The Genom of Homo sapiens.pdf

More documents

Recommendations

Info

GENOMIC VARIATION IN MULTIGENIC TRAITS: HSCR 379Figure 2. Identification of conserved coding and noncoding sequences at the RET gene. VISTA pair-wise analysis, aligning 73 kb encompassinghuman RET with orthologous sequence from the mouse. (Blue) Exons; (pink) noncoding multispecies conserved (MCS;70% identity over ≥100 bp). Repeats are indicated by colored boxes above the plot with a color key embedded in the lower right corner,indicating their identity. Sequence identity is displayed in the 50–100% range.scripts (Ret +/+ ; Ednrb +/+ versus Ret +/+ ; Ednrb s-l/s ) whoselevels differ significantly (p
380 MCCALLION ET AL.Figure 3. Transcript profiling in the postnatal intestinal tracts ofmice wild-type and mutant for key HSCR genes. (A) Table ofgenotypes and genders of animals whose colon RNA profileswere interrogated on transcript profiling microarrays. (B) Geneswhose orthologs localize to human chromosome 21 and are dysregulatedin HSCR mutant mice compared to wild type. Also reportedare p values for these comparisons and cytogenetic positionsfor each gene. (C) Examples of semi-quantitative RT-PCRassays used to confirm the differential expression observed in ourarray comparisons. W, Ret +/+ ; Ednrb +/+ ; A, Ret +/– ; Ednrb s-l/s ; C,non RT control.has been implicated in the degeneration of neuronal populations(Rosen et al. 1993; Tu et al. 1996), and overexpressionof this key protein has been shown to impede thedimerization of RET receptor tyrosine kinase (Kato et al.2000). We have used semi-quantitative RT-PCR assaysto confirm the differential expression observed in our arraycomparisons (Fig. 3). In light of the elevated incidenceof HSCR among individuals with Down syndrome,we considered this observation to be particularly significant.We hypothesize that increased dosage of genes containedwithin human Chromosome 21 may compromiseENS integrity and/or increase susceptibility to variants atother HSCR loci.DISCUSSIONObservations on phenotypic resemblance between relativesclearly show that most traits are inherited but thatthe patterns are decidedly non-Mendelian. Thus,Mendelian inheritance of traits is the exception ratherthan the rule. However, it is not clear why any phenotypeshould be genetically complex. Is this simply a result ofmultiple gene segregation? Does the nature and effect ofthe underlying mutation matter? Which properties of agene render its mutations likely to contribute to non-Mendelian patterns of inheritance? In other words, themajor question in human disease genetics is, Why complexinheritance? Before we can answer this with anygenerality, we must first decipher the molecular details ofa number of complex traits and disorders.The choice of these traits is critical. There is currentlygreat interest in understanding the genetic basis of manycommon and chronic diseases of humans. This is crucial,because the disease and economic burdens of these disordersare immense. However, studying a number of modeldisorders in which genetic dissection is currently feasibleis just as important. We have selected HSCR as an exampleof a complex disease in which one may constructtractable questions. A key component in elucidating thegenetic basis of non-Mendelian disorders is an understandingof the nature of genetic variation in outbred populations,such as humans. As in nature, the mutations thatjointly contribute to HSCR include variants at multiplegenes encoding different components of an integratedpathway(s). Mutations therein may independently lead todisease but most frequently require contributions from(and interaction with) mutations in other genes. Thesevariants run the gamut of simple nucleotide substitutionsto larger insertions/deletions and chromosomal rearrangements,indicating that differences in both the qualityand quantity of gene product play a critical role in diseaseexpression. Consistent with this observation,non-Mendelian inheritance patterns may also arise fromnontraditional methods of gene action, including imprintingmutations and the dynamic expansion of a coding sequence(e.g., triplet repeats). Furthermore, different geneticeffects of Watson and Crick sister strands may alsolead to profoundly different, non-Mendelian phenotypes(Klar 1996). Thus, non-Mendelian should not necessarilybe equated with multiple gene inheritance. These hypothesesmay be distinguished using genomic approaches.However, our studies suggest that a comprehensiveunderstanding of a complex disease will notresult from a monolithic “genome scan” but will requireintegrated analyses, scanning the entire genome for substitutionalmutations, insertion/deletion mutations, genedosage changes, and/or gene expression changes at thelevel of RNA and protein. Importantly, scanning forchanges in specific chemical modifications of thegenome (e.g., methylation of DNA) will also be required.An important characteristic of Mendelian disease is thehigh correlation between the mutation and phenotype, althoughother aspects of the phenotype (severity, onset,etc.) may not be as predictable based on the mutationtype. Conversely, for complex disorders, proving that aset of genes thought to be necessary and sufficient for diseaseonset is difficult in humans. However, this has to beproven in animal or cellular model systems. Indeed, synthesisof the complex trait from the constituent gene mutationsis an absolute necessity in complex disease research.In other words, the genetic dissection of acomplex trait should be considered incomplete in the absenceof trait synthesis. HSCR has proven this pointclearly.
