Human Genetic Diversity: Functional Consequences for Health and Disease

0199227691......Page 1
Contents......Page 6
Preface......Page 18
Acknowledgements......Page 20
1.1 Introduction......Page 22
1.2.1 A difference at the protein level between haemoglobin molecules......Page 24
1.2.2 Mendelian inheritance, alleles and traits......Page 27
1.2.3 Sequencing the HBB gene and defining the variant responsible for Hb S......Page 30
1.2.4 Methods of detecting the Hb S DNA sequence variant......Page 45
1.3.1 Structural variants of haemoglobin and the thalassaemias......Page 48
1.3.2 HBB sequence diversity and sickle cell disease......Page 51
1.3.3 Transitions versus transversions......Page 53
1.3.4 Synonymous versus nonsynonymous changes......Page 54
1.3.5 Insertions or deletions may result in frameshift events......Page 56
1.3.6 Deletions, duplications, and copy number variation......Page 57
1.3.7 Gene fusion......Page 58
1.3.8 Sequence variation, RNA splicing, and RNA processing......Page 59
1.3.9 Sequence diversity in noncoding DNA modulating gene expression......Page 61
1.3.11 Mobile DNA elements and chromosomal rearrangements......Page 64
1.3.12 Monosomy and trisomy of the terminal end of chromosome 16p......Page 65
1.4.1 Classifying genetic variation......Page 67
1.4.2 Sequencing the human genome......Page 69
1.4.5 Resequencing diploid human genomes......Page 71
1.6 Reviews......Page 73
2.2.1 Defining linkage......Page 74
2.2.2 Genetic markers......Page 75
2.3 Application of linkage analysis and positional cloning to mendelian diseases......Page 77
2.3.1 Cystic fibrosis and the delta-F508 mutation......Page 80
2.3.2 Treacher Collins syndrome......Page 81
2.3.3 Linkage disequilibrium mapping and mendelian disease......Page 82
2.3.4 Allelic and genetic heterogeneity in mendelian diseases......Page 85
2.4 Genetic association studies and common disease......Page 87
2.4.2 Study design and statistical power......Page 88
2.4.3 Genetic admixture and association with disease......Page 91
2.5 Alzheimer’s disease......Page 93
2.5.1 Early onset familial Alzheimer’s disease: rare variants underlying a mendelian trait......Page 95
2.5.2 APOE ε4 and late onset Alzheimer’s disease......Page 98
2.6 Common and rare genetic variants associated with venous thrombosis......Page 101
2.6.1 Factor V Leiden......Page 102
2.6.2 Genetic diversity and thrombophilia: insights and applications......Page 103
2.7 Summary......Page 104
2.8 Reviews......Page 105
3.2 A historical perspective on cytogenetics......Page 106
3.3.1 Constitutional and somatic variation in chromosome number......Page 110
3.3.3 Polyploidy......Page 111
3.3.5 Monosomy......Page 112
3.4.1 Reciprocal translocations......Page 114
3.4.2 Robertsonian translocations......Page 115
3.5.1 Large scale structural variation resulting from intrachromosomal rearrangements......Page 119
3.5.4 Isochromosomes......Page 120
3.6 Summary......Page 122
3.7 Reviews......Page 124
4.2 Surveys of copy number variation......Page 126
4.2.1 Copy number variation is common within normal populations......Page 127
4.2.2 Towards a global map of copy number variation......Page 129
4.2.3 Finding deletions across the genome within normal human populations......Page 133
4.2.4 Integrating surveys of structural variation......Page 134
4.2.6 Segmental duplications and identifying copy number variation......Page 137
4.3 Copy number variation and gene expression......Page 138
4.4.1 Duplication of the salivary amylase gene and high starch diet......Page 139
4.4.2 Copy number variation and drug metabolism: role of CYP2D6......Page 140
4.5.1 Psoriasis risk and β defensin gene copy number......Page 142
4.5.3 CCL3L1, HIV, and autoimmunity......Page 143
4.6 Summary......Page 144
4.7 Reviews......Page 145
5.2.1 Segmental duplications and genomic disorders......Page 146
5.2.2 Recurrent rearrangements involving chromosome 22q11......Page 147
5.2.3 Reciprocal genomic disorders......Page 149
5.2.4 Non-recurrent genomic disorders......Page 152
5.3 Terminal deletions and subtelomeric disease......Page 153
5.4.2 Copy number variation among cases of mental retardation......Page 157
5.4.3 De novo copy number mutations and autism......Page 159
5.5.1 Inversions may cause severe disease......Page 160
5.5.3 Finding inversions across the human genome......Page 161
5.7 Reviews......Page 162
6.2.1 Segmental duplications are common in the human genome......Page 164
6.2.2 Pericentromeric and subtelomeric regions are hotspots for segmental duplications......Page 165
6.2.5 Segmental duplications in primates and other species......Page 168
6.3.2 Gene creation......Page 169
6.3.4 Evolutionary fate of duplicated genes......Page 171
6.4.1 Olfactory receptor and globin supergene families......Page 172
6.4.2 Models for the evolution of multigene families......Page 173
6.4.3 Immunoglobulin gene families......Page 176
6.5.1 Lessons from the study of the genetics of colour vision......Page 177
6.6 Insertion/deletion polymorphisms: ‘indels’......Page 182
6.6.2 Mapping the extent of indel polymorphism......Page 184
6.7 Summary......Page 186
6.8 Reviews......Page 187
7.2 Satellite DNA......Page 188
7.2.2 Satellite repeats and disease......Page 190
7.3.1 Polymorphic minisatellites......Page 191
7.3.3 Minisatellites and disease: examples from epilepsy and diabetes......Page 192
7.4.1 DNA fingerprinting......Page 194
7.5.2 Classification and occurrence of microsatellites......Page 195
7.5.3 Generation and loss of microsatellite DNA......Page 197
7.5.4 Utility of microsatellite markers......Page 200
7.5.5 Functional consequences of microsatellites......Page 201
7.6 Unstable repeats and neurological disease......Page 203
7.6.1 Trinucleotide repeat expansion and loss of function: lessons from fragile X and Friedreich’s ataxia......Page 205
7.6.2 Polyglutamine disorders......Page 208
7.6.3 Disease resulting from RNA-mediated gain of function: myotonic dystrophy......Page 211
7.7 Summary......Page 212
7.8 Reviews......Page 214
8.1 Introduction......Page 216
8.2 DNA transposons: a fossil record in the genome......Page 219
8.3 L1 retrotransposable elements......Page 220
8.4.2 Consequences of Alu insertions......Page 223
8.5.1 Genetic diversity and human origins......Page 225
8.6 Summary......Page 228
8.7 Reviews......Page 230
9.2 SNPs, association, and genetic susceptibility to common disease......Page 232
9.2.1 Strategic approaches......Page 233
9.2.2 Surveying SNP diversity: lessons from the SNP Consortium and Human Genome Project......Page 234
9.2.3 Haplotype blocks and haplotype tagging SNPs......Page 235
9.2.4 The International HapMap Project......Page 236
9.2.5 Large scale SNP mapping and insights into recombination......Page 242
9.3 Genome-wide association studies......Page 245
9.3.1 Insights into the design, analysis, and interpretation of genome-wide association studies......Page 247
9.3.2 The Wellcome Trust Case Control Consortium study of seven common diseases......Page 251
9.4 Age-related macular degeneration......Page 255
9.4.1 Genome-wide association, linkage, and complement factor H gene......Page 258
9.4.2 Disease association at the 10q26 susceptibility locus......Page 259
9.5.1 A role for inherited factors in inflammatory bowel disease......Page 261
9.5.2 Crohn’s disease and variants of the NOD2 gene......Page 262
9.5.3 Linkage studies and other inflammatory bowel disease susceptibility loci......Page 266
9.5.5 Genetic diversity in IL23R pathway genes and inflammatory bowel disease......Page 269
9.5.6 Autophagy and Crohn’s disease......Page 273
9.5.7 Insights from the Wellcome Trust Case Control Consortium study......Page 274
9.5.8 Gene deserts and other loci......Page 275
9.6 Summary......Page 276
9.7 Reviews......Page 277
10.2 Genetic diversity and evidence of selection......Page 278
10.2.3 Differences in allele frequency......Page 279
10.2.4 Comparisons between species......Page 281
10.3.1 Diversity between the human and chimpanzee genomes......Page 282
10.3.2 Sequencing the rhesus macaque provides new insights into genetic diversity and selection......Page 285
10.4 Lactase persistence......Page 286
10.4.1 Genetic diversity and lactase persistence in European populations......Page 287
10.4.3 Lactase persistence in Middle Eastern populations......Page 290
10.4.4 Diversity within an enhancer region modulating LCT expression......Page 291
10.5.2 Golden zebrafish mutants led to the identification of SLC24A5......Page 292
10.6 Genome-wide analyses......Page 293
10.7 Summary......Page 296
10.8 Reviews......Page 297
11.1 Introduction......Page 298
11.2 Variation in gene expression is common and heritable......Page 299
11.3.1 Genetical genomics......Page 300
11.3.2 Local and distant regulatory variation......Page 301
11.3.3 Genetical genomics and model organisms......Page 302
11.4.1 Insights from lymphoblastoid cell lines......Page 306
11.4.2 Insights into genetic susceptibility to asthma......Page 309
11.4.3 Genetics of gene expression in primary human cells and tissues......Page 312
11.5.1 Allele-specific gene expression among autosomal non-imprinted genes......Page 315
11.5.2 Large scale analysis of allele-specific gene expression......Page 319
11.5.3 Allele-specific expression based on RNA polymerase loading......Page 320
11.6 Genetic variation and alternative splicing......Page 321
11.6.2 Common genetic variation and alternative splicing......Page 322
11.7 Genetic variation: from transcriptome to proteome......Page 324
11.8 Summary......Page 327
11.9 Reviews......Page 328
12.2 MHC genes, the immune response, and disease......Page 330
12.2.1 MHC class I and II molecules......Page 331
12.2.2 Biological complexity among the many genes found in the human MHC......Page 333
12.2.3 Genetic diversity in the MHC and disease: insights from rheumatoid arthritis......Page 334
12.3.1 Infectious disease, selection, and maintenance of MHC polymorphism......Page 337
12.3.3 Abacavir hypersensitivity......Page 338
12.3.4 Extreme polymorphism at HLA-DRB1......Page 339
12.3.5 The MHC Haplotype Project......Page 340
12.4.1 Narcolepsy......Page 342
12.4.2 Coeliac disease......Page 344
12.4.3 Type 1 diabetes......Page 345
12.5 HLA-B27 and susceptibility to ankylosing spondylitis......Page 347
12.6 Genetic variation and haemochromatosis......Page 351
12.7 Many forms of genetic diversity are exhibited by complement C4......Page 354
12.8 A SNP modulating the splicing of the BTNL2 gene is associated with sarcoidosis......Page 358
12.9 Summary......Page 360
12.10 Reviews......Page 361
13.1 Introduction......Page 362
13.2.1 Inherited factors and resistance to malaria......Page 363
13.2.2 Thalassaemia, natural selection and malaria......Page 366
13.2.3 Malaria and structural haemoglobin variants......Page 369
13.2.4 Duffy antigen and vivax malaria......Page 371
13.2.5 Malaria parasites, oxidative stress, and G6PD enzyme deficiency......Page 373
13.2.6 Polymorphism of immune genes......Page 374
13.2.7 Cytoadhesion and immune evasion: host and parasite diversity......Page 378
13.3 Genetic diversity and susceptibility to Leishmaniasis in mouse and man......Page 379
13.4.2 Schistosomiasis and other helminth infections......Page 381
13.5 Summary......Page 384
13.6 Reviews......Page 385
14.1 Introduction......Page 386
14.2.1 Polymorphism of CCR5 and HIV-1 infection......Page 388
14.2.2 Haplotypic structure of the CCR5 locus: evolutionary insights, variation between ethnic groups, and relationship to HIV-1 disease susceptibility......Page 393
14.2.3 Coreceptor ligands and HIV-1......Page 396
14.2.4 Copies count: copy number variation in CCL3L1, a natural ligand of CCR5, and HIV disease......Page 397
14.3.1 Genetic diversity in TRIM5α gives insights into the impact of retroviruses during primate evolution......Page 398
14.3.2 APOBEC3G: an innate host defence mechanism against retroviral infection......Page 401
14.4 Genetic diversity in HLA, KIR, and HIV-1: strategies for survival......Page 402
14.5 Summary......Page 405
14.6 Reviews......Page 406
15.2 Cataloguing human genetic variation......Page 408
15.4 Functional consequences of genetic variation......Page 410
15.5 Medical applications and pharmacogenomics......Page 411
15.6 Lessons from the past, looking to the future......Page 412
C......Page 414
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References......Page 422
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