MEDICAL GENETICS AND GENOMICS
k k k
Summary
Thek bookk containsk thek substancek ofkthek lecturesk andk partlykofk thek practicesk ofkthek subjectk ofk‘
GeneticskandkGenomics’kheldk inkSemmelweiskUniversitykforkmedical,kpharmacologicalkandk de
ntalkstudents.k Thek bookk updatedk ink2016k startskwithkak shortk introductionktok basick geneticskandk
moleculark biologyk andk thenk topicsk fromk humank geneticsk mainlyk fromk medicalk pointk ofkview
s.kSomekofkthek16kchapterskdealkwithkmedicalkgenetics,kbutkthekchapterskalsokintroducektokthekbasi
ckknowledgekofkcellkdivision,kcytogenetics,kepigenetics,kdevelopmentalkgenetics,kstemkcellk biol
ogy,k oncogenetics,k immunogenetics,k populationk genetics,k evolutionk genetics,knutrigeneti
cs,kandktokakrelativeknewksubject,kthekhumankgenomicskandkitskapplicationsk forkthek studyk ofk thek
genomick backgroundk ofk complexk diseases,k pharmacogenomicsk andk fork thekinvestigationk o
fk thek genomek environmentalk interactions.k Ask genomicsk belongsk tok sytemskbiology,kakchapter
kintroducesktokbasicktermskofksystemskbiology,kandk concentratingkonk diseases,ksomekexamplesko
fkthekapplicationkandkutilizationkofkthiskscientifickfieldkarekalsokbekshown.kThekmodernk humank ge
neticsk cank alsok bek associatedk withkseveralk ethical,k socialk andklegalk issues.kThek lastk chapterk o
fk thisk bookk dealsk withk thesek issues.k Atk thek endk ofk eachkchapterk therek arekquestions,k withkwh
ichkthek readersk cankascertainkwhetherk theykunderstoodkand/ork learnedk thekchapter.kBecausekitki
skanke-
book,ksomektermskandkdefinitionskhaskakhyperlinkkforkmorekdetailedkexplanationsk ink thek World
k Widek Web.k Besidesk universitykstudents,k thek bookk isk alsokrecommendedk tok allk thosek wh
ok arek interestedk ink modernkmedicalkgeneticsk andk genomicsk andkwantktokbekup-
tokdatekinktheseksubjects.
Keywords:kMitosis,kmeiosis,kmutations,kcytogenetics,kepigenetics,kMendeliankinheritance,kgene
ticskofksex,kdevelopmentalkgenetics,kstemkcellkbiology,koncogenetics,kimmunogenetics,khumankg
enomics,kgenomicskofkcomplexkdiseases,kgenomickmethods,kpopulationkgenetics,kevolutionkgene
tics,kpharmacogenomics,knutrigenetics,kgenekenvironmentalkinteraction,k systemskbiology,kbioet
hics.
,COPYRIGHT:kAndráskFalus,kValériakLászló,kFerenckOberfrank,kErnakPap,kCsabakSzalai,kSárakTó
th,kBudapestkUniversitykofkTechnologykandkEconomics
CreativekCommonskNonCommercial-NoDerivsk3.0k(CCkBY-NC-NDk3.0)
Thiskworkkcankbekreproduced,kcirculated,kpublishedkandkperformedkforknon-
commercialkpurposeskwithoutkrestrictionkbykindicatingkthekauthor'skname,kbutkitkcannotkbekm
odified.
Lector:kViktorkMolnár,kMD,kheadkofkCsertexkResearchkLaboratory
ISBNk978k963k279k187k6
PreparedkunderkthekeditorshipkofkTypotexkKiadókRes
ponsiblekmanager:kVotiskykZsuzsa
MadekwithinkthekframeworkkofkthekprojectkNr.kTÁMOP-4.1.2/A/1-11/1-2011-0079,kentitled
„Konzorciumkakbiotechnológiakéskbioinformatikakaktívktanulásáért”.
2
,Content
1. Basickgeneticskandkmolecularkbiology ................................................................................. 9
1.1. Basickgenetics ................................................................................................................. 9
1.2. Mendeliankinheritance..................................................................................................... 9
1.2.1.1. Dominant-recessivekinheritance ............................................................................ 10
1.2.2. Polygenickinheritance ................................................................................................ 10
1.2.3. Genetickpleiotropy..................................................................................................... 11
1.2.4. Sex-linkedkinheritance .............................................................................................. 11
1.2.5. Linkedkinheritance,krecombination ............................................................................ 12
1.2.6. Mutation.................................................................................................................... 13
1.3. Basicskofkmolecularkbiology .......................................................................................... 13
1.3.1. SomekcharacteristicskofkthekhumankDNA................................................................... 14
1.3.2. Replication ................................................................................................................ 17
1.3.3. Transcription ............................................................................................................. 18
1.3.4. Structurekofkthekgenes ................................................................................................ 18
1.3.5. Thekgenetickcode ....................................................................................................... 19
1.3.6. Translation ................................................................................................................ 20
2. Transmissionkofkgenetickinformation ............................................................................. 22
2.1. Cellkcyclekandkregulationkofkcellkcycle ....................................................................... 22
2.1.1. G0k-kG1ktransition ................................................................................................... 23
2.1.2. G1k–kSktransition,kS-phase ...................................................................................... 25
2.1.3. G2k–kMktransition ................................................................................................... 26
2.1.4. M-phase ................................................................................................................ 27
2.1.4.1. Chromosomekstructure ...................................................................................... 29
2.1.4.2. Structurekandkrolekofkmitotickspindle ................................................................. 32
2.1.4.3. Metaphasek–kanaphasektransition ....................................................................... 35
2.1.5. Cytokinesis ........................................................................................................... 37
2.1.6. Operationkofkcellkcyclekcheckpoints....................................................................... 37
2.2. Chromosomekterritories............................................................................................. 39
2.3. Meiosis ..................................................................................................................... 41
2.3.1. Phaseskofkmeiosis .................................................................................................. 42
2.3.2. Oogenesis.............................................................................................................. 46
2.3.3. Spermatogenesis ................................................................................................... 47
2.3.4. Regulationkofkmeiosis ........................................................................................... 50
3.1. Mutationkandkpolymorphism ......................................................................................... 52
3.2. Thekclassificationkofkmutations ..................................................................................... 53
3.3. Genekmutations ............................................................................................................. 55
3.4. DNAkrepair ................................................................................................................... 61
3.5. Mutagenicityktests ......................................................................................................... 64
3.6. Nomenclaturekofkthekgenetickvariants ............................................................................ 65
3.6.1. Levelskofkvariations ................................................................................................... 65
3.6.2. Positionskofkthekvariations ......................................................................................... 66
3.6.3. Specifickchanges ....................................................................................................... 67
3.7. Usefulkweb-sites ............................................................................................................ 67
3.8. Questions ...................................................................................................................... 68
4. Cytogenetics ..................................................................................................................... 69
4.1. Structuralkchromosomekaberrations............................................................................... 70
4.1.1. Deletions ................................................................................................................... 71
4.1.2. Duplications .............................................................................................................. 71
4.1.3. Translocations ........................................................................................................... 72
3
, 4.1.3.1. Reciprocalktranslocations ...................................................................................... 72
4.1.4. Inversions.................................................................................................................. 74
4.1.5. Ringk(ring)kchromosome ........................................................................................... 75
4.1.6. Isochromosome ......................................................................................................... 75
4.1.7. Dicentrickchromosome .............................................................................................. 79
4.1.8. Acentrickfragment ..................................................................................................... 80
4.2. Numericalkchromosomekaberrations.............................................................................. 80
4.2.1. Euploidkchromosomekmutations................................................................................ 80
4.2.2. Aneuploidkchromosomalkaberrations ........................................................................ 81
4.2.3. Thekmostkcommonknumericalkchromosomalkabnormalities ....................................... 83
4.2.3.1. Trisomyk21 ............................................................................................................ 84
4.2.3.2. Trisomyk13 ............................................................................................................ 85
4.2.3.3. Trisomyk18 ............................................................................................................ 85
4.2.4. Numericalksexkchromosomekaberrations ................................................................... 85
4.2.4.1. Turnerksyndrome ................................................................................................... 85
4.2.4.2. Klinefelterksyndrome ............................................................................................ 86
4.2.4.3. TriplekXksyndrome ................................................................................................ 86
4.2.4.4. Double-Yksyndrome,k"superman"korkJacobsksyndrome ......................................... 86
4.3. Uniparentalkdisomyk(UPD) ........................................................................................... 87
4.4. Mixoploidkmutations ..................................................................................................... 87
4.4.1. Mosaicism ................................................................................................................. 88
4.4.2. Chimerism ................................................................................................................ 88
4.5. Usefulk web-sites ........................................................................................................... 89
4.6. Questions ...................................................................................................................... 89
5. Epigenetics ........................................................................................................................ 91
5.1. Epigenetickchangesk-kmolecularkmodifications .............................................................. 91
5.1.1. DNAkmethylation ...................................................................................................... 92
5.1.2. CpGkaskmutationkhotkspot .......................................................................................... 92
5.1.3. Histonekmodifications ............................................................................................... 93
5.2. Non-codingkRNAs ........................................................................................................ 94
5.3. Epigenetickphenomena .................................................................................................. 94
5.3.1. X-chromosomekinactivation ...................................................................................... 94
5.3.2. Genomickimprinting .................................................................................................. 96
5.3.2.1. Imprintingkrelatedkdiseases.................................................................................... 97
5.3.2.2. Evolutionaryktheorieskofkimprinting ...................................................................... 98
5.4. Theksignificancekofkepigenetickeffects ........................................................................... 98
5.5. Usefulkweb-sites .......................................................................................................... 101
5.6. Questions .................................................................................................................... 101
6. MendeliankInheritance:kautosomalkinheritance................................................................ 102
6.1. Introduction................................................................................................................. 102
6.2. Interpretationkofksomekbasickgenetickterms .................................................................. 104
6.3. Phenomenakthatkfine-tunekclassicalkmonogenickinheritance ........................................ 106
6.4. Autosomalkdominantkinheritance ................................................................................ 110
6.4.1. Generalkcharacteristicskofkautosomalkdominantk(AD)kinheritance ........................... 110
6.4.2. Diseaseskduektokthekmutationkofkstructuralkgenes ..................................................... 112
6.4.2.1. Marfanksyndrome ................................................................................................ 112
6.4.2.2. Osteogenesiskimperfecta ..................................................................................... 112
6.4.3. Diseaseskduektokmutationskofkreceptorkgenes ........................................................... 112
6.4.3.1. Achondroplasia ................................................................................................... 112
6.4.4. Mutationskofkthekgenekofkakproteinkwithkak yetk unknownkfunction ............................. 113
4
k k k
Summary
Thek bookk containsk thek substancek ofkthek lecturesk andk partlykofk thek practicesk ofkthek subjectk ofk‘
GeneticskandkGenomics’kheldk inkSemmelweiskUniversitykforkmedical,kpharmacologicalkandk de
ntalkstudents.k Thek bookk updatedk ink2016k startskwithkak shortk introductionktok basick geneticskandk
moleculark biologyk andk thenk topicsk fromk humank geneticsk mainlyk fromk medicalk pointk ofkview
s.kSomekofkthek16kchapterskdealkwithkmedicalkgenetics,kbutkthekchapterskalsokintroducektokthekbasi
ckknowledgekofkcellkdivision,kcytogenetics,kepigenetics,kdevelopmentalkgenetics,kstemkcellk biol
ogy,k oncogenetics,k immunogenetics,k populationk genetics,k evolutionk genetics,knutrigeneti
cs,kandktokakrelativeknewksubject,kthekhumankgenomicskandkitskapplicationsk forkthek studyk ofk thek
genomick backgroundk ofk complexk diseases,k pharmacogenomicsk andk fork thekinvestigationk o
fk thek genomek environmentalk interactions.k Ask genomicsk belongsk tok sytemskbiology,kakchapter
kintroducesktokbasicktermskofksystemskbiology,kandk concentratingkonk diseases,ksomekexamplesko
fkthekapplicationkandkutilizationkofkthiskscientifickfieldkarekalsokbekshown.kThekmodernk humank ge
neticsk cank alsok bek associatedk withkseveralk ethical,k socialk andklegalk issues.kThek lastk chapterk o
fk thisk bookk dealsk withk thesek issues.k Atk thek endk ofk eachkchapterk therek arekquestions,k withkwh
ichkthek readersk cankascertainkwhetherk theykunderstoodkand/ork learnedk thekchapter.kBecausekitki
skanke-
book,ksomektermskandkdefinitionskhaskakhyperlinkkforkmorekdetailedkexplanationsk ink thek World
k Widek Web.k Besidesk universitykstudents,k thek bookk isk alsokrecommendedk tok allk thosek wh
ok arek interestedk ink modernkmedicalkgeneticsk andk genomicsk andkwantktokbekup-
tokdatekinktheseksubjects.
Keywords:kMitosis,kmeiosis,kmutations,kcytogenetics,kepigenetics,kMendeliankinheritance,kgene
ticskofksex,kdevelopmentalkgenetics,kstemkcellkbiology,koncogenetics,kimmunogenetics,khumankg
enomics,kgenomicskofkcomplexkdiseases,kgenomickmethods,kpopulationkgenetics,kevolutionkgene
tics,kpharmacogenomics,knutrigenetics,kgenekenvironmentalkinteraction,k systemskbiology,kbioet
hics.
,COPYRIGHT:kAndráskFalus,kValériakLászló,kFerenckOberfrank,kErnakPap,kCsabakSzalai,kSárakTó
th,kBudapestkUniversitykofkTechnologykandkEconomics
CreativekCommonskNonCommercial-NoDerivsk3.0k(CCkBY-NC-NDk3.0)
Thiskworkkcankbekreproduced,kcirculated,kpublishedkandkperformedkforknon-
commercialkpurposeskwithoutkrestrictionkbykindicatingkthekauthor'skname,kbutkitkcannotkbekm
odified.
Lector:kViktorkMolnár,kMD,kheadkofkCsertexkResearchkLaboratory
ISBNk978k963k279k187k6
PreparedkunderkthekeditorshipkofkTypotexkKiadókRes
ponsiblekmanager:kVotiskykZsuzsa
MadekwithinkthekframeworkkofkthekprojectkNr.kTÁMOP-4.1.2/A/1-11/1-2011-0079,kentitled
„Konzorciumkakbiotechnológiakéskbioinformatikakaktívktanulásáért”.
2
,Content
1. Basickgeneticskandkmolecularkbiology ................................................................................. 9
1.1. Basickgenetics ................................................................................................................. 9
1.2. Mendeliankinheritance..................................................................................................... 9
1.2.1.1. Dominant-recessivekinheritance ............................................................................ 10
1.2.2. Polygenickinheritance ................................................................................................ 10
1.2.3. Genetickpleiotropy..................................................................................................... 11
1.2.4. Sex-linkedkinheritance .............................................................................................. 11
1.2.5. Linkedkinheritance,krecombination ............................................................................ 12
1.2.6. Mutation.................................................................................................................... 13
1.3. Basicskofkmolecularkbiology .......................................................................................... 13
1.3.1. SomekcharacteristicskofkthekhumankDNA................................................................... 14
1.3.2. Replication ................................................................................................................ 17
1.3.3. Transcription ............................................................................................................. 18
1.3.4. Structurekofkthekgenes ................................................................................................ 18
1.3.5. Thekgenetickcode ....................................................................................................... 19
1.3.6. Translation ................................................................................................................ 20
2. Transmissionkofkgenetickinformation ............................................................................. 22
2.1. Cellkcyclekandkregulationkofkcellkcycle ....................................................................... 22
2.1.1. G0k-kG1ktransition ................................................................................................... 23
2.1.2. G1k–kSktransition,kS-phase ...................................................................................... 25
2.1.3. G2k–kMktransition ................................................................................................... 26
2.1.4. M-phase ................................................................................................................ 27
2.1.4.1. Chromosomekstructure ...................................................................................... 29
2.1.4.2. Structurekandkrolekofkmitotickspindle ................................................................. 32
2.1.4.3. Metaphasek–kanaphasektransition ....................................................................... 35
2.1.5. Cytokinesis ........................................................................................................... 37
2.1.6. Operationkofkcellkcyclekcheckpoints....................................................................... 37
2.2. Chromosomekterritories............................................................................................. 39
2.3. Meiosis ..................................................................................................................... 41
2.3.1. Phaseskofkmeiosis .................................................................................................. 42
2.3.2. Oogenesis.............................................................................................................. 46
2.3.3. Spermatogenesis ................................................................................................... 47
2.3.4. Regulationkofkmeiosis ........................................................................................... 50
3.1. Mutationkandkpolymorphism ......................................................................................... 52
3.2. Thekclassificationkofkmutations ..................................................................................... 53
3.3. Genekmutations ............................................................................................................. 55
3.4. DNAkrepair ................................................................................................................... 61
3.5. Mutagenicityktests ......................................................................................................... 64
3.6. Nomenclaturekofkthekgenetickvariants ............................................................................ 65
3.6.1. Levelskofkvariations ................................................................................................... 65
3.6.2. Positionskofkthekvariations ......................................................................................... 66
3.6.3. Specifickchanges ....................................................................................................... 67
3.7. Usefulkweb-sites ............................................................................................................ 67
3.8. Questions ...................................................................................................................... 68
4. Cytogenetics ..................................................................................................................... 69
4.1. Structuralkchromosomekaberrations............................................................................... 70
4.1.1. Deletions ................................................................................................................... 71
4.1.2. Duplications .............................................................................................................. 71
4.1.3. Translocations ........................................................................................................... 72
3
, 4.1.3.1. Reciprocalktranslocations ...................................................................................... 72
4.1.4. Inversions.................................................................................................................. 74
4.1.5. Ringk(ring)kchromosome ........................................................................................... 75
4.1.6. Isochromosome ......................................................................................................... 75
4.1.7. Dicentrickchromosome .............................................................................................. 79
4.1.8. Acentrickfragment ..................................................................................................... 80
4.2. Numericalkchromosomekaberrations.............................................................................. 80
4.2.1. Euploidkchromosomekmutations................................................................................ 80
4.2.2. Aneuploidkchromosomalkaberrations ........................................................................ 81
4.2.3. Thekmostkcommonknumericalkchromosomalkabnormalities ....................................... 83
4.2.3.1. Trisomyk21 ............................................................................................................ 84
4.2.3.2. Trisomyk13 ............................................................................................................ 85
4.2.3.3. Trisomyk18 ............................................................................................................ 85
4.2.4. Numericalksexkchromosomekaberrations ................................................................... 85
4.2.4.1. Turnerksyndrome ................................................................................................... 85
4.2.4.2. Klinefelterksyndrome ............................................................................................ 86
4.2.4.3. TriplekXksyndrome ................................................................................................ 86
4.2.4.4. Double-Yksyndrome,k"superman"korkJacobsksyndrome ......................................... 86
4.3. Uniparentalkdisomyk(UPD) ........................................................................................... 87
4.4. Mixoploidkmutations ..................................................................................................... 87
4.4.1. Mosaicism ................................................................................................................. 88
4.4.2. Chimerism ................................................................................................................ 88
4.5. Usefulk web-sites ........................................................................................................... 89
4.6. Questions ...................................................................................................................... 89
5. Epigenetics ........................................................................................................................ 91
5.1. Epigenetickchangesk-kmolecularkmodifications .............................................................. 91
5.1.1. DNAkmethylation ...................................................................................................... 92
5.1.2. CpGkaskmutationkhotkspot .......................................................................................... 92
5.1.3. Histonekmodifications ............................................................................................... 93
5.2. Non-codingkRNAs ........................................................................................................ 94
5.3. Epigenetickphenomena .................................................................................................. 94
5.3.1. X-chromosomekinactivation ...................................................................................... 94
5.3.2. Genomickimprinting .................................................................................................. 96
5.3.2.1. Imprintingkrelatedkdiseases.................................................................................... 97
5.3.2.2. Evolutionaryktheorieskofkimprinting ...................................................................... 98
5.4. Theksignificancekofkepigenetickeffects ........................................................................... 98
5.5. Usefulkweb-sites .......................................................................................................... 101
5.6. Questions .................................................................................................................... 101
6. MendeliankInheritance:kautosomalkinheritance................................................................ 102
6.1. Introduction................................................................................................................. 102
6.2. Interpretationkofksomekbasickgenetickterms .................................................................. 104
6.3. Phenomenakthatkfine-tunekclassicalkmonogenickinheritance ........................................ 106
6.4. Autosomalkdominantkinheritance ................................................................................ 110
6.4.1. Generalkcharacteristicskofkautosomalkdominantk(AD)kinheritance ........................... 110
6.4.2. Diseaseskduektokthekmutationkofkstructuralkgenes ..................................................... 112
6.4.2.1. Marfanksyndrome ................................................................................................ 112
6.4.2.2. Osteogenesiskimperfecta ..................................................................................... 112
6.4.3. Diseaseskduektokmutationskofkreceptorkgenes ........................................................... 112
6.4.3.1. Achondroplasia ................................................................................................... 112
6.4.4. Mutationskofkthekgenekofkakproteinkwithkak yetk unknownkfunction ............................. 113
4