Page 6 and 7:
ForewordIn 2001, as we considered t
Page 8:
The Finished Genome Sequence of Hom
Page 11 and 12:
4 ROGERSFigure 2. Accumulation of h
Page 13 and 14:
6 ROGERSFigure 4. Sequencing center
Page 15 and 16:
8 ROGERSabcFigure 5. Ensembl view o
Page 17 and 18:
10 ROGERS2000. Analysis of vertebra
Page 20 and 21:
The Human Genome: Genes, Pseudogene
Page 22 and 23:
VARIATION ON CHROMOSOME 7 15rived f
Page 24 and 25:
VARIATION ON CHROMOSOME 7 17DNAs an
Page 26 and 27:
VARIATION ON CHROMOSOME 7 19expecte
Page 28 and 29:
VARIATION ON CHROMOSOME 7 21Drosoph
Page 30 and 31:
Mutational Profiling in the Human G
Page 32 and 33:
HUMAN MUTATIONAL PROFILING 25Anothe
Page 34 and 35:
HUMAN MUTATIONAL PROFILING 27Figure
Page 36:
HUMAN MUTATIONAL PROFILING 29Rieder
Page 39 and 40:
32 SCHMUTZ ET AL.algorithm itself,
Page 41 and 42:
34 SCHMUTZ ET AL.Figure 2. Genomic
Page 43 and 44:
36 SCHMUTZ ET AL.compared. Some of
Page 46 and 47:
Human Subtelomeric DNAH. RIETHMAN,
Page 48 and 49:
HUMAN SUBTELOMERIC SEQUENCES 41The
Page 50 and 51:
HUMAN SUBTELOMERIC SEQUENCES 43cate
Page 52 and 53:
HUMAN SUBTELOMERIC SEQUENCES 45Figu
Page 54:
HUMAN SUBTELOMERIC SEQUENCES 47pres
Page 57 and 58:
50 COLLINSand expand the genomics r
Page 59 and 60:
52 COLLINSFigure 2. A public-sector
Page 61 and 62:
54 COLLINSdefine all the parts of t
Page 63 and 64:
56 BENTLEYmon over many generations
Page 65 and 66:
58 BENTLEYTable 1. Genetic Disease
Page 67 and 68:
60 BENTLEY(Clark et al. 1998; Reich
Page 69 and 70:
62 BENTLEYACKNOWLEDGMENTSThe author
Page 72 and 73:
SNP Genotyping and Molecular Haplot
Page 74:
GENETIC ANALYSIS OF DNA POOLS 67gen
Page 77 and 78:
70 FAN ET AL.matrix is then mated t
Page 79 and 80:
72 FAN ET AL.Figure 3. Views of gen
Page 81 and 82:
74 FAN ET AL.including 32 duplicate
Page 83 and 84:
76 FAN ET AL.Figure 7. Allele-speci
Page 85 and 86:
78 FAN ET AL.microsphere-based assa
Page 87 and 88:
80 BERTRANPETIT ET AL.function, may
Page 89 and 90:
82 BERTRANPETIT ET AL.diversity in
Page 91 and 92:
84 BERTRANPETIT ET AL.gree of block
Page 93 and 94:
86 BERTRANPETIT ET AL.Figure 1. Dec
Page 95 and 96:
88 BERTRANPETIT ET AL.1999. Populat
Page 97 and 98:
