | | |
| pathologicalalterationsfollowdisturbedfunctionsofmutated |
| | | | | | | | | | genes. Many | types | of mutagens | | have the | ability | to induce all | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ----------- | ----- | ----------- | --- | -------- | ------- | ------------- | |
| 3.Mutagens |
| | | | | | | | | | types of | mutagenic | damage | to | the cell. | Particulate | and non- | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ----------- | ----------- | ------ | ------------ | --------- | ----------- | ----------- | |
| | | | | | | | | | particulate | radiations, | | for example, | are | effective | carcinogens | |
| Mutagensarefactorscapableofaffectingthestructuralinteg- capableofcausingmalignanttransformationofaffectedcells. |
| rity of the genome. The number of harmful mutagens we are They can also cause chromosomal gaps and breaks. In |
| continuallyexposedto,andinteractingwith,inourlife,start- addition, teratogenic effects in developing fetuses following |
| | ing with | fertilization | | and ending | by | death, | is innumerable. | | | | | | | | | |
| | -------- | ------------- | --- | ---------- | --- | ------ | --------------- | --- | -------- | ----------- | --- | ----- | ------------ | --- | ------------ | |
| | | | | | | | | | exposure | of pregnant | | women | to radiation | are | a well-known | |
| However,duetothemanylinesofdefenseagainsttheharmful hazard of overexposure to radiation during pregnancy. This |
| effectsofthesefactors,representedbythemanyanti-mutation globalmutagenic effectis also shared bymany othertypes of |
| mechanisms of the genome and proteome, only a small per- mutagenslikemutagenicvirusesandchemicalsthatcaninduce |
| centage of mutational events can reach a threshold level malignant transformation, chromosomal breaks and terato- |
| | beyondwhich | geneticdefects | | candevelop. | | | | | | | | | | | | |
| | ---------------- | -------------- | ----------- | ----------- | -------- | --- | ---------- | ---- | -------------------------- | --- | --- | ---------------- | --- | --- | --- | |
| | | | | | | | | | genicmalformations | | in | exposedsubjects. | | | | |
| | 4.Classification | | of mutagens | | | | | | | | | | | | | |
| | | | | | | | | | 5. Factorsaffectingactions | | | of mutagens | | | | |
| | (A) According | | to their | nature, | mutagens | are | classified | into | | | | | | | | |
| threemaincategories: Thepathologicaleffectsofmutagensaredeterminedbymany |
| | | | | | | | | | different | factors. | Each | of these | factors | has its | relative muta- | |
| | --- | -------- | --- | --------- | ----- | --- | --------- | --- | --------- | -------- | ---- | -------- | ------- | ------- | -------------- | |
| | (1) | Chemical | | mutagens: | these | | compounds | are | | | | | | | | |
| innumerable in the environment and include, for genic potential depending on the circumstances of its action. |
| example,organiccompounds,asbestos,insecticides, Congenital malformations caused by teratogens, for instance, |
| herbicides,heavymetals, etc. depend largely on timing of exposure of the developing |
|
|
| 4 M.S.Z. Salem |
| | | | | | | Figure2 | Classificationsofmutagens. | | | | | |
| | --- | --- | --- | --- | --- | ------- | -------------------------- | --- | --- | --- | --- | |
| embryo or growing fetus to their effects. Exposure to terato- The effects of mutation differ widely according to many |
| gensbeforeorafterperiodsofembryonicorfetalgrowthsen- factors. These factors include the nature and target of the |
| sitive to their specific teratogenic effects might result in no or mutagenicfactorcausingmutation,thetimingandmagnitude |
| minimal harm. The dose of exposure, whether of a chemical oftheresultingdamage,thegenotypeorthegeneticconstitution |
| orradiologicalnature,isalsoanimportantfactorindetermin- of the affected individual and the balance between synergistic |
| ing the resultant mutagenic effects. This dose-threshold effect mutageniceffectsandanti-mutationmechanismsofthegenetic |
| mightactindifferentsynergisticways.Alargerexposuredose material. The damaging effects of mutation are attributed to |
| willquantitativelycausemoredamagetowiderportionsofthe the defects they cause in functioning of the mutated genes. |
| geneticmaterial,thusresultinginwidespreadmutationsofthe Sincesynthesisofpropergeneproducts,necessaryformediating |
| genome. It might also cause damage to genes responsible for cellular activities, depends primarily on the integrity of the |
| repair of mutated DNA, thus preventing repair of mutated geneticinformationembodiedwithinthespecificbasesequence |
| genes. In addition, direct non-genetic destructive effects of of the gene, changes or mutation of the exact number or |
| cellularcompartments,ofbloodsupplytocellsorofextracel- the peculiar arrangement of these bases is expected to result |
| lular environment of affected cells will both hasten and in disturbed gene function. This disturbance might express |
| increasethe resulting damage. itself as production of structurally defective gene product, |
| Thegeneticconstitution,orgeneticbackground,ofexposed deficient synthesis of enough product or disturbances in the |
| subjects plays a critical role in determining the sensitivity to construction of regulatory/metabolic networks responsible for |
| mutagenic factors as well as the extent of damage following monitoring, harmonizing andcontrolling cellular functions. |
| | exposure | to their | effects. | The outstanding | | examples | in this | | | | | |
| | -------- | -------- | -------- | --------------- | --- | -------- | ------- | --- | --- | --- | --- | |
| respect are the chromosome breakage syndromes, sometimes 7. Classification ofmutation |
| referredtoasDNAorgeneticinstabilitysyndromes.Thesedis- |
| | eases include | xeroderma | pigmentosum, | | ataxia | telangiectasia, | | | | | | |
| | ------------- | --------- | ------------ | --------- | ------- | --------------- | --- | ----------- | --------------- | -------- | -------- | |
| | | | | | | | | (1) Induced | vsspontaneous | mutation | | |
| | Nijmegen | syndrome, | Bloom | syndrome, | Fanconi | anemia | and | | | | | |
| | | | | | | | | (2) Nuclear | vsmitochondrial | | mutation | |
| someothersimilardiseases.Subjectsaffectedbythesegenetic |
| | | | | | | | | (3) Somatic | vsgerminal | mutation | | |
| | ----------- | -------------- | -------- | --------- | ------------ | ---------- | --------- | ---------------------- | --------------- | ---------------- | -------- | |
| | disorders | have deficient | and/or | defective | | DNA repair | systems | | | | | |
| | | | | | | | | (4) Static vs | dynamicmutation | | | |
| | necessary | for repairing | | mutations | arising | during | DNA | | | | | |
| | | | | | | | | (5) Pathological | vs | non-pathological | mutation | |
| | replication | or following | exposure | | to mutagens. | Exposure | to | | | | | |
| | | | | | | | | (6) Point, small,gross | | andgenomic | mutation | |
| | mutagenic | factors | in doses | that | have no | effects | in normal | | | | | |
| | | | | | | | | (7) Base,sugar, | phosphategroup | | mutation | |
| subjects causes drastic genetic alterations in these patients (8) Persistent vs reversible mutation [Table 1]. |
| | dueto their | defective | geneticconstitution. | | | | | | | | | |
| | ----------- | --------- | -------------------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| 6. Mutation |
| Table1 Classificationofmutation. |
| Mutation entails any uncoded or unprogramed permanent Classificationofmutation |
| structuralalterationofthegeneticmaterialatanyofitsorga- 1.Inducedversusspontaneousmutation |
| nizational levels. These levels comprise a spectrum beginning 2.Nuclearversusmitochondrialmutation |
| withsinglenucleotideorapartofthenucleotide(base,sugar, 3.Somaticversusgerminalmutation |
| phosphate),DNA,RNA,genes,chromosomes,mitochondrial 4.Staticversusdynamicmutation |
| DNA (mtDNA) up to the whole genome. Mutations may 5.Pathologicalversusnon-pathologicalmutation |
| 6.Point,Small,Gross,Genomicmutation |
| | occur without | an | identifiable | cause | and | are termed | sponta- | | | | | |
| | ------------- | --- | ------------ | ----- | --- | ---------- | ------- | --- | --- | --- | --- | |
| 7.Base,Sugar,Phosphategroupmutation |
| | neous mutations, | | or they | may occur | secondary | to | exposure | | | | | |
| | ---------------- | --- | ------- | --------- | --------- | --- | -------- | --- | --- | --- | --- | |
| 8.Persistentversusreversiblemutation |
| | toa known | cause,andare | | referred | to as | inducedmutations. | | | | | | |
| | --------- | ------------ | --- | -------- | ----- | ----------------- | --- | --- | --- | --- | --- | |
|
|
| Pathogenetics 5 |
| 7.1.Inducedandspontaneousmutation recessivediseases.Thepresenceofmostnucleargenesaspairs |
| of alleles derived equally from both parents, paternal and |
| maternal alleles, allows for this classification of genetic dis- |
| Induced mutations are structural alterations of the genetic |
| eases due to nuclear gene mutations to be formulated clearly. |
| material that occur due to exposure to the effects of any of |
| Mitochondrial mutations, on the other hand, have different |
| the known mutagens. Spontaneous mutations, on the other |
| features due to the peculiar nature of the mtDNA. Each |
| hand, are mutations that occur without recognizable causes. |
| mtDNA molecule consists of 37 genes and exists inside the |
| Spontaneous mutations happen, probably, on a regular basis |
| mitochondrioninlargenumbers,tenstothousands,depending |
| becauseoftheintrinsicnatureofthegenome.Possiblepoten- |
| onthemetabolicactivitiesofthecellanditsdemandforATP. |
| tial causes of spontaneous mutation of the genome can be |
| Thus, the copy number of each mtDNA molecule, and of |
| delineated and include: transposon activity, tautomerism and |
| mitochondrial genes is extremely huge in metabolically active |
| changes of energy states of hydrogen bonds of bases. |
| organs, e.g. brain, retina, heart, liver, kidney and skeletal |
| Transposon activity represents a major potential cause of |
| muscles. Mutations of mitochondrial genome can affect a |
| spontaneous mutations [2]. The movement of transposons |
| considerableportionofitsgeneswithoutaffectingitsefficiency |
| results in insertional mutagenesis and disruption of targeted |
| in mediating its functions. It is estimated that mitochondrial |
| genes or other functional genetic elements. Disturbed gene |
| dysfunction begins to occur when approximately 80% of its |
| functionwithresultantdeficiencyofgeneproduct,production |
| genome gets mutated. This threshold effect does not apply |
| ofdefectiveprotein/RNAorlossofgeneticregulatorymecha- |
| for nuclear mutations where mutation of one single allele |
| nisms exerted by mutated genes follows transposon-induced |
| cancauseaseriousdisease,asisthecaseformanyautosomal |
| mutations. Tautomerism of bases of the DNA also accounts |
| dominantdisorders. |
| for a considerable fraction of spontaneous mutations of the |
| Mitochondria in somatic cells are derived from maternal |
| geneticmaterial. Changes of energystates of hydrogenbonds |
| mitochondria in the ovum. The sperm, with rare exceptions, |
| between complementary bases of DNA represent a third |
| doesnotofferanymitochondrialgenestothezygote,because |
| potentialcauseofspontaneousmutation.Alterationsresulting |
| spermmitochondriaarepresentintheneckpieceofthesperm, |
| from changes in electron resonanceand/or proton transfer or |
| whichexistsnexttoitsheadpro-nucleusandwhichdonotpar- |
| relocation between the bonds can lead to tautomeric shift or |
| ticipate in fertilization. Accordingly, mitochondrial disorders |
| tautomerization and momentary change of one base to |
| resultfrommutationsofmaternalmitochondriaandaretrans- |
| another base, thus inducing point mutation, transition muta- |
| mittedbycarrieroraffectedmotherstoalltheiroffspring.This |
| tion [1]. The actual mechanisms underlying the occurrence of |
| difference underlies the specific features that characterize the |
| these changes are still largely undefined, precisely. Analysis |
| natureandthe inheritance pattern ofmitochondrial diseases. |
| of DNA base dynamics according to quantum, rather than |
| to Newtonian, principles seems essential for clarifying these |
| mechanisms,andtheconceptofquantumbiology,orstudying 7.3. Somatic andgerminalmutation |
| the structure and function of the genetic material based on |
| principles and rules of quantum mechanics, would certainly |
| Somatic mutations refer to mutations of the genome of |
| prevail due to the progressive increase in our knowledge of |
| somaticcells.Sincesomaticcellsdonotparticipateinfertiliza- |
| thestructureandfunction(s)ofourgenomeandourproteome. tion or determination of the genetic constitution of the off- |
| Replicative errors occurring during cell division and repli- |
| spring they can’t be transmitted to the offspring, i.e. they are |
| cation of the DNA are, arbitrarily, considered as one source |
| not heritable mutations. They can be transmitted only to the |
| of spontaneous mutations. These errors occur, and persist, daughtercellsofmutatedcellsupontheirdivision.Theeffects |
| duetomanycausesincludingfailureoftheproofreadingsys- of somatic mutations depend on many factors including the |
| temofDNAreplicationorfailureoftheDNArepairsystemto |
| typeof cell, the geneticconstitution of affected cells, selective |
| repair or correct the errors. It is estimated that during every targeting of nuclear and/or mitochondrial genome and the |
| somatic cell division cycle of nearly 20h duration, about mutationburdenofthecell.Accordingtotheinteractivepro- |
| 12,000 point mutations occur along the whole genome. The |
| cesses involving these factors, somatic mutations might result |
| vast majority of these replicative errors are repaired by the |
| incelldeathifthemutation-inducedpathophysiologicalalter- |
| DNA repair system of the cell. If some of these errors escape ationsofthecellexceeditsabilitytoobviateandcorrectthese |
| detection and repair they will persist and be transferred to |
| alterations. Milder alterations can cause deranged cellular |
| the genome ofdaughter cells andbecome fixed mutations. |
| function(s)andlimitedorprogressivefailureandlossofcellu- |
| laractivities,e.g.progressiveorganfailuresyndromefollowing |
| 7.2.Nuclear andmitochondrial mutation overexposure to radiation. Somatic mutations affecting the |
| proto-oncogenes or genes regulating DNA repair systems |
| Nuclear mutations are mutations that affect the nuclear gen- canresultinmalignanttransformationofthecellanddevelop- |
| ome, and mitochondrial mutations are mutations that affect mentof cancer. |
| the mitochondrial genome. Mutations of nuclear genes Somatic cells overburdened with mutation are driven to a |
| account for the occurrence of most genetic diseases. Due to special suicidal pathway involving its involuntary death to |
| the marked differences between the specific structural organi- protect other cells from the hazardous risk of its malignant |
| zation of each genome, each type of these mutations has its transformation. It might also be looked at as a cellular |
| own characteristic features. Nuclear mutations may affect economic adaptation behavior by getting rid of mutated |
| one or both alleles of a structural gene on an autosome or diseased,energyconsumingandharmfulcells.Thismechanism |
| onasexchromosome,thusgivingrisetoanyofthetraditional ofcompulsoryinvoluntaryorprogramedcelldeath,referredto |
| genetic disorders: autosomal and sex linked dominant and asapoptosis,representsanimportantprotectiveanti-mutation |
|
|
| 6 M.S.Z. Salem |
| mechanismoftheorganismtomaintainitsgenomicintegrity, |
| anddemonstratesoneofthebasicconservativefeaturesofliv- |
| ing organisms by executing over mutated cells to prevent |
| spread of their mutations through division to daughter |
| generations. |
| Germinal mutations are mutations that affect genomes of |
| germlinecells,i.e.ovaandsperms,thatparticipateinfertiliza- |
| tion and determination of the genetic constitution of the off- |
| spring. If the particular ovum or sperm affected by the |
| Figure3 TripletrepeatexpansioninfragileXsyndrome. |
| mutationhappenstoparticipateinfertilizationandzygotefor- |
| mation, the mutation will be inherited and transferred to all |
| cells the offspring and a carrier or disease state might result repeats.Thedeleteriouseffectsofthismutationandtheresult- |
| according to the nature of the mutated gene and the pattern ing pathological phenotypes of the disease are due to disrup- |
| ofits inheritance. tion of functions of the FMR1 gene via silencing of the gene |
| activity and cessation of synthesis of the FMRP, or through |
| 7.4. Static anddynamicmutation disrupting the structure of the gene leading to production of |
| adefectiveproteinthatcan’tmediateitsglobalcellularphysi- |
| ologicalregulatoryfunctionsinpost-translationmodifications |
| Static mutations signify mutations that are transmitted with- |
| andtargeting ofsynthesized proteins(Fig. 3). |
| out change in type or extent of the mutation from a parent |
| to his progeny. For instance, a father suffering from Marfan |
| 7.5. Pathological andnon-pathologicalmutation |
| syndrome due to a specific mutation in the fibrillin gene may |
| transfer the mutation as it is to some of his offspring. |
| Mutation analysis by molecular diagnostic techniques of the The deleterious effects of mutation are determined by many |
| geneofbothfatherandchildwillrevealidentityofthemuta- factors. Mutations affecting functional elements of the gen- |
| tionbetweenthemintheaffectedgene.Staticmutationschar- ome,i.e.functionalgenes,canresultingenedysfunctioncaus- |
| acterizethemutationaleventsthatunderliethedevelopmentof ing deficient synthesis of the gene product or synthesis of |
| most currently definedgeneticdiseases. defective product. These mutations are expected to cause |
| Dynamicmutations,ontheotherhand,representapeculiar pathophysiologicalchangesanddiseasephenotypesinaffected |
| category of genetic mutations that increase in magnitude or individuals,andrepresentanovertexampleofharmfulpatho- |
| extentupontransmissionfromacarrierparenttoanoffspring. logical disease causing mutations. On the other hand, muta- |
| The discovery of this type of mutation clarified the patho- tions affecting non-functional regions of the genome, e.g. |
| geneticmechanismsresponsibleforthepathogenesisofalarge intergenic areas of DNA and intronic segments of genes, do |
| number of genetic diseases known as triplet repeat expansion not result in pathophysiological alterations and are referred |
| disorders.Thelistofthesediseasesduetothistypeofmutation toas non-pathological mutations. |
| is expanding progressively and includes many common and Though the vast majority of mutational eventsof the gen- |
| relevant genetic disorders like fragile X syndrome, Friedreich omeare harmful, somemutations, conversely, have beneficial |
| ataxia, Huntington disease, myotonic dystrophy, some types effects. Such mutations, known as beneficial mutations, exert |
| ofspino-cerebellar ataxia andmanyothers. theireffectsbyconferringselectiveadvantageonaffectedcells |
| In this type of mutation, a normal defined number of secondarytotheresultingchangeofthestructureandfunction |
| codons, triplets of nucleotides, along a specific segment of of protein/enzyme product of the mutated gene. The most |
| the gene increases in number when the gene is inherited. A obviousexampleofbeneficialmutationsisthesicklemutation |
| thresholdeffectcharacterizesthisdynamicmutationalprocess. of the b-globin gene. Carriers, but not homozygotes, of this |
| Withinacertainrange,wecanidentifyanormalrepeatnum- mutationhaveaselectivevaluebecausetheyaremoreresistant |
| ber in the normal gene, a larger repeat number in carriers or to infestation by the malaria parasite compared to normal |
| pre-mutation state and a much larger number in affected subjects. Another example of beneficial mutations is the dele- |
| patients. For instance, the fragile X mental retardation gene tion mutation of the human CCR5 or CD195 or chemokine |
| (FMR1 gene) which is mutated in fragile X syndrome, regu- receptortype5.TheproteinofthenormalgeneactsasaTcell |
| lates the synthesis of a protein, fragile X mental retardation membrane receptor and is used by human immunodeficiency |
| protein (FMRP) which acts, partly, as RNA binding protein virus (HIV) as a gate to enter the cell and build up infection |
| that regulates in a global fashion cellular protein translation with the virus. Mutation of the CCR5 gene, CCR5 Delta32 |
| andmicoRNA regulatory pathways,and hasimportant func- deletion,resultsinthesynthesisofanalteredproteinthatloses |
| tionsinmanyorganslikethenervoussystemandtheovaries. its receptor function and can’t bind the HIV. Carriers of this |
| Thenormaltranscriptofthegenehasasequenceconsistingof beneficial mutation are resistant to infection and genetic |
| six to forty-five (6–45) repeats of CGG nucleotides at the 50- homozygosity of the mutation is known to confer protection |
| untranslated region. Carrier mothers have a larger number againstinfection with thevirus [3]. |
| of these repeats ranging from 55–200 repeats. When this per- |
| mutation state of the gene is transmitted to a male offspring, 7.6. Point,small, gross andgenomic mutation |
| progressive increase, or dynamic expansion of the number of |
| the repeats happens and the gene in the affected male off- Mutations are arbitrarily classified according to the size of |
| spring, or full mutation state, is found to contain more than affected component or region of the genome and the magni- |
| 200,sometimes muchmorenumbersuptohundreds,ofthese tude of the mutational damage into point, small, gross and |
|
|
| | Pathogenetics | | | | | | | | | | | | | | 7 | |
| | ------------- | --- | --- | --- | ------- | ----------------------------------------- | --- | --- | --- | --- | --- | --- | --- | --- | --- | |
| | | | | | Figure4 | Types&molecularmechanismsofpointmutation. | | | | | | | | | | |
| genomic mutations. Point mutations refer to mutation of one 7.6.2.1.Same-sensemutation.Duetodegeneracyofthegenetic |
| single base of the gene irrespective of the size of the gene. codethatallowsfordefiningthesameaminoacidbydifferent |
| Small mutations involve larger mutations of many bases, one codons,apointmutationmightinvolveonebaseofaspecific |
| ormoreexonsorintronsandoneormoregenes.Grossmuta- codonchangingittoanothercodon,thatstilldefinesthesame |
| tionscomprisechromosomalabnormalitieswheretens,oreven aminoacid.Forexample,theaminoacidleucineisdefinedor |
| hundreds,ofgenesareaffectedbydeletion/inversion/transloca dictated by six different codons, TTA–TTG–CTT–CTC–CT |
| tion of even tiny pieces of affected chromosomes. Genomic A–CTG. Replacement of one base of some of these codons, |
| mutationsrepresenttheextremeendofthespectrumofmuta- TTAtoTTG,CTTtoCTCorCTAtoCTG,byanotherbase |
| tionswherethewholegenomeundergoesmutationalchanges. does not change the specified amino acid, leucine, in the syn- |
| Triploidyandtetraploidyrepresentrareexamplesofstructural thesized protein, hence the term same-sense because the same |
| | | | | | | | | | amino acid | is | dictated | by the | new codon | and | no change in | |
| | ----------- | ------- | ---------- | --- | -------------- | --- | ----------- | --- | ---------- | --- | -------- | ------ | --------- | --- | ------------ | |
| | ornumerical | genomic | mutations. | | Also, aberrant | | development | | | | | | | | | |
| ofvesicularmolesanddermoidcystsrepresentsclearexamples the synthesizedprotein results. |
| offunctionalgenomicmutationsduetodisorderedimprinting |
| of the whole haploid genome of the germinal cells following 7.6.2.2. Mis-sense mutation. Due to the rigid rules of the |
| fertilization. genetic code, a change of one base of a codon might turn it |
| | | | | | | | | | into another | codon | that | defines | a different | amino | acid in the | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ------------ | ----- | ---- | ------- | ----------- | ----- | ----------- | |
| 7.6.1.Molecularmechanisms of pointmutation synthesizedprotein.Ifbasereplacementresultsinanewcodon |
| Point mutations refer to mutational events that involve one that specifies a different amino acid, a mis-sense mutation |
| | | | | | | | | | results. For | instance, | a | point | mutation | of the | codon (TTT) | |
| | -------------- | -------- | ----------------- | --------- | ------ | ------ | ------- | ----- | ---------------------------- | --------- | ---------- | ----- | -------- | ------- | ------------- | |
| | single base | of the | gene irrespective | | of the | size | of the | gene. | | | | | | | | |
| | | | | | | | | | or (thymine–thymine–thymine) | | | | that | defines | phenylalanine | |
| | Lethal genetic | diseases | can | be caused | by | single | point | muta- | | | | | | | | |
| | | | | | | | | | may change | it | to another | codon | (TCT) | or | (thymine–cyto | |
| | tions, even | in very | large | genes. | A well | known | example | is | | | | | | | | |
| Duchennemyopathyduetosinglepointmutationsofthedys- sine–thymine) that defines serine. For protein translation sys- |
| trophingenewhichisthelargesthumangenecomposedof2.4 tem this change is considered as wrong code, hence the term |
| | | | | | | | | | missense, | since | it dictates | a different | amino | acid. | The effects | |
| | --- | --- | --- | --- | --- | --- | --- | --- | --------- | ----- | ----------- | ----------- | ----- | ----- | ----------- | |
| millionbases.Sicklecellanemiaisanotherexampleofadrastic |
| ofmis-sensemutationdependontheroleplayedbytheorigi- |
| | genetic disease | resulting | from | a | single point | mutation | | of the | | | | | | | | |
| | --------------- | --------- | ---- | --- | ------------ | -------- | --- | ------ | --- | --- | --- | --- | --- | --- | --- | |
| nalaminoacidinproteinfunctioning,e.g.proteinstabilityand |
| | beta globin | gene. | Point mutations | | account | for nearly | 70% | of | | | | | | | | |
| | ----------- | ----- | --------------- | --- | ------- | ---------- | --- | --- | --- | --- | --- | --- | --- | --- | --- | |
| currently definedhuman single gene disorders. aggregation. If it has important roles within fundamental |
| Molecular mechanisms of point mutation comprise a wide structural or functional domains of the protein that could |
| notbeperformedbythenewdifferentaminoacid,thenpatho- |
| | spectrum | of alterations | at | the molecular | | level | of the | genetic | | | | | | | | |
| | -------- | -------------- | --- | ------------- | --- | ----- | ------ | ------- | --- | --- | --- | --- | --- | --- | --- | |
| physiologicalalterationofthestructureand/orfunctionofthe |
| | material | (Fig. 4). | These mechanisms | | include | replacement | | of | | | | | | | | |
| | --------- | ------------ | ---------------- | -------- | ------------ | ----------- | --------- | --- | ------------ | --------- | --------- | ---------------- | ---------- | --- | ---------------- | |
| | | | | | | | | | protein are | expected | and | the pathogenesis | | of | a genetic defect | |
| | one base | (nucleotide) | of the | gene | by another | base, | deletion, | | | | | | | | | |
| | or loss, | of one base | of the | gene | and addition | of | one base | to | might ensue. | | | | | | | |
| | the gene. | Replacement | of | one base | by another | | base may | not | | | | | | | | |
| | | | | | | | | | 7.6.2.3. | Non-sense | mutation. | The | sixty-four | | codons of the | |
| affectthefunctionofthegeneor,ontheotherhand,canhave |
| geneticcodeincludethreecodonsthatdonotdefineordictate |
| drasticeffectsongenefunctionaccordingtothetypeandfunc- |
| anyaminoacidsandareusedbythegenetosignaltheendof |
| | tional consequences | | ofthe | change. | | | | | | | | | | | | |
| | ------------------- | --- | ----- | ------- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | |
| theproteinsynthesisprocessinordertoformtheproperpro- |
| 7.6.2.Typesof pointmutations tein with the proper number of amino acids. These codons |
| | | | | | | | | | (TAA–TGA–TAG) | | are | termed | stop | or termination | codons | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ------------- | --- | --- | ------ | ---- | -------------- | ------ | |
| Fivedifferenttypesofpointmutationcanbedelineated:same- |
| | | | | | | | | | because | they are | recognized | by | both | the mRNA | transcript | |
| | ---------------- | --- | ---------- | -------- | --- | ----- | ----- | ----- | ------- | ----------- | ---------- | --- | ------- | ---------- | ---------- | |
| | sense, missense, | | non-sense, | re-sense | and | frame | shift | point | | | | | | | | |
| | | | | | | | | | and the | translation | system | as | signals | or markers | of the end | |
| mutations. |
| | | | | | | | | | of the translation | | process | since | they do | not define | any amino | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ------------------ | --- | ------- | ----- | ------- | ---------- | --------- | |
|
|
| 8 M.S.Z. Salem |
| acids,hencethetermnon-sense,sothatnomoreaminoacids 7.6.2.5.Frame-shiftmutation.Frameshiftingsignifieschangeof |
| are tobe addedto the growing polypeptide chain. thespecificsequenceofthenucleotidesofthegeneduetodele- |
| Non-sensemutationsresultwhenafunctionalcodondefin- tion or addition of nucleotide(s) followed by corresponding |
| ing a specific amino acid is changed to a stop or termination changeoftheaminoacidsequenceofthesynthesizedprotein. |
| codon. If base replacement results in the formation of a new Deletionoradditionofonebasewithinthegenewillresultin |
| stop or termination codon, for instance change of cytosine in shifting of the reading frame of the newly formed codons. |
| (TAC) codon that defines tyrosine to adenine turns it to the This type of point mutation is called frame-shift mutation. |
| stopcodon(TAA)resultinginprematurecessationoftransla- The resulting effects may lead to the formation of new same- |
| tion and the production of a short or truncated protein. The sense,missenseorstopterminationcodonswithultimatecon- |
| resulting alterations depend on many factors. If the mutation sequences similar to the results of the similar aforementioned |
| happensatthebeginningofthecodingpartofthegene,most mechanisms. These same rules apply for mutational events |
| of the protein coded by the gene will not be translated from involvingthe additionordeletionof twobases. Ifthreebases |
| this point on. A short, or truncated, mostly non-functional are added or deleted, a whole new codon will be added or |
| protein will be synthesized and marked deterioration of gene removed, respectively. Whereas addition or deletion of one |
| function might result. If the mutation happens at or near the codontoa functionalexonof thegenemightresultin awide |
| endofthecoding partofthegene,most oftheproteincoded spectrum of alterations as previously explained, whole codon |
| bythegenewillbetranslatedandlessdeterioration,orevenno addition or deletion within non-coding parts of the gene, |
| change,ofgenefunctionoccurs.Inbothsituations,theresult- introns,hasnoeffectontranslatedproteinorongenefunction. |
| ing pathogenetic alterations depend on the physiological role Frameshiftingofthegenesequenceleadstoframeshiftingin |
| played by the missing non-translated part or domain of the theaminoacidsequenceofthesynthesizedproteinandanew |
| protein. If these roles are important in mediating functions proteinwithnewsequenceofaminoacidsmightbetranslated. |
| ofvitalmetabolicnetworksinthecell,thengeneticdefectswill Thesimilaritybetweentheaminoacidsequenceofthewildtype |
| happenandthepathogenesisofageneticdisordermightensue. proteinandthatofthenewproteindependsonthestartsiteof |
| theframeshiftmutationofthegenesequence.Thesesamerules |
| 7.6.2.4. Re-sense mutation. In this type of arbitrarily defined applyformutationaleventsinvolvingtheadditionordeletion |
| mutational event, the termination or stop codon at the end of two bases. If three new bases are inserted between existing |
| of the last exon of the gene might suffer a point mutation codons, however, a whole new codon will be added and an |
| turning it to a functional codon. In this case, part of the additional amino acid will be added to the polypeptide chain |
| un-translatedregionofthemRNAtranscriptwillbeincluded of the protein. Also, if three bases constituting a functional |
| within the translation process which will continue with codon are removed or deleted from the gene, the amino acid |
| addition of more amino acids, not originally comprised in specified by the deleted codon will not be translated and will |
| the protein sequence, till another stop codon is met with and be missing from the synthesized polypeptide chain. Whereas |
| recognition of the end signal and cessation of translation additionordeletion of onecodon to a functionalexon of the |
| processoccurs.Theresultingabnormalpathologicallengthening gene might result in a wide spectrum of alterations as previ- |
| ofthepolypeptidechainresultsinthesynthesisofalongerand ously explained, whole codon addition or deletion within |
| larger protein. Such abnormal polypeptides are usually non-codingpartsofthegene,e.g.introns,usuallyhasnoeffect |
| unstable macromolecules that degrade easily or faster than ontranslatedproteinorongenefunction[4]. |
| normal correspondent chains because of defective folding Changeinthestructureofonebaseofthegene,e.g.methy- |
| andimproper structural configuration thusleading to quanti- lationofcytosine,canaffectgenetranscriptionthroughseveral |
| tative functional deficiency. Also, due to their redundancy different mechanisms. Each cell has a specific methylation |
| and defective primary structure, they might fail to undergo pattern necessary for normal cell differentiation during |
| necessary post-translation modifications or post-translation development.Changesinthispatternbymutationsofregulatory |
| targeting and trafficking to their proper cellular location. In genes controlling its timing and its magnitude can have |
| either condition, genetic disease due to the functional markeddeterioratingeffectsonthecellduringdifferentiation. |
| deficiencyof the proteinmight result. This type of mutation must not be confused with epigenetic |
| Figure5 Splicesitemutations. |
|
|
| Pathogenetics 9 |
| Figure6 Typesofchromosomalabnormalities. |
| Figure7 Structuralchromosomalabnormalities. |
| mutationsthatinvolvestructuralchangesinthechromatinor ormultipleintrondeletionorduplication,deletionorduplica- |
| the DNA-associated proteinsrather thanthe DNA itself [5]. tionofageneoroffewgenes,amplificationofgenes,inactiva- |
| tion ofgenes andtransposon-induced mutations. |
| 7.6.3.Small mutations The pathophysiological consequences of these mutations |
| Small mutations are arbitrarily classified so as to comprise dependontheresultingchangesineitherthegeneticregulatory |
| structural changes involving more than one base of a gene. networks or the metabolic networks of the cell secondary to |
| Accordingly, they span a very wide spectrum of pathogenetic deficient and/or defective synthesis of the gene product. The |
| structural alterations of the genetic material beginning with resulting deterioration of gene function leading to the patho- |
| mutations involving at least two nucleotides and ending with genesisofageneticdisordercorrelateswiththeextentofdefi- |
| mutations involving part of a gene, a whole gene or, even, ciencyofthegeneproduct,whetherduetoactualdeficiencyof |
| few genes. Small mutations include addition or removal of theproteinorregulatorysmallRNAcodedbythegenedueto |
| two or more bases, addition or removal of one or more suppression of gene function and inability to synthesize the |
| codons,singleormultipleexondeletionorduplication,single gene product, or to relative or absolute deficiency of the |
|
|
| | 10 | | | | | | | | | | | | | | M.S.Z. Salem | |
| | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | ------------ | |
| functionofafaultysynthesizedgeneproduct.Deletionoflarge of acentric chromosomes. Because chromosome segregation |
| portionsofagene,multipleexondeletionsforinstance,result during cell division depends on attachment of the spindle fib- |
| in the synthesis of grossly defective protein lacking most or rilstospecificcentromericreceptorproteins,acentricchromo- |
| muchofitsdomainsneededtomediateitsdestinedphysiolog- somes are lost during the anaphase stage of cell division and |
| icalrolescausingmarkedpathophysiologicaldeteriorationsin chromosome monosomy of affected daughter cell results. |
| the functioning metabolic networks dependent on these roles, Autosomal monosomy is incompatible with life of the cell in |
| thuspredisposing todevelopment ofgeneticdisorders. view of the deleterious functional deficiency of the proteome |
| Small mutations of bases involved in splisosome mecha- due to loss of hundreds, even thousands, of genes located on |
| nisms mediating intron excision and splicing of remaining themissing chromosome. |
| exons, as part of the post-transcription modifications of (b) Translocation |
| mRNA, can have marked effects on the translation efficiency Translocationinvolvesbreakageofpartofthechromosome |
| ofthefinalmRNAandisawell-knownmutationalmechanism and its insertion within the genetic material of another |
| that underlies the pathogenesis of many common and serious chromosome. It may be unidirectional when a segment of |
| geneticdiseases(Fig.5).Thesesplicesitemutationsmayresult the chromosome is broken at both ends, detached from its |
| in over excision of parts of adjacent exons and synthesis of original site and translocated to another chromosome, or it |
| shorter polypeptide chains. If the missing amino acids coded may be reciprocal when two different chromosomes inter- |
| bythe overexcised parts are important for mediating protein changepartsoftheirgeneticmaterial.Translocationcanresult |
| function or maintaining its structural integrity, then patho- in functional deficiency and development of genetic disease if |
| physiological alterations and pathogenesis of disease might the translocated chromosome segments are inserted within |
| beexpected. On the otherhand,if splice sitemutations result intact gene sequences on the recipient chromosome leading |
| in skipping of an intron, part of an intron, a whole intron or toitsdisruption.Conversely,translocationmightleadtoover |
| multipleintronsfromexcision,theresultingtranslatedprotein expressionofthegenesattheendofthetranslocatedsegment |
| mightbelargeenoughtobeunstableandeasilydegradable,or if they get inserted next to an over expressive promoter of a |
| itsstructuralconfigurationmightbealteredinsuchawaythat recipient gene. Translocations leading to over activation of |
| itsfunctionaldomainsarenomoreaccessibletoeachotheror oncogenes or causing disruption of critical regulatory genes, |
| to other components, e.g. substrates or intermediary metabo- or genes responsible for maintaining genomic stability and |
| lites, needed for mediating its physiological functions, and a integrity, are known to underlie the development of many |
| pathogenetic defect results. malignant tumors secondary to these peculiar pathogenetic |
| | | | | | | | | | mechanisms. | Examples | of | such | cancers | include | Burkitt lym- | |
| | --- | --- | --- | --- | --- | --- | --- | --- | -------------- | ---------- | --- | --------- | ------- | ------- | ------------- | |
| | | | | | | | | | phoma t(8;14), | follicular | | carcinoma | | of the | thyroid gland | |
| 7.6.4. Grossmutations |
| t(2;3),Ewingsarcomat(11;22),chronicmyelogenousleukemia |
| | Gross mutations | | are mutations | | that involve | large | portions | of | | | | | | | | |
| | --------------- | --------- | ------------- | ------------ | ------------ | ----- | --------- | -------- | ------------------- | ------------- | --- | -------- | -------------- | ------- | ------------- | |
| | | | | | | | | | t(9;22), follicular | lymphoma | | t(14;18) | andmanyothers. | | | |
| | the genetic | material. | Chromosomal | | aberrations | | represent | the | | | | | | | | |
| | | | | | | | | | Robertsonian | translocation | | is | a specific | type | of transloca- | |
| | prototype | of this | type | of mutation, | since | even | the | smallest | | | | | | | | |
| | | | | | | | | | tion involving | translocation | | of | a small | (21–22) | or large | |
| functional portion of a chromosome may consist of tens to (13–15) acrocentric chromosome to another, large or small |
| hundredsofgenes.Duetothepeculiarstructuralorganization |
| | | | | | | | | | acrocentric | chromosome. | | This | defect | involves | fusion of the | |
| | -------------- | ----- | --- | ------- | ----------- | --- | ------------- | --- | ----------- | ----------- | --- | ----------- | ----------- | -------- | ------------- | |
| | of the nuclear | human | | genome, | chromosomal | | abnormalities | | | | | | | | | |
| | | | | | | | | | long arms | of the | two | acrocentric | chromosomes | | at their | |
| caninvolveeitherthestructureofthechromosome,structural |
| | | | | | | | | | centromeres | and loss | of | both short | arms | of the | two chromo- | |
| | ----------- | ------------- | --- | --- | ---------- | --- | -------------- | --- | --------------- | -------- | -------- | ---------- | ------ | ------ | -------------- | |
| | chromosomal | abnormalities | | or | the number | | of the chromo- | | | | | | | | | |
| | | | | | | | | | somes. Balanced | | carriers | of this | defect | are | phenotypically | |
| somes, numerical chromosomal abnormalities. Mutations of normal because they do not suffer relevant genetic deletions, |
| chromosomestructuremightinvolvetheautosomes,autosomal |
| sincetheshortarmsofacrocentricchromosomesdonotcode |
| | chromosomal | abnormalities, | | of | chromosomes | | 1–22, | or sex | | | | | | | | |
| | ----------- | -------------- | --- | --------- | ----------- | ------- | ----------- | ------ | ------------ | -------------- | ------------- | --- | ------- | --------- | -------- | |
| | | | | | | | | | foressential | orunique | geneproducts. | | | | | |
| | chromosomal | abnormalities | | involving | | the sex | chromosomes | | | | | | | | | |
| | | | | | | | | | Robertsonian | translocations | | | have an | incidence | of about | |
| (XandYchromosomes).Structuralchromosomalaberrations |
| oneinathousandnewbornswithitsmostfrequentformsbeing |
| | include different | | pathogenetic | | types like | deletions, | | duplica- | | | | | | | | |
| | ------------------ | ---------- | --------------- | -------------- | ---------- | ---------- | -------------- | -------- | ------------- | ----------- | ------------ | ------------ | -------------- | --------- | -------------- | |
| | | | | | | | | | between | chromosomes | 13 | and 14, | 14 and | 21, | and 14 and 15. | |
| | tions, inversions, | | ring chromosome | | formation, | | unidirectional | | | | | | | | | |
| | | | | | | | | | Most people | with | Robertsonian | | translocations | | have only 45 | |
| | translocation, | mutual | | translocations | | and | Robertsonian | | | | | | | | | |
| | | | | | | | | | chromosomes | in each | of | their cells. | Their | children, | however, | |
| | translocations, | chromosome | | gaps | and | breaks, | and other | less | | | | | | | | |
| | | | | | | | | | might inherit | the fusion | chromosome | | and | become | phenotypi- | |
| commonabnormaltypes.Numericalchromosomalabnormal- |
| callynormalbalancedcarriersliketheircarrierparentorthey |
| | ities that | affect | the number | | of chromosome | | encompass | | | | | | | | | |
| | ------------- | ------ | -------------- | --------- | ------------- | -------- | ----------- | --- | ----------- | ------------- | --- | --------- | ------------ | -------- | -------------- | |
| | | | | | | | | | may inherit | a missing | or | an extra | long | arm of | an acrocentric | |
| | varied group | of | aberrations | including | | trisomy, | monosomy, | | | | | | | | | |
| | | | | | | | | | chromosome. | In unbalanced | | forms, | Robertsonian | | transloca- | |
| | hypodiploidy, | | hyperdiploidy, | | triploidy | and | tetraploidy | | | | | | | | | |
| | | | | | | | | | tions cause | chromosomal | | deletions | or | addition | and result in | |
| (Fig. 6) [6]. |
| | | | | | | | | | chromosome | trisomy | syndromes | | including | trisomy | 13 (Patau | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ---------- | ----------- | --------- | ----- | ---------- | ------- | --------------- | |
| | | | | | | | | | syndrome) | and trisomy | 21 | (Down | syndrome). | | Rarely, if both | |
| 7.6.4.1. Types and molecular mechanisms of chromosomal parentsareheterozygousforthesametranslocation,theyhave |
| aberrations. (1)Structural chromosomal aberrations(Fig. 7). the possibility of giving birth to homozygous viable offspring |
| | (a)Deletion | | | | | | | | with44chromosomesin | | | eachof | their somaticcells. | | | |
| | ----------- | --- | -------- | ----- | ------- | ---- | -------------- | --- | ------------------- | --- | --- | ------ | ------------------- | --- | --- | |
| | Chromosome | | deletion | means | loss of | part | of the chromo- | | (c)Inversion | | | | | | | |
| some. It may be terminal deletion when it involves the end Inversion denotes breakage of a chromosome segment at |
| pieceofthechromosomeorinterstitialdeletionwhenitaffects both ends and its reinsertion at its original site in reversed |
| otherpartsofthechromosome.Interstitialdeletionsinvolving up-downposition.Inversionsareclassifiedintotwomaintypes |
| the centromeric region of the chromosome lead to formation dependingonwhethertheyincludethecentromere,pericentric |
|
|
| Pathogenetics 11 |
| Figure8 Isochromosomeformation. |
| inversions,oroccurononearmofthechromosomeawayfrom The finding that specific genomic regulatory elements, e.g. |
| thecentromere,paracentricinversions.Sinceinversionsdonot zincfingernucleaseenzyme,caninduce specificchromosomal |
| result in loss or gain of extra genetic material, inversions do rearrangements, like duplications and inversions, suggest an |
| notcausemarkedfunctionaldeficiency.However,ifthebreak evolutionary role for these chromosomal abnormalities. This |
| points of the inversion disrupt the sequence of an important event might be considered as a mechanism of genomic evolu- |
| gene, disease state might ensue. Inversions result in disturbed tion through formation of novel genes that can amplify the |
| crossing over during meiosis and production of defective function of parent genes or, alternatively, can undergo one |
| gametes with low recombination frequency. Depending on orsuccessivemutationaleventsconvertingthemtonewgenes |
| theextentofchromosomesegmentsaffectedbytheinversion, with new functions. However, the beneficial role of this pre- |
| thesedefectsmightbeincompatiblewithnormaldevelopment sumed evolutionary pathway as identified in some organisms, |
| andleadto early spontaneousabortions. e.g. the mutational conversion of a duplicated digestive gene |
| (d)Ring chromosomeformation inicefishintoanantifreezegene[7]isstillamatterofdebate |
| Ring chromosomes are incomplete chromosome segments waiting for clarification in human race since most of these |
| resultingfromterminaldeletionofvariablepartsofbothchro- chromosomal rearrangements have pathological effects on |
| mosome arms with subsequent joining of both arms to form affected subjects. This might be attributed to their being an |
| ring structures. The net loss of genetic material from the expressionofgenomicinstability,ratherthanofgenomicevo- |
| chromosome depends on the extent of deletion of both arms. lution, ofthe human genome. |
| Ring chromosome formation can also occur with terminal or (f) Isochromosomes |
| totaldeletionofonechromosomearmonly,andinrarecases Normally, duplicated chromosome pairs separate from |
| it occurs when telomeres at the ends of a chromosome fuse each other and get equally distributed to daughter cells by |
| without any loss of genetic material from the chromosome. the attachment of the spindle fibrils to specific receptor pro- |
| Pathological consequences of ring chromosomes are caused teinsontheircommoncentromerewithconsequentdisjunction |
| by deletion of genes in the telomeric regions of affected alongtheirlongitudinalaxis(Fig.8).Abnormalattachmentof |
| chromosomes. thespindlefibrilsorinstabilityofthecentromericregionmight |
| (e)Duplication result in abnormal separation of the chromosome pair along |
| Chromosome duplication occurs when part of a chromo- itstransverseaxissothattwochromosomesresult:oneconsist- |
| some iscopied abnormally, resulting in extra geneticmaterial ingofthelongarmsofthepairandtheotherconsistingofthe |
| fromtheduplicatedsegment.Duplicationsarisefromaberrant short arms only, i.e. mirror-image chromosomes. This results |
| recombination or unequal crossing-over that occurs between in complete deletion and functional monosomy of the short |
| misaligned homologous chromosomes during meiosis with arm or the long arm of each resulting isochromosome, |
| consequent reciprocal deletion of the homologous chromo- respectively. Isochromosomes have equal arms with identical |
| somes. Chromosome duplications offer the etiological basis banding pattern of both arms. They are seen in some female |
| of gene duplication and gene amplification. They also offer patientswithTurner syndromeandinmanytypes ofmyeloid |
| an explanation for the presence of multiple repetitive and lymphoblastic leukemias. They may rarely involve |
| sequences along the DNA, since placement of the duplicated autosomes,e.g. isochromosome18qsyndrome. |
| regions adjacent to the original sequence results in formation (g) Mosaicism |
| of tandem repeats along the DNA. Gene amplification due Chromosomal mosaicism describes the presence of two or |
| toduplicationisacommonphenomenonformanyoncogenes more cell populations with different chromosome comple- |
| because duplication and amplification of oncogenes results in mentsinoneindividual.Forinstance,mosaicDownsyndrome |
| their over expression with over production of oncoproteins (46,XY/47,XY,+21), mosaic Turner syndrome (46,XX/45,X) |
| that confer the malignant phenotype on transformed cells. and mosaic Klinefelter syndrome (46,XY/47,XXY). |
| Examples of human cancers due to oncogene duplication Normally,duetoLyonizationorXchromosomeinactivation, |
| and amplification include esophageal cancer, gastric cancer, allfemalecellsarefunctionallymosaicasregardstheXchro- |
| cervical cancer, colorectal cancer, breast cancer and mosome, i.e. cells with the maternal X inactivated depend on |
| neuroblastoma. the paternal X chromosome genes for mediating X |
|
|
| 12 M.S.Z. Salem |
| Figure9 Numericalchromosomalabnormalities. |
| chromosome-dependent genetic functions, and vice versa. (a) Trisomy, or the presence of three copies of a chromo- |
| Pathological mosaicism, on the other hand, occurs when a some instead of two, results from non-disjunction, or non- |
| mutationaleventselectivelyaffectsonecellandgetstransmit- separation, of duplicated chromosomes after replication. |
| tedtoalldescendentdaughtercells.Itcanaffectgonadalcells Normally, during cell division, replication of DNA occurs |
| during meiosis resulting in some gametes carrying the muta- andchromosomesduplicatethemselvessothateachdaughter |
| tion with the rest of the germ cells being free from mutation, cellreceivesthesamenumberofchromosomesliketheparent |
| gonadalmosaicism,aswellassomaticcellsatanystagealong cell,inordertokeepgeneticidentityofthespecies.Ifadupli- |
| thepathwayofcelldivisionafterthefirstpost-zygoticdivision. cated chromosome pair fails to separate from each other and |
| Accumulating evidence suggests that chromosomal mosai- both chromosomes are distributed to one daughter cell only, |
| cism, probably, represents a significant genetic phenomenon then trisomy of this cell results with concomitant monosomy |
| with widespread effects on many aspects of human biology oftheotherdaughtercell.Partialtrisomyreferstoduplication |
| andhealthsinceasignificantproportionofhumanpathogenic of certain parts of a chromosome, e.g. the long arm or the |
| conditionsisassociatedwithchromosomalmosaicism.Though short arm only. It has similar etiological bases like complete |
| mosaicismisacleardemonstrationofgeneticdiversity,itstrue trisomy including non-disjunction, spindle derangements and |
| significanceremains,asyet,unknowninviewofthecontradic- centromericbreaks dueto genomic instability. |
| tory genetic effects attributed to and associated with its (b)Monosomymeansthepresenceofonesinglecopyofthe |
| occurrence.Forinstance,mosaicismisquiteafrequentfinding chromosome.Autosomalmonosomyisincompatiblewithnor- |
| among human fetuses and is observed in nearly 25% of maldevelopment andcells withthis typeofabnormalities die |
| spontaneous abortions. It also plays a role in the generation becauseoflackofthevitalfunctionsofhundredsorthousands |
| of meiotic aneuploidy known to be the leading genetic cause of genes on the missing chromosome. Monosomy of the X |
| of human prenatal death, congenital malformations, prenatal chromosome is the only monosomy compatible with life in |
| mortalityandpostnatalmorbidity,manyneuropsychiatricdis- viewofthepeculiarnatureofthegeneticsoftheXchromosome. |
| orders, chromosomal syndromes, learning disabilities, cancer Partialmonosomy,duetodeletionofapartofachromosome, |
| and immune diseases. Contrariwise, there is strong and is a common cytogenetic abnormality seen in many genetic |
| substantial evidence suggesting that increased incidence of syndromes. The spectrum of pathological findings in each |
| mosaic aneuploidy in the developing human brain is an syndrome depends on the extent of functional impairment |
| integral component of normal prenatal development of the causedbylackof functionsof genes lostdueto the deletion. |
| human centralnervous system. (C) Hypodiploidy refers to chromosome complement less |
| (h) Chromosome gapsandbreaks thanthe normaldiploid(46)chromosomenumber ofsomatic |
| These distinctive types of chromosomal abnormalities cells. Cells of Turner syndrome with 45 chromosomes repre- |
| reflecteffectsandconsequencesofmutationsleadingtointer- sent the only viable hypodiploid events. Hypodiploidy is a |
| ruptionoftheintegrityofthechromosomeDNA.They,prob- common cytogenetic abnormality in many malignant cells. In |
| ably, predispose to development of many other types of some cases it might be so extensive that some malignant cells |
| structuralaberrations ofthe chromosomes [8]. havechromosomenumberreachingnearhaploidy,or23chro- |
| (2)Numerical chromosomal aberrations mosomes. Hypodiploidy is an important prognostic marker |
| Numerical chromosomal abnormalities refer to chromoso- for the karyotypic evolution of cancer cells since the smaller |
| malabnormalitiescausedbythepresenceofabnormalnumber thenumberofchromosomesacellcanlivewith,themorevir- |
| ofchromosomeswithinthecell.Thesegrossmutationalevents ulent malignant phenotype these cells can have. Milder states |
| caninvolveautosomes,e.g.trisomy21inDownsyndromeand ofhypodiploidy,lowhypodiploidywith(33–38)chromosomes |
| hypodiploidy and hyperdiploidy in cancer cells, or the sex andhighhypodiploidywith(42–45)arealsocommoncytoge- |
| chromosomes like monosomy X (45,X) in Turner syndrome neticfindings in malignant cells. |
| and XXY abnormality in Klinefelter syndrome (47,XXY) (d) Hyperdiploidy, orchromosome numbers more than 46 |
| (Fig. 9). chromosomes, underlies the pathogenesis of some genetic |
|
|
| Pathogenetics 13 |
| disorders, e.g. trisomy 13–18–21, XXY, XYY and multiple X ifthepaternalgenomeisprematurelyinducedtostartitsroles |
| syndromes with three or more X chromosomes in cells of in genetic regulation of development and differentiation as a |
| affected female patients. Marked pathological hyperdiploidy resultofthesegenomicimprintingmutations,normalembryo- |
| withchromosomenumberreachinguptoseventy(70)oralit- genesisand/orfetalgrowthisbroughttoastand-still[5]. |
| tlebitmorechromosomes,however,isquitecommoninmany Genomic functional mutations might, also, be caused by |
| malignancies like acute lymphoblastic leukemia and acute otherpathogeneticmechanisms,oneoftheseabnormalmech- |
| myeloidleukemia [9]. anismsentailsexclusivepredominanceofoneparentalgenome |
| inzygoteformationanddevelopment.Thediploidgenomeof |
| 7.6.4.2. Pathogenetic mechanisms of chromosomal aberrations. thezygotemaybeformedfromtwomaternalhaploidgenomes |
| The pathogenetic mechanisms involved in the pathogenesis (46, XX) without any sperm genome, or from two paternal |
| of chromosomal aberrations are, still, mysterious and hardly haploid sperm genomes (46,YY) without participation of any |
| understandable.Theycannotbeinterpretedonmolecularbasis maternalgenome.Theseabnormalitiesinchromosomalconsti- |
| evenforchromosomegapsandbreaksinviewofthecomplex tutionofthezygotecanbecausedbymanypathogeneticmuta- |
| structuralassemblyofthechromosomeanditsintimateinteg- tional events. Endoreduplication of one parental genome of |
| rity with the chromatin material. Gross regulatory defects of the zygote with suppression, involution and disappearance of |
| mechanisms controlling cell division, including the formation the other genome, or fertilization of the ovum by two sperm |
| of the spindle and the timing of its action in synchronization genomeswithconsequentdisappearanceof theovumgenome |
| with other biochemical and signal transduction effectors are from the developing zygote can lead to pathogenesis of these |
| hold responsible for predisposing to non-disjunction and the genomic chromosomal abnormalities. A well-known wide |
| development of chromosomal trisomies and chromosomal spectrum of pathological embryonic and fetal malformations |
| monosomies as well. Similar defective regulatory mechanisms andabnormalconceptionproductsresultsfromthesegenomic |
| might underlie the development of polyploidy conditions like functionalmutations (Fig. 10).[6]. |
| triploidy andtetraploidy. Normal development of human embryos is an extremely |
| However, the regular and persistent occurrence at nearly complex process mediated under strict control of thousands |
| constant incidence rates of well recognized and well defined ofregulatorygenomicpathways.Fertilizationresultsinbring- |
| genetic defects, including chromosomal aberrations, irrespec- inguptwodifferentgenomesthatmustworktogetherinpre- |
| tive of ethnic, racial or environmental factors, indicates that ciseconcerttoattainthefinalaimofthewholeprocess,thatis |
| these types of genetic changes or mutations might have, still formationofanormalcompleteoffspring.Thoughtheimme- |
| unknown,deeprootedsignificancebackgroundinourgenome. diate post-fertilization period is the most genetically active |
| Disclosureofmastergenesandrelatedgeneticfactorsresponsi- amongallotherperiodsoflifeoftheorganism,selectiveacti- |
| bleforregulatingboththestabilityandbehaviorofthegenome vationandsilencingofthelargenumberofgenesconstituting |
| asawholewill,surely,throwmorelightonfactorsunderlying thegenomeofthezygoteisaremarkablefeatureofthisearly |
| pathogenesisanddevelopmentofchromosomalabnormalities. stage. Some maternal genes are activated and others are |
| silenced. The same process applies to parental genes as well. |
| 7.6.5.Genomic mutations |
| This phenomenon of selective activation or silencing of genes |
| Genomic mutations refer to mutations involving the whole based on their parental origin is referred to as imprinting. |
| genome (either the 23 chromosomes haploid genome or the Imprintingmightinvolveasinglegene,multiplegenesormost |
| 46 chromosomes diploid genome). They comprise numerical genes on a chromosome as in Lyonization of the X chromo- |
| genomic mutations involving the whole chromosome set of some, where it is known as gene or genetic imprinting, or it |
| the genome like triploidy (69 chromosomes genome) and mightinvolveawholesetofchromosomesofacertainparent, |
| tetraploidy (92 chromosomes genome). They, also, include a conditionreferred to as genomic imprinting. |
| functional genomic mutations leading to disturbed and/or Imprintingseemstobeaglobalbiologicalfeatureofallliv- |
| defectiveexpressionofthewholegenomefunctions.Genomic ing systems.Inspiteof accumulating observations,itremains |
| functionalmutationsrevealtheirconsequencesinmanypheno- tobeoneofthemostpuzzlingphenomenainbiologybecause |
| types.Inhumans,thedevelopmentofvesicularorhydatidiform of lack of sufficient information regarding the underlying |
| malls and the formation of dermoid cysts, instead of normal mechanismsthatmediate itseffectsandalsoduetothe many |
| development of the zygote, represent obvious examples of species-specificandinter-speciesunrelatedaspectsandmecha- |
| genomic functional mutations. Normally, during the first five nisms ofimprinting. Forinstance, regulationof expressionof |
| days following fertilization and zygote formation, all cellular specificgenesbyimprintingisuniquetotherianmammals,i.e. |
| processes including cell growth, differentiation and division placentalmammalsandmarsupials,andfloweringplants.The |
| are controlled and mediated exclusively by the maternal majority of imprinted genes in mammals have fundamental |
| genome of the ovum. The sperm genome begins its participa- roles in embryogenesis and development of the placenta. |
| tion in these processes after these critical five days post- Other imprinted mammalian genes are involved in post-natal |
| fertilization period. Improper temporal programing of these developmentalprocesses.Withinadifferentbiologicalcontext, |
| genomic balances and interactions, e.g. due to genomic for example in insects, imprinting plays a crucial role in sex |
| imprinting mutations, leads to disturbed genomic regulation determinationwheregenomicimprintingofthewholepaternal |
| of development and differentiation of the developing zygote, genome with consequent functional haploidy is a prerequisite |
| with drastic consequences leading to actual cessation and fornormal development into males. |
| disturbedprogressofnormaldevelopmentanddifferentiation. Though many hypotheses have been proposed to explain |
| Ifthematernalgenomefailstostartfunctioningproperlyafter thebiologicalaimsandtheevolutionaryoriginsofimprinting, |
| fertilizationorfailstomaintainitsgeneticregulationofdevel- e.g.naturalselectionhypothesisandparentalconflicthypoth- |
| opmentoverthecriticalimmediatepost-fertilizationperiod,or esis, imprinting in essence represents a programed regulatory |
|
|
| | 14 | | | | | | | | | | M.S.Z. | Salem | |
| | --- | --- | -------- | --- | ------------------------------------------------------------------ | --- | --- | --- | --- | --- | ------ | ----- | |
| | | | Figure10 | | pathologicalconsequencesofgenomicstructuralandfunctionalmutations. | | | | | | | | |
| mechanismofthegenometoharmonizefunctionsandinterac- backbone of the DNA with ultimate breakage mutations of |
| tions of the large number of genes that constitute it, so that thenucleic acid[1]. |
| | integrity | and stability | of | the genome, | hence | genomic | identity, | | | | | | |
| | --------- | ------------- | --- | ----------- | ----- | ------- | --------- | --- | --- | --- | --- | --- | |
| ismaintained, preserved andconservedin spite ofthe contin- 7.8. Persistentandreversible mutation |
| | uously ever | changing | | proteome | phenotype | and | proteome | | | | | | |
| | ----------- | -------- | --- | -------- | --------- | --- | -------- | --- | --- | --- | --- | --- | |
| dynamicsoflivingsystems.Ifgenesconstitutingaspecificgen- |
| Mutationsarefrequentstructuralgeneticalterationsinviewof |
| omeareimprinted,eitherexpressedorsilenced,withoutstrict |
| thedynamicnatureofthegenome.Italmostalwaysaccompa- |
| regulatorymechanism(s) controlling temporal aspects oftheir niesreplicationofDNAandtranscriptionofRNA.However, |
| functions, widespread random and conflicting qualitative and most of these mutations are corrected and repaired by the |
| quantitativechangesoftheproteomesynthesizedbythatgen- |
| genomicrepairmechanisms.Mutationsinonecellthatescape |
| | ome will | disturb | the stability | and | integrity | of | the genome, | | | | | | |
| | -------- | -------------- | ------------- | ----------- | --------- | ------- | ----------- | ---------- | ------------------------ | ----------- | ----------- | ---- | |
| | | | | | | | | repair are | liable to be transferred | to daughter | cells | upon | |
| | through | many different | | mechanisms, | | leading | ultimately | to | | | | | |
| | | | | | | | | division | and a whole progeny | of mutated | cells makes | its | |
| decadence and loss of the genomic identity that characterizes appearance. Persistence of the mutation and its transfer to |
| livingorganisms [10]. progeny cells results in fixation of the mutation, the change |
| | | | | | | | | becomes | persistent and appears | in all | daughter cells. | The | |
| | ---------------- | --- | ----------------- | --- | --- | --- | --- | ---------------- | ------------------------ | ------------- | ---------------- | --- | |
| | 7.7. Base,sugar, | | phosphatemutation | | | | | | | | | | |
| | | | | | | | | outcome | of this scenario depends | on the | type of the cell | and | |
| | | | | | | | | the pathogenetic | effects of | the resulting | damage. Acquired | | |
| Mutations, in general, refer to changes of the bases of the persistent somatic mutations have the same effects as classic |
| nucleicacids(A,G,C,T,U)andrepresentthecommonesttypes somatic mutations, they can cause cell death, dysfunction, |
| ofmutationsofthegeneticmaterial.However,severalkindsof apoptosis or malignant transformation. Acquired persistent |
| mutations can affect the sugar and the phosphate group, and germinalmutationsmightbetransferredtooffspring,become |
| can have deleterious effects on the genetic material. Several heritable andresult ininherited geneticdisease. |
| kinds of mutation can affect the sugar portion of the nucleo- Since mutations are un-programed genetic events, the |
| tide. For instance, some physical and chemical mutagens can term reversible mutations is actually a misnaming since these |
| add oxygen to the deoxyribose of DNA or remove oxygen mutations represent programed structural genetic alterations |
| from the ribose of RNA, or a whole deoxyribonucleotide aiming at conducting specific purposes, e.g. regulation of |
| might be substituted by a ribonucleotide. Such mutations of gene function. For instance, methylation of bases to silence |
| DNA, containing a ribonucleotide instead of a deoxyribonu- gene transcription, acetylation of regulatory DNA associated |
| cleotideareusuallysilent,butunderabnormalconditionsthey histones to enhance transcription and methylation of the |
| might be attacked by ribonucleases leading to DNA breaks. adenine base in some types of mRNA/siRNA species to reg- |
| Another type of mutation of the sugar portion of the nucleo- ulate energy balance or ATP homeostasis of the cell, are |
| tide involves methylation of ribose of a coding nucleotide in examples of such reversible changes of the genetic material. |
| mRNAandcanleadtosilencingor,even,tototalsuppression These alterations are sometimes considered as various mech- |
| oftranslation. anisms of epigenetic alterations, i.e. temporary imposed |
| Mutations that affect the phosphorus atom of the nucleo- structural changes that do not alter the basic nucleotide |
| tide can cause widespread detrimental effects on the integrity sequence of DNA. For simplification and to obviate confu- |
| of the DNA strand. Irradiation turns ordinary phosphorus sion, at least within the scope of human genetics, it might |
| toradioactivephosphoruswhich,uponreleaseofanelectron, be more plausible to omit both terms, epigenetics and rever- |
| changestonon-radioactivesulfurandsuffersarecoilindiam- sible mutations, and refer to structural genetic alterations |
| eterleadingtolossofitsconnectiontotheadjacentsugar.This either as mutations or as temporary structural genomic |
| | results in | multiple | recoil | breaks | in | the sugar-phosphate | | alterations. | | | | | |
| | ---------- | -------- | ------ | ------ | --- | ------------------- | --- | ------------ | --- | --- | --- | --- | |
|
|
| Pathogenetics 15 |
| 8.Pathogeneticmechanisms of genetic diseases (7) Transcriptionof defective mRNA |
| (8) Deficient/defective post-transcription mRNA repair |
| (9) Deficient/defective post-transcription modifications of |
| Thegeneticmaterialcontrolslifeactivitiesofthecellthrough |
| mRNA |
| regulating synthesis of proteins which directly mediate these |
| (10) Deficienttranslation of proteins |
| activities.Regulatorygenes,inaddition,controlthetranscrip- |
| (11) Translationof defective proteins |
| tion of many classes of small RNAs that have fundamental |
| (12) Deficient/defective post-translation modification of |
| roles in direct and feed-back regulation of most aspects of |
| proteins |
| the geneticmaterial. |
| (13) Deficient/defective post-translation repair of misfolded |
| Mutationscausestructuralalterationsofthegeneticmate- |
| proteins |
| rial. Depending on the site, nature, magnitude and effects of |
| (14) Deficient/defective post-translation targeting and traf- |
| the mutational event as well as on the functions and impor- |
| fickingof proteins |
| tance of the mutated genes, pathogenetic mechanisms that |
| (15) Deficient/defective regulationof cell growth |
| result in deficient synthesis of gene products, synthesis of |
| (16) Deficient/defective regulationof cell division |
| defective gene products or disturbed regulation of cellular |
| (17) Deficient/defective regulationof cell differentiation |
| activities will lead to development of genetic disorders, |
| (18) Deficient/defective regulationof cell migration |
| secondary to the ensuing pathophysiological alterations of |
| (19) Deficient/defective regulation of intercellular contact |
| cellular functions[9]. |
| andcell movement |
| Maintainingstability,integrityandspecies-specificidentity |
| (20) Deficient/defective apoptosis/selection repair |
| ofthegenomerepresentsaprerequisite,notonlyforexecuting |
| (21) Deficient/defective regulation of cell architecture and |
| cellfunctionsproperly,butmorefundamentallyforbeginning, |
| cytoskeleton: e.g. ciliary dyskinesia disorders |
| continuationandconservationoflife.Itisthepreservationof |
| (bronchiectasis, dextrocardia and situs-inversus, |
| thecollaborativeandintegratedintimaterelationshipofthese |
| hydronephrosis, hydrocephaly, male infertility and |
| threeaspectsofthegenomethatrepresenttherealkerneland |
| repeated abortions), hereditary spherocytosis, Wiskott– |
| trueessenceofexistenceofallformsoflife.Manypathogenetic |
| Aldrich syndromeand neuraltubedefects. |
| mechanisms that drastically affect genome stability and gen- |
| (22) Imprintingdisorders:genomicimprintingdisorders,e.g. |
| ome integrity have been defined. These particular groups of |
| ovarian teratomas and hydatidiform moles, and genic |
| mutations constitute important detrimental events that act |
| imprinting diseases, e.g. Prader–Willi syndrome, |
| via different pathways, e.g. defective genetic repair mecha- |
| Angelman syndrome, Silver–Russell syndrome, |
| nismsorprematureinductionofapoptosis,leadingultimately |
| Beckwith–Wiedemann Syndrome. |
| to loss of genome stability and integrity and induction of cell |
| (23) Deficient/defective regulationof cellular functions: |
| death. On molecular or cellular level, these mutations might |
| (a) Deficient/defective transport across cell membrane or |
| beconsideredaslife-endingmutations.Thesemutationsmight |
| membranes ofcell organelles(transport defects) |
| also act in a different way through total loss of reproductive |
| (b) Deficient/defective transport across cell pores, nuclear |
| fitnessanddisappearanceofindividualgenomesfromthegene |
| poresorpores ofcell organelles(chanellopathies) |
| poolof certain species. |
| (c) Deficient/defective secretion of gene products (pro- |
| Thespectrumofpathogeneticmechanismsandtheresulting |
| tein/enzymedeficiency disorders) |
| pathophysiologicaldisturbancesthatunderliethedevelopment |
| (d) Deficient/defective excretion of metabolic waste prod- |
| ofgeneticdisordersisquitewideinviewofthecomplexity of |
| ucts (storagedisorders) |
| the structural organization of the genome and the strict func- |
| (e) Deficient/defective regulation of intra and inter net- |
| tionalspecializationthatcharacterizeseachofitscomponents. |
| work reactions and interactions: signal transduction |
| Additionally, the obscure nature and unclear functions of |
| disorders: e.g. neurodegeneration, diabetes mellitus, |
| many components of the genetic material, undoubtedly, con- |
| schizophreniaand Noonansyndrome. |
| ceal many, still unknown, pathogenetic mechanisms and hin- |
| (f) Deficient/defective positioning of structural proteins |
| der proper understanding of their exact pathways. It is |
| (cellcytoskeleton disorders) |
| hoped that final completion of the human genome project |
| (g) Deficient/defective regulation of intracellular |
| might disclose the exact and complete structural organization |
| trafficking. |
| ofthehumangenome[11].However,aparallelhumangenome |
| (h) Deficient/defective production of cellular energy: |
| function project aiming at defining the complete functional |
| oxidative-phosphorylationdisorders. |
| spectrum of the genome seems to be an indispensable and |
| (i) Ubiquitination/proteasome degradation defects: e.g. |
| imperative task in order to finalize our knowledge of our |
| Friedreich ataxia, Huntington disease, Parkinson dis- |
| geneticmaterial. |
| ease, Alzheimer disease, Angelman syndrome, motor |
| Currently defined pathogenetic mechanisms and patho- |
| neurondiseaseandimmunodeficiency. |
| physiological alterations implicated in the pathogenesis of |
| (j) Apoptosis defects: e.g. congenital malformations, |
| geneticdisorders includethe following: |
| autoimmunedisorders, cancerandneurodegeneration. |
| (1) Loss/damage/duplication/inactivation of nucleargenes |
| 9. Anti-mutation mechanisms ofthe humangenomeandhuman |
| (2) Mutationof mitochondrial genes(mitDNA) |
| proteome |
| (3) Deficient/defective DNA replication/repair |
| (4) Triplet repeatexpansiondisorders |
| (5) Loss/acquisition/damage of chromosomes The human genome develops, persists and works in a hostile |
| (6) Deficienttranscription of mRNA environment full of existing, and continuously generated, |
|
|
| | 16 | | | | | | | | | | | | | M.S.Z. | Salem | |
| | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | ------ | ----- | |
| mutagens. Mutational events induced by external factors, forsynthesisofproteinandofregulatorysmallRNAspecies, |
| which include physical, chemical and biological mutagens, the human genome has a considerable amount of repetitive |
| havewidespreaddetrimentaleffectsonthestabilityandinteg- DNA sequences, including both noncoding repetitive DNA |
| rity of the genome as well as on the stability and integrity of sequencesandmultiplecopygenesandgenefragments,alarge |
| the proteome. Additionally, further and considerable damage number(19,000–21,000)ofpseudogenes,aconsiderablesizable |
| of the structural organization and functional capabilities of portion (about 1/6th of the total genome size) as pyknons, a |
| boththegenomeandtheproteomeregularlyoccursoncontin- quite large portion (nearly 40% of the total genome size) as |
| uous and progressive basis due to the continuously generated transposonsandlargenumbersofmultiplecopiesoffunctional |
| burdenofinternalmutagensthatresultfromthediversemeta- genesthatsharethesameregulatoryfunctionandwhosesup- |
| bolic activities of the exceedingly large number of metabolic pressionordamagebymutationcanbetoleratedbyothergenes |
| networksofthecell.Unlessapowerfulandeffectiveprotective havingthesamefunction.Thesepeculiarstructuralfeaturesof |
| and repair system actively participates in protecting the gen- thehumangenomeallowsforoccurrenceofmutationalevents |
| ome and proteome of the cell against the deleterious effects in many segments of the genome without having appreciable |
| ofmutations,andinefficientrepairofresultingdamage,main- functional defects. Even if some of these genes or DNA |
| tainingthestabilityandintegrityofbothofthesebio-systems sequenceshaveimportantrolesingenomefunction,theirpres- |
| that constitute the framework of life activities within the cell ence in multiple repetitive copies can greatly reduce, or even |
| wouldhavebeen impossible. nullify,theconsequencesofmutationaldamageresultingfrom |
| The human genome is endowed with a spectacular multi- affectingmanycopies. |
| facetedstronganti-mutationsystemresponsibleformaintain- Thepresenceofmultiplecopies,hundredstothousands,of |
| ing stability and integrity of the genome and preserving its mitochondrial genes within the mitochondria of each cell is |
| identity.Itactsbyprotectingthegenomefromthedetrimental crucial in obviating devastating mutation-induced damage to |
| effects of mutation and by repairing mutation-induced dam- these vital organelles in view of their role in production of |
| age. Obviously, the balance between the pathological effects ATP.Thisfeatureofmitochondrialgenomeallowsforconsid- |
| of mutation and the ability of the anti-mutation system to erable burden of mutations to affect it before appreciable |
| counteractandtoreducetheconsequencesoftheseeffectsrep- pathological consequences result. It is estimated that muta- |
| resents the mainfactor that determines the likelihood of hav- tions affecting nearly 80% of certain mitochondrial genes |
| ing a mutation-induced genetic disease. The human anti- might occur before pathological manifestations of mitochon- |
| mutation system comprises both innate mechanisms common drialgeneticdiseasesmaketheirappearanceduetothismulti- |
| to,andsharedby,allindividuals,e.g.degeneracyofthegenetic plecopyfeature of mtDNA[1]. |
| code,andacquiredaspectsdeterminedbytheinheritedgenetic |
| background ofeach humanbeing, e.g.DNA repair system. 10.2. Structural featuresof DNA |
| | The | human | transcriptome, | | being | subjected | to the | same | | | | | | | | |
| | ------------- | ---------- | -------------- | --------- | ------------- | ---------- | ------------- | ---- | --------------- | -------- | -------- | -------- | ---------- | ----------- | ---------- | |
| | mutational | events | that | can | affect, | alter and | damage | the | | | | | | | | |
| | | | | | | | | | DNA exists | as a | double | stranded | structure | composed | of two | |
| | DNA, seems | to | have efficient | | anti-mutation | mechanisms | | to | | | | | | | | |
| | | | | | | | | | tightly bound | strands, | each | strand | consisting | of | a straight | |
| | guard against | occurrence | | of errors | during | RNA | transcription | | | | | | | | | |
| | | | | | | | | | sugar-phosphate | | backbone | with | opposing | nitrogenous | bases | |
| and to correct and repair some post-transcription defects of linked by glycosidic linkage to the sugar of one strand and |
| mRNA that can cause errors during protein translation. A by hydrogen bonds with a complementary base on the other |
| | separate | RNA-proofreading | | | system | seems to | exist | and it | | | | | | | | |
| | ------------------------------- | ---------------- | --- | --- | --------- | -------- | -------- | ------ | ------------ | -------- | ---------- | ------------ | --- | ------ | ------ | |
| | | | | | | | | | strand. This | specific | structural | organization | | of DNA | serves | |
| | probablyactsduringtranscription | | | | byrelying | onthe | sequence | | | | | | | | | |
| manypurposes.Itstabilizesthedynamicsofthemolecule,per- |
| | complementarity | | information | | or database | stored | | within | | | | | | | | |
| | --------------- | --- | ----------- | --- | ----------- | ------ | --- | ------ | ---------------- | --- | --------------- | --- | -------------- | --------- | ---- | |
| | | | | | | | | | mits replication | | and duplication | | of the genetic | material, | pro- | |
| the complementary silent or non-transcribing strand of tects the interiorly located bases and, most important, stores |
| DNA. Depending on the sequence of the active strand to a template or copy of the genetic information ready for use |
| | ensure | accurate | transcription | | might | result | in improper | | | | | | | | | |
| | ------ | -------- | ------------- | --- | ----- | ------ | ----------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| incaseofdamageoftheotherstrand.Ifsmallorgrossmuta- |
| transcriptionifmismatcherrorsoccurdueto,e.g.polymerase |
| | | | | | | | | | tional events | affect | important | | functional | portions | of the | |
| | ------------ | ---- | ---------- | --- | ------ | --------------- | --- | ----- | ------------- | --------- | --------- | ---------- | ---------- | -------- | --------- | |
| | dysfunction. | This | assumption | | might, | partly, explain | the | still | | | | | | | | |
| | | | | | | | | | genetic | material, | repair | mechanisms | can | restore | the exact | |
| un-understandable behavior of gene function which involves, sequence of the damaged or lost or deleted parts through |
| seemingly needless, indirect and energy consuming mecha- restorationmechanismsbasedonthecomplementaryinforma- |
| | nisms by | transcribing | | a complementary | | mRNA | molecule, | | | | | | | | | |
| | -------- | ------------ | --- | --------------- | --- | ---- | --------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| tionoftheotherstrand.Mutationsleadingtodamageofcor- |
| ratherthananidenticalmRNA,thathastobedecodedagain |
| | | | | | | | | | responding | segments | of both | strands | represent | a catastrophic | | |
| | --------- | ------ | --- | ------------------ | --- | ------------ | --- | --- | ---------- | -------------- | ------- | ------------ | --------- | -------------- | --- | |
| | byrRNAand | tRNAin | | the ribosomeduring | | translation. | | | | | | | | | | |
| | | | | | | | | | eventtothe | genomeduetothe | | absenceofthe | | sequencedata- | | |
| baseneededfortherepairmechanismtodefinetheexactbase |
| 10. Anti-mutation mechanisms ofthe humangenome sequence of the newly synthesized segment in place of the |
| | | | | | | | | | deletedorgrossly | | damaged | segment. | | | | |
| | ---------------- | --- | -------------- | --- | --------------- | --- | --- | --- | ------------------ | --- | ---------- | -------- | --- | --- | --- | |
| | 10.1. Structural | | organizationof | | the humangenome | | | | | | | | | | | |
| | | | | | | | | | 10.3. Degeneracyof | | thegenetic | code | | | | |
| Thepeculiarstructuralorganizationofthehumangenomerep- |
| resentsthefirstinnateanti-mutationmechanisminviewofthe Degeneracyofthegeneticcoderepresentsthethirdinnateanti- |
| presenceoflargeinterspersedportionsofnon-functionalintra- mutationmechanism ofthe humangenome. Thisfeature per- |
| genic, introns, and inter-genic DNA sequences and segments mits the occurrence of same-sense point mutations in func- |
| that can be mutated without having appreciable deleterious tional codons without changing the amino acid defined by |
| | functional | effects. | In addition | | to functional | sequences | | needed | | | | | | | | |
| | ---------- | -------- | ----------- | --- | ------------- | --------- | --- | ------ | ----------- | ------ | ----- | ---- | ------------ | --- | ----------- | |
| | | | | | | | | | the mutated | codon. | Since | some | amino acids, | as | a part of a | |
|
|
| | Pathogenetics | | | | | | | | | | | | | | 17 | |
| | ------------- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | |
| specific protein domain, play critical roles in attaining and responsible for DNA synthesis, the DNA polymerases, most |
| maintainingcorrectproteinstructureandinmediatingproper of them have additional proofreading ability to ensure accu- |
| protein function, point mutations leading to replacement of rate error-free DNA replication and, hence, maintaining and |
| these essential amino acids by other amino acids, missense preserving the stability, integrity and identity of the genome |
| mutations, that can’t perform the functions of the original during cell division, as well as during transfer of the genetic |
| amino acids might result in detrimental effects on the struc- materialfrom parentsto offspring. |
| turalintegrityandstabilityoftheproteinfollowedbydeleteri- |
| ous consequences on physiological function of the protein. 10.7. Genetic repairsystems |
| | Hence, degeneracy | | of the | genetic | code | allows | for occurrence | | | | | | | | | |
| | ----------------- | --- | ------ | ------- | ---- | ------ | -------------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| of many point mutations, the commonest type of mutational Geneticrepairsystemsresponsibleforcorrectingandrepairing |
| eventsandthecommonestcauseofgeneticdisorders,without many different types of point and small mutations that affect |
| | changing | the final | structure | of | the synthesized | | protein, | thus | | | | | | | | |
| | -------- | --------- | --------- | --- | --------------- | --- | -------- | ---- | --- | --- | --- | --- | --- | --- | --- | |
| thegeneticmaterial,whetherinducedbyexogenousmutagens |
| | protecting | against, | and | obviating, | the pathological | | effects | of | | | | | | | | |
| | ---------- | -------- | --- | ---------- | ---------------- | --- | ------- | --- | ------------ | --------- | --- | ---------- | ----------- | --- | ------ | |
| | | | | | | | | | or occurring | secondary | to | endogenous | spontaneous | | alter- | |
| thesemutations. |
| | | | | | | | | | ations, comprise | both | nuclear | DNA | repair system | | and mito- | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ---------------- | ---------- | ------- | ------- | ------------- | --- | --------- | |
| | | | | | | | | | chondrial | DNA repair | system. | Genetic | function | and | genetic | |
| 10.4.Nuclear localizationof DNA repairrepresenttwosidesofonecoin.Withoutthepersevering |
| | | | | | | | | | continuous, | active and | effective | surveillance | | exerted | by the | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ----------- | ---------- | --------- | ------------ | --- | ------- | ------ | |
| The localization of DNA deep inside the cell nucleus repre- genetic repair systems to detect and repair the continuously |
| sents a fourth innate anti-mutation mechanism of the human and persistently occurring mutations, maintaining stability |
| genome because it acts as a physical barrier against many and integrity of the genome would be an impossible task. |
| mutagens that have to overcome many obstacles of cellular Theserepairsystemsconsistoflargenumbersofenzymes,pro- |
| defense mechanisms in order to affect the nuclear genome. teins and related factors that function in complementary and |
| Thesedefensesincludetheextra-cellularenvironment,thecell collaborative mechanisms along specific pathways, with each |
| membrane, the cytoplasmic mass, the cytoplasmic enzymes of them having a predefined role in the repair process. For |
| and phagocytic cellular organelles and the cytoplasmic and instance,ifmutationcausesdamageofageneticsegmentcon- |
| nuclear antioxidantenzymesystems. sisting of sequence of nucleotides, an endonuclease enzyme |
| cutsbothsidesofthedamagedsegment,followedbyaddition |
| 10.5.DNA-associated proteins of proper nucleotides instead of the damaged or deleted ones |
| | | | | | | | | | by a polymerase | enzyme, | then | a ligase | enzyme | joins | the ends | |
| | ------------------ | ----------- | -------- | ----------- | --------------- | --------- | ----------- | --- | --------------- | ------------ | ------- | -------------- | ----------------- | ------------ | -------- | |
| | | | | | | | | | of the newly | added | segment | of nucleotides | | to the | original | |
| | The DNA-associated | | or | DNA-binding | | proteins, | in addition | | | | | | | | | |
| | | | | | | | | | neighboring | nucleotides | by | forming | phosphor-di-ester | | bonds | |
| | to their | essential | roles in | regulating | transcriptional | | processes | | | | | | | | | |
| | | | | | | | | | between the | phosphateand | | the sugarof | adjacent | nucleotides, | | |
| | of most | genes, also | play | fundamental | roles | in | protecting | the | | | | | | | | |
| DNA from the damaging effects of many mutagens, in par- thus,regainingthesugar-phosphatebackboneoftheDNA[2]. |
| | ticular the | free radicals | | that are | generated | during | metabolic | | | | | | | | | |
| | ----------- | ------------- | --- | -------- | --------- | ------ | --------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| activities of the cell. They act as physical barriers and bio- 10.7.1. Nuclear DNArepair |
| chemical buffers, modifiers or deactivating biomolecules of Nuclear DNA repair mechanisms comprise many approaches |
| | many chemical | mutagens | | or damaging | | factors | that | might | | | | | | | | |
| | ------------- | -------- | --- | ----------- | --- | ------- | ---- | ----- | --- | --- | --- | --- | --- | --- | --- | |
| torepairmutationsofDNA.Theseapproachesincludediffer- |
| | harm the | DNA. | They mediate | | this protective | | role by | many | | | | | | | | |
| | -------- | ---- | ------------ | --- | --------------- | --- | ------- | ---- | --- | --- | --- | --- | --- | --- | --- | |
| entpathwaysandsub-pathwaysaccordingtothetype,siteand |
| | mechanisms | including | | modulation | of | charge | transport | of | | | | | | | | |
| | ---------- | --------- | --- | ---------- | --- | ------ | --------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| extentofthemutation-induceddamageandalsoaccordingto |
| oxidative agents within the DNA, limitation of DNA helix the stage of cell cycle affected by the mutation. They include: |
| distortion and regulation of protein-dependent alterations in base excision repair (BER), nucleotide excision repair |
| | DNA base | stacking | [1]. | | | | | | | | | | | | | |
| | ---------------- | ------------ | ---- | ------ | --- | --- | --- | --- | ------------- | -------- | ---------------- | -------- | ------- | -------------- | ---- | |
| | | | | | | | | | (NER), direct | reversal | repair, | mismatch | repair, | transcription- | | |
| | | | | | | | | | coupledrepair | (TCR) | andrecombination | | repair | (Fig. | 11). | |
| | 10.6.Replication | proofreading | | system | | | | | | | | | | | | |
| 10.7.1.1.Baseexcisionrepair(BER).Thisrepairmechanismis |
| Preservation of genomic identity of the organism depends probablythemostfrequentDNArepairpathwayinthecell.It |
| | | | | | | | | | is used for | single strand | point | mutations | affecting | one | or few | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ----------- | ------------- | ----- | --------- | --------- | --- | ------ | |
| exclusivelyonaccuratereplicationandsynthesisoftwoidenti- |
| cal copies of the genome during cell division, followed by basesofoneDNAstrand.Itinvolvesrecognitionofthedam- |
| transfer, or inheritance, of each copy to each daughter cell. aged base of a nucleotide by a glycosylase enzyme and its |
| In this manner, all cells descendent from a parent cell have removalbydetachingitfromthedeoxyribosesugarviahydrol- |
| nuclear genomes identical to those of the mother cell. The ysis of the N-glycosyl bond. Breakage of the hydrogen bond |
| majority of spontaneous point mutations of the nuclear gen- betweenthedamagedbaseandtheopposingbaseonthecom- |
| ome are prone to occur during cell division, mostly during plementarystrandoccurs,probably,viaATP-inducedchanges |
| DNA synthesis or the replication phase of the process. The oftheenergydynamicsofthebond.Removalofthedamaged |
| replication proofreading system acts in a prophylactic way to or mutated base results in creation of abasic site or |
| ensureaccurateinsertionoradditionofthepropernucleotide apurinic/apyrimidinicsite(AP)oftheDNAwhicharetargeted |
| tothenewlysynthesizedstrandofreplicatingDNA.Thispro- by endonuclease and lyase activity to remove the damaged |
| phylacticfunctionisfundamentaltoreducetherateofinevita- base(s)followedbyadditionofnewnormalbase(s)byaspeci- |
| blereplicationmistakestominimumlevelsthatcouldbedealt fic polymerase enzyme and, finally, regaining the phosphodi- |
| with efficiently with the DNA repair mechanisms. In spite of ester bonds and, hence, the phosphate-sugar backbone of the |
| the impressively fast and accurate ability of the enzymes DNA strandbythe actionofDNA ligase. |
|
|
| | 18 | | | | | | | | | | | | M.S.Z. | Salem | |
| | --- | --- | --- | --- | --- | -------- | -------------------- | --- | --- | --- | --- | --- | ------ | ----- | |
| | | | | | | Figure11 | DNArepairmechanisms. | | | | | | | | |
| 10.7.1.2. Nucleotide excision repair (NER). Nucleotide exci- be caused either endogenously during DNA replication due |
| sion repair is one of the most important DNA repair systems to replication errors, e.g. replication fork collapse, or exoge- |
| andishighlyconservedamongspecies,thoughitismuchmore nouslyby,e.g.ionizingradiation.Recombinationrepairmech- |
| complicatedinhighereukaryotesthanprokaryotes.Themost |
| | | | | | | | | anisms consist | | of many | various | steps: end | resection, | strand | |
| | --- | --- | --- | --- | --- | --- | --- | -------------- | --- | ------- | ------- | ---------- | ---------- | ------ | |
| prominent feature of this repair system is its broad substrate invasion, DNA repair synthesis, branch migration and |
| specificity because it can excise DNA lesions such as UV- Hollidayjunctionresolution,andinclude,atleast,twodiffer- |
| induced pyrimidine dimers as well as more bulky adducts of ent repair pathways: homologous recombination repair (HR) |
| | DNA. | | | | | | | andnonhomologousend-joiningrepair.HRrepairmechanism | | | | | | | |
| | ---- | --- | --- | --- | --- | --- | --- | --------------------------------------------------- | --- | --- | --- | --- | --- | --- | |
| istheaccuratepathwayandmakesuseofundamagedhomol- |
| 10.7.1.3. Direct reversal repair. This repair mechanism can ogous DNA as a template for repair. Non-homologous end- |
| directly repair UV-induced pyrimidine dimer formation and joining repair mechanism directly ligates two double-strand |
| alkylation adducts by DNA photolyase enzymes and alkyl- break ends together, and although it is efficient, it is prone |
| transferaseproteins,respectively.Directreversal repairmech- to loss of genetic information at the ligation sites. However, |
| anisms are not followed by incision of DNA strands or there are many anti-recombination mechanisms to suppress |
| resynthesis of new DNA since the changed or mutated bases excessive recombination that might lead to loss of genetic |
| are directly reverted to their original states either by light- information andgenomic instability [1]. |
| | dependent | photoreactivation | | process, | for pyrimidine | | dimers | | | | | | | | |
| | --------- | ----------------- | --- | -------- | -------------- | --- | ------ | --- | --- | --- | --- | --- | --- | --- | |
| repair, or by use of alkyltransferase. Placental mammals do 10.7.2. RNA repair/editing system |
| nothavephotolyase-dependentrepairmechanismsanddepend |
| RNAeditingreferstomolecularmodificationsofnucleotidesof |
| onnucleotideexcisionrepairtocorrectandrepairUV-induced RNA through chemical changes in the base makeup of the |
| pyrimidinedimer formation. molecule. Such changes appear to be present in all three |
| | | | | | | | | domains | of life, | and involve | both | coding, | mRNA, | and non- | |
| | --------- | -------- | ------ | ------ | --- | -------- | ------ | ------- | -------- | ----------- | ---- | -------------- | ----- | --------- | |
| | 10.7.1.4. | Mismatch | repair | (MMR). | The | mismatch | repair | | | | | | | | |
| | | | | | | | | coding, | tRNA | and mRNA, | | types of small | or | microRNA. | |
| (MMR)systemrecognizesandcorrectsmismatchedorunpaired |
| RNAeditingoccursinthecellnucleusandthecytosol,aswell |
| basesthatresultfromerrorsofDNApolymeraseduringDNA asinmitochondriaandismediatedbyacomplexrepairsystem |
| replication. It involves complex reactions and interactions of comprisingmanyspeciesofsmallRNA(guideRNA)andlarge |
| manyenzymes,proteinsandsignaldiscriminationfactors,prob- |
| proteincomplexesknownastheeditosomes.Thepathwaysof |
| ablyincollaborationwiththeproofreadingsystem,torecognize |
| | | | | | | | | RNA editing | include | many | diverse | processes: | nucleoside | base | |
| | --- | --- | --- | --- | --- | --- | --- | ----------- | ------- | ---- | ------- | ---------- | ---------- | ---- | |
| themutatedstrandfirstandthentolocatethesiteofthemis- |
| modificationssuchascytidine(C)touridine(U)andadenosine |
| | matched | pair. This | is followed | by | removal | of the | mutated | | | | | | | | |
| | ------- | ---------- | ----------- | --- | ------- | ------ | ------- | --- | --- | --- | --- | --- | --- | --- | |
| (A)toinosine(I)deaminations,aswellasnon-templatedinser- |
| sequencebyanendonuclease,additionofnewpair(s)byDNA tions of nucleotide. RNA editing in mRNAs effectively alters |
| polymeraseandfinalregainoftheDNAdoublestrandedstruc- |
| theaminoacidsequenceoftheencodedproteinsothatitdiffers |
| | ture by | DNA | ligases. Post-replication | | mismatch | | repair is | | | | | | | | |
| | -------- | ---------- | ------------------------- | ------------ | ---------- | --- | --------- | --------- | --------- | --- | ----------- | --- | --------- | ------ | |
| | | | | | | | | from that | predicted | by | the genomic | DNA | sequence. | Though | |
| | achieved | by removal | of | a relatively | long tract | of | mismatch- | | | | | | | | |
| mRNAeditingisusedinmanyinstancestoallowforsynthesis |
| containingoligonucleotides,aprocesscalledlong-patchMMR. |
| bythecellofmorethanoneproteinfromthesamemRNAtran- |
| | | | | | | | | script, e.g. | synthesis | | of both | apolipoprotein | | B-100 and | |
| | --- | --- | --- | --- | --- | --- | --- | ------------ | --------- | --- | ------- | -------------- | --- | --------- | |
| 10.7.1.5. Recombination repair. Recombination repair mecha- apolipoprotein B-48 from the same mRNA in liver cells, it |
| nisms aim primarily at repairing double-strand breaks of can also be used to repair missense or termination mutations |
| DNA which represent the most devastating mutation- ofthemoleculewhichcanhavedeleteriouseffectsonthesynthe- |
| induced lesions of DNA because they can lead to loss of sized protein. Specific endonucleases and ligases for double |
| geneticinformationandchromosomalinstabilitieswithconse- strandedspeciesofRNAhavebeendefinedinmanyprokary- |
| quent pathological alterations including chromosome break- otesanditmightbejustamatteroftimebeforedefiningtheir |
| age syndromes and carcinogenesis. Double-strand breaks can functionalcounterpartsineukaryotesandhumancells. |
|
|
| | Pathogenetics | | | | | | | | | | | | | | | 19 | |
| | ------------- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | |
| 10.7.3.Mitochondrial DNA(mtDNA) repair nuclear genome. They might behave in a harmful way and |
| | | | | | | | | | act as major | potential | | causes | of spontaneous | | mutations | of | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ------------ | --------- | --- | ------ | -------------- | --- | --------- | --- | |
| Thepivotalroleplayedbythemitochondrialgenomeingener- |
| | | | | | | | | | the nuclear | genome. | They | can | make | a copy | of themselves | | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ----------- | ------- | ---- | --- | ---- | ------ | ------------- | --- | |
| atingATP,withoutwhichlifecanneitherbeginnorpersist,in |
| | | | | | | | | | and insert | the | new copy | in another | | site, or | they can | detach | |
| | -------- | ------ | ---- | ----- | ------------------ | --- | --- | ---------- | ---------- | --- | -------- | ---------- | --- | -------- | -------- | ------ | |
| | addition | to the | many | other | critical metabolic | | and | regulatory | | | | | | | | | |
| functions of mitochondrial genes, requires the presence of an themselves from their location and get inserted at different |
| efficient system for repairing mtDNA mutations. The need sites of the genome (Fig. 12). In both conditions they result |
| | | | | | | | | | in insertional | mutagenesis | | with | consequent | deleterious | | effects | |
| | ----------------- | --- | ------ | ------ | ------ | --- | ------- | ------- | -------------- | ----------- | --- | ---- | ---------- | ----------- | --- | ------- | |
| | for mitochondrial | | genome | repair | system | is | further | imposed | | | | | | | | | |
| ongenomicstabilityandgenomicintegrity.Iftheygetinserted |
| onthecellinviewofthehighmutationrateofmitochondrial |
| | | | | | | | | | in a functional | | segment | of the | genome | they lead | to structural | | |
| | ----------- | ---- | ---- | ------ | ------------- | --- | --- | ---------- | --------------- | --- | ------- | ------ | ------ | --------- | ------------- | --- | |
| | genes which | lack | many | of the | anti-mutation | | and | protective | | | | | | | | | |
| mechanisms available to nuclear genes. Similarto the nuclear disruption and loss of function of the affected segment with |
| genome repair system, mitochondrial repair system includes resultant pathological effects. Alternatively, transposon activ- |
| itymayleadtocreationandconstructionofnewgeneticcom- |
| | many repair | pathways: | | base | excision | repair, | direct | reversal | | | | | | | | | |
| | ----------- | --------- | --- | ---- | -------- | ------- | ------ | -------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| binationsthatmayhavespecificfunctions.Withinthiscontext, |
| | repair, | mismatch | repair, | | and | recombination | | repair. | | | | | | | | | |
| | ---------- | -------- | ------- | ----- | -------- | ------------- | -------- | ------- | ---------- | --- | ---------- | --- | ------ | ----------- | ---------- | --- | |
| | | | | | | | | | they would | be | considered | as | one of | the genetic | biological | | |
| | Nucleotide | excision | repair | (NER) | pathway, | | however, | seems | | | | | | | | | |
| notto beworkingin the mitochondria [12]. mechanisms involved in, and responsible for, evolutionary |
| diversityofthegenomeandtheproteome.Theycanalsocause |
| 10.8.Protein repair systems tangibleincreasesintheamountofthegeneticmaterialdueto |
| | | | | | | | | | recurrent | synthesis | and | addition | of | multiple | new copies | of | |
| | -------- | ---------------- | --- | ---------- | --- | ------------- | --- | -------- | -------------------- | --------- | ----- | -------- | --- | -------- | ---------- | --- | |
| | | | | | | | | | transposableelements | | tothe | nuclear | | genome. | | | |
| | Accurate | post-translation | | structural | | configuration | | of newly | | | | | | | | | |
| synthesized polypeptide chains is a fundamental conforma- Transposonsprobablyhaveacentralregulatoryroleinthe |
| earlydevelopmentoftheembryo.Akeyfeatureofthisactivity |
| | tional modification | | for | most | proteins | to become | | functionally | | | | | | | | | |
| | -------------------- | --------- | --- | ---------- | -------- | ------------ | --- | ------------ | -------- | ---------- | ------ | --------------- | --- | ---------- | --------- | -------- | |
| | | | | | | | | | involves | a specific | type | of transposable | | element | (MuERV-L) | | |
| | active biomolecules. | | The | maturation | | from primary | | to quater- | | | | | | | | | |
| | | | | | | | | | which is | uniquely | active | during | the | totipotent | cell | phase of | |
| | nary protein | structure | | involves | many | changes, | | e.g. folding | | | | | | | | | |
| embryogenesis.Anetworkofregulatorygenesthatarepartic- |
| | and maintenance | | of steric | and | spatial | relationships | | between | | | | | | | | | |
| | --------------- | --- | --------- | --- | ------- | ------------- | --- | ------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| the different domains of the protein. Conformational defects ularly active during early development depends on this trans- |
| | | | | | | | | | posable | element | to activate | their | promoter | areas | in | order to | |
| | ----------- | ------------- | ----- | ------------ | ------ | ------ | ------------- | ---- | ----------- | --------------- | ----------- | ----------- | -------- | ----- | ----- | -------- | |
| | in proteins | that | might | happen | during | these | modifications | can | | | | | | | | | |
| | | | | | | | | | start their | transcriptional | | activities. | The | early | timed | enhance- | |
| | lead to | the formation | | of misfolded | | and/or | aggregated | non- | | | | | | | | | |
| mentoftheregulatoryfunctionsofthisgeneticnetworkseems |
| functionalmolecules. |
| essentialforproperdifferentiationofthetotipotentcellswhich |
| | Human | genome | comprises | | a large | number | of | genes that | | | | | | | | | |
| | ----- | ------ | --------- | --- | ------- | ------ | --- | ---------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| playfundamentalrolesindevelopmentanddifferentiation.As |
| codeacomplexsystemcomposedoflargenumbersofspecific |
| | | | | | | | | | development | continues, | | progressive | silencing | | of the | genes of | |
| | ---------------- | -------- | --------------- | ---- | --------- | ------------ | ----------- | ------- | --------------- | ---------- | ------- | ----------- | --------- | ------------- | ----------- | -------- | |
| | protein families | | and subfamilies | | known | as | molecular | chaper- | | | | | | | | | |
| | | | | | | | | | this regulatory | | network | takes | place. | This delicate | balance | in | |
| | ones. These | proteins | have | many | important | | and diverse | func- | | | | | | | | | |
| | | | | | | | | | temporal | regulation | of | transposon | | activity | is critical | for | |
| | tions in | cellular | activities, | e.g. | assisting | non-covalent | | folding | | | | | | | | | |
| embryogenesisanddevelopmentaswellasforproperdevelop- |
| | orunfoldingand | | assembly | ordisassembly | | ofmacromolecular | | | | | | | | | | | |
| | -------------- | --- | -------- | ------------- | --- | ---------------- | --- | --- | ------- | ---- | ----------- | ------------ | --- | -------- | ------------- | --- | |
| | | | | | | | | | ment of | germ | line cells, | particularly | | those in | spermatocytes | | |
| structures,includingproteins.Preventionofmisfoldingand/or |
| aggregation of newly synthesized polypeptide chains, which duringspermatogenesis [14]. |
| | | | | | | | | | Over | activity | or uncontrolled | | activity | of transposons | | can, | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ---- | -------- | --------------- | --- | -------- | -------------- | --- | ---- | |
| turnthemtononfunctionalbiomolecules,isamajorandfun- |
| | | | | | | | | | thus, have | detrimental | and | devastating | | effectson | embryogen- | | |
| | ------------------ | --- | ------------------------- | --- | -------- | ----------- | --------- | ---------- | --------------------- | ----------- | ------ | ------------ | ------------- | --------- | ------------- | ------ | |
| | damentalfunctionof | | molecularchaperones.Other | | | | | physiolog- | | | | | | | | | |
| | | | | | | | | | esis, differentiation | | and | development, | | and | can lead | to the | |
| | ical functions | | of chaperones | | include: | | transport | across | | | | | | | | | |
| | | | | | | | | | pathogenesis | of | a wide | variety | of congenital | | malformations | | |
| | mitochondrial | | membranes | and | the | endoplasmic | | reticulum | | | | | | | | | |
| andassistance in proteindegradation. and genetic defects. The human genome, however, has a |
| uniquecontrolsystemcomposedofaspecificsubtypeofsmall |
| | Molecular | chaperones, | | probably, | | exert | critical | roles in | | | | | | | | | |
| | --------- | ----------- | --- | --------- | --- | ----- | -------- | -------- | -------- | --- | ---------- | ----- | --- | -------- | --- | ------ | |
| | | | | | | | | | or micro | RNA | molecules, | known | as | piwiRNA, | or | piRNA, | |
| maintainingstabilityandintegrityoftheproteome.Thisstate |
| | | | | | | | | | composed | of RNA-piwi | | protein | complexes. | They | are | thought | |
| | ---------- | ------------ | --- | ------------- | --- | --- | -------------- | --- | -------- | ----------- | --- | ------- | ---------- | ---- | --- | ------- | |
| | of protein | homeostasis, | | proteostasis, | | is | a prerequisite | for | | | | | | | | | |
| tobeinvolvedingenesilencing,mostspecificallythesilencing |
| | proper control | | and regulation | | of cellular | metabolic | | networks | | | | | | | | | |
| | -------------- | --- | -------------- | --- | ----------- | --------- | --- | -------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| byproteinsandismandatoryforefficientmediationofcellular of transposons. The majority of piRNAs are antisense to |
| transposonsequencessuggestingthattransposonsarethemain |
| | activities. | Specific | species | of | molecular | chaperones, | | surveil- | | | | | | | | | |
| | ----------- | -------- | ------- | --- | --------- | ----------- | --- | -------- | --- | --- | --- | --- | --- | --- | --- | --- | |
| targetofpiRNA.Inmammals,themarkedactivityofpiRNAs |
| | lance chaperones, | | are | responsible | for | constant | surveillance | of | | | | | | | | | |
| | ----------------- | ------- | --------- | ---------------- | ------ | -------- | ------------ | -------- | -------------- | --- | ----------- | --------------- | ------- | -------- | ---------- | --- | |
| | | | | | | | | | in silencing | of | transposons | and | control | of their | activities | is | |
| | the proteome | | to ensure | | proper | protein | homeostasis. | | | | | | | | | | |
| | | | | | | | | | most important | | during | the development | | of | the embryo | in | |
| | Age-related | decline | or | mutation-induced | | defects | in | proteome | | | | | | | | | |
| stability and integrity results in progressive aggregation and ordertoreducetherateandriskoftransposon-inducedmuta- |
| | | | | | | | | | tions duringthis | | sensitiveperiod | | of life[15]. | | | | |
| | --------------------- | ----- | --- | --------- | ------------ | ----------- | ------- | --------- | ---------------- | --- | --------------- | --- | ------------ | --- | --- | --- | |
| | faulty conformational | | | changes | of proteins, | | both of | which are | | | | | | | | | |
| | associated | with, | and | underlie, | the | development | | of many | | | | | | | | | |
| genetic diseases like Alzheimer disease, Parkinson disease, 10.10. Antioxidant enzymesystems |
| | priondiseases | and | manyothers[13]. | | | | | | | | | | | | | | |
| | ------------- | --- | --------------- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | |
| Thecontinuousfunctioningoftheexceedinglyhugenumberof |
| | 10.9.Silencingof | | transposon | | activityduring | | development | | | | | | | | | | |
| | ---------------- | --- | ---------- | --- | -------------- | --- | ----------- | --- | --- | --- | --- | --- | --- | --- | --- | --- | |
| metabolicnetworksthatmediatecellularactivitiesinlivingcells |
| resultsincontinuousgenerationofmanydifferenttypesofuse- |
| Transposonsconstituteaconsiderableportion,nearly40%,of ful and harmful metabolic by-products. Oxidant free radicals |
| the human nuclear genome. Transposon activities might have constitute one of the most crucial categories of these by- |
| contradictory effects on the stability and integrity of the productsinviewoftheirabilitytoinducewidespreaddamage |
|
|
| | 20 | | | | | | | | M.S.Z. Salem | |
| | --- | --- | --- | --- | --- | --- | --- | --- | ------------ | |
| Figure12 Transposons:methodsoftransposition.(LaurenSolomon,BroadInstituteofHarvardandMIT), |
| inmanycellularcomponentsincludingmembranes,organelles incorrect accomplishment of specific and selective apoptotic |
| and structural macromolecules like lipids and proteins. This processes during each of these life stages of the cell might |
| structural damage, unless counteracted by opposing antioxi- results in devastating consequences on cellular functions that |
| dantmechanisms,resultsinprogressivedegradationofcellular rangefrom dysfunctiontomalformation,andmay,even,cul- |
| constituents with consequent resultant pathophysiological minateultimatelyinprematurecelldeathandpathogenesisof |
| | alterations | of cellular functions, | leading | ultimately to disease. | disease [17]. | | | | | |
| | ----------- | ---------------------- | ------- | ---------------------- | ------------- | --- | --- | --- | --- | |
| Although low concentrations of reactive oxygen species may Apoptosis plays a crucial role in maintaining genomic sta- |
| bebeneficial,orevennecessary,inmediatingmanycellularpro- bilityandintegrity,notofindividualcells,butoftheorganism |
| cesses,e.g.defenseagainstinvadingmicro-organismsandintra- as a whole. Induction of apoptotic mechanisms in heavily |
| cellularsignalingpathways,nevertheless,higherconcentrations mutated or lethally mutated cells leads to death of the cell |
| ofthesefreeradicalsplayacausativeroleintheagingprocess and prevents transfer of these mutations to its putative |
| as well as in the pathogenesis of many human disease descendant daughter cells. This fundamental prophylactic |
| states, including immune deficiency, neurodegeneration and anti-mutation role of apoptosis in cellular activities and life |
| cancer. Oxidative damage of nDNA, mtDNA, RNA and prospectsoflivingorganismshasmorefar-reachingeffectson |
| DNA-bindingproteinsbyfreeradicalsrepresentsanimportant many important aspects related to the balance between, and |
| category of detrimental genetic mutations induced by the incidence of, normal and mutant genotypes within |
| endogenous chemical mutagens inevitably generated during species-specific gene pools. Additionally, apoptosis can affect |
| cellularmetabolicactivitiesandothercellularfunctions. inanappreciablemannergenomicidentityoflivingorganisms |
| Living cells have several efficient non-enzymatic and enzy- becausemutation-inducedevolutionaryordecadencepathways |
| maticantioxidantactivitiesthatareresponsibleforeliminating are largely dependent on the outcome of certain apoptotic |
| and/orterminatingthechainreactionsfollowinggenerationof mechanismsoperatingduringcertainstagesofthecellcycle. |
| freeradicals,asasafeguardagainsttheirdamagingeffectson |
| | cellularcomponentsandcellularfunctions.Enzymaticantiox- | | | | 10.12. Melatonin | | | | | |
| | ------------------------------------------------------- | ----------- | -------------- | ------------------- | ---------------- | --- | --- | --- | --- | |
| | idant systems | of the cell | comprise large | numbers of multiple | | | | | | |
| typesofantioxidantenzymes,notablycatalase,superoxidedis- Melatoninisahormonesynthesizedbythepinealgland,bone |
| mutase, thioredoxin reductase, glutathione peroxidase and marrow cells, epithelial cells and lymphocytes. Melatonin |
| variousotherperoxidases.Efficientproductionoftheseantiox- |
| | | | | | receptors | are distributed | in most organs, | a finding | reflecting | |
| | ------------- | ---------- | ---------- | ------------------ | -------------- | --------------- | ------------------ | ------------- | ---------- | |
| | idant enzymes | and proper | regulation | of their functions | is | | | | | |
| | | | | | its widespread | roles in | regulating various | physiological | and | |
| mandatorytokeepandmaintainredoxhomeostasisofthecell |
| | | | | | psychological | processes. | Many in vitro | and | animal studies | |
| | --- | --- | --- | --- | ------------- | ---------- | ------------- | --- | -------------- | |
| whichisacriticalprerequisitefornormalmediationofcellular revealed that melatonin has diverse functions including effec- |
| activities [16]. tiveprotectionofcellsagainstradiation-inducedchromosome |
| | | | | | breakage | and inhibition | of tumor development | | in animals | |
| | ---------------- | ------------------- | ------------ | --- | --------- | --------------- | -------------------- | -------------- | -------------- | |
| | 10.11. Apoptosis | of heavily,lethally | mutatedcells | | | | | | | |
| | | | | | exposed | to experimental | chemical | carcinogenesis | [18]. | |
| | | | | | Melatonin | was shown | to have protective | | effect against | |
| Apoptosis, or programed cell death, is a universal biological oxidative DNA damage by chemical inactivation of |
| behavior of most living cells necessary, in conjunction with DNA-damaging agent as well as by stimulating DNA repair |
| other life-regulating mechanisms, for maintaining the vital mechanisms.Theseanti-mutagenicandanti-clastogeniceffects |
| balancebetweenlifeanddeaththatgovernsoptimallifecondi- of melatonin can be linked with its ability to protect DNA |
| tionsofmulticellularorganisms.Apoptosisplaysfundamental againstoxidativedamage.Itmayexertthisantioxidantaction |
| andcrucialrolesinnormalgrowthanddevelopmentaswellas byeliminatingharmfulreactiveoxygenradicalsorbystimulat- |
| innormaldifferentiationanddeterminationoftheproperfinal ingtherepairprocessesofoxidativestress-induceddamageof |
| architecture of cells, tissues and organs. Faulty timing or DNA[19] [Table2]. |