90 WINDEMUTH ET AL.Expression data.
Page 99 and 100:
92 WINDEMUTH ET AL.Table 1. A Summa
Page 101 and 102:
94 WINDEMUTH ET AL.Table 2. Signifi
Page 103 and 104:
96 WINDEMUTH ET AL.Table 3. Summary
Page 105 and 106:
98 WINDEMUTH ET AL.Table 6. List of
Page 107 and 108:
100 WINDEMUTH ET AL.Table 6. (Conti
Page 109 and 110:
102 WINDEMUTH ET AL.Table 6. (Conti
Page 111 and 112:
104 WINDEMUTH ET AL.much of a surpr
Page 113 and 114:
106 WINDEMUTH ET AL.Given our resul
Page 116 and 117:
Genetic Variation and the Control o
Page 118 and 119:
GENETIC CONTROL OF TRANSCRIPTION 11
Page 120 and 121:
GENETIC CONTROL OF TRANSCRIPTION 11
Page 122 and 123:
Genome-wide Detection and Analysis
Page 124 and 125:
RECENT SEGMENTAL DUPLICATIONS 117Fi
Page 126 and 127:
RECENT SEGMENTAL DUPLICATIONS 119St
Page 128 and 129:
RECENT SEGMENTAL DUPLICATIONS 121Co
Page 130 and 131:
RECENT SEGMENTAL DUPLICATIONS 123Ho
Page 132 and 133:
The Effects of Evolutionary Distanc
Page 134 and 135:
EVOLUTIONARY DISTANCE AND GENE PRED
Page 136 and 137:
EVOLUTIONARY DISTANCE AND GENE PRED
Page 138 and 139:
Lineage-specific Expansion of KRAB
Page 140 and 141:
EVOLUTION OF ZNF GENES 133Figure 2.
Page 142 and 143:
EVOLUTION OF ZNF GENES 135Figure 4.
Page 144 and 145:
EVOLUTION OF ZNF GENES 137get gene,
Page 146 and 147:
EVOLUTION OF ZNF GENES 139Y., Goodw
Page 148 and 149:
Sequence Organization and Functiona
Page 150 and 151:
CENTROMERE ANNOTATION 143THE CENTRO
Page 152 and 153:
CENTROMERE ANNOTATION 145Figure 4.
Page 154 and 155:
CENTROMERE ANNOTATION 147CONCLUSION
Page 156:
CENTROMERE ANNOTATION 149Schueler M
Page 159 and 160:
152 PARKHILL AND THOMSONFigure 1. T
Page 161 and 162:
154 PARKHILL AND THOMSONshow very h
Page 163 and 164:
156 PARKHILL AND THOMSONGene Loss a
Page 165 and 166:
158 PARKHILL AND THOMSONYersinia ad
Page 167 and 168:
160 MCKAY ET AL.Choosing Candidate
Page 169 and 170:
162 MCKAY ET AL.new comparative too
Page 171 and 172:
164 MCKAY ET AL.rich. Based on a th
Page 173 and 174:
166 MCKAY ET AL.Embryonic Muscle an
Page 175 and 176:
168 MCKAY ET AL.native polyadenylat
Page 178 and 179:
Building Comparative Maps Using 1.5
Page 180 and 181:
HUMAN CHROMOSOME 1p IN THE DOG 1731
Page 182 and 183:
HUMAN CHROMOSOME 1p IN THE DOG 175(
Page 184:
HUMAN CHROMOSOME 1p IN THE DOG 177l
Page 187 and 188:
180 GEORGES AND ANDERSSON5. There i
Page 189 and 190:
182 GEORGES AND ANDERSSONplied to r
Page 191 and 192:
184 GEORGES AND ANDERSSONbe common
Page 193 and 194:
186 GEORGES AND ANDERSSONin humans
Page 196 and 197:
Evolving Methods for the Assembly o
Page 198 and 199:
ASSEMBLING LARGE GENOMES 191Figure
Page 200 and 201:
ASSEMBLING LARGE GENOMES 193tant ad
Page 202 and 203:
Mouse Genome Encyclopedia ProjectY.
Page 204 and 205:
MOUSE GENOME ENCYCLOPEDIA PROJECT 1
Page 206 and 207:
Page 208 and 209:
Page 210 and 211:
Page 212 and 213:
DNA Sequence Assembly and Multiple
Page 214 and 215:
EULERIAN ASSEMBLY AND MULTIPLE ALIG
Page 216 and 217:
Page 218 and 219:
Page 220 and 221:
Ensembl: A Genome InfrastructureE.
Page 222:
ENSEMBL 215projects often submit th
Page 225 and 226:
218 ZHANGthe majority of these are
Page 227 and 228:
220 ZHANGFigure 2. Demonstration of
Page 229 and 230:
222 ZHANG(G.X. Chen et al., in prep
Page 231 and 232:
224 ZHANGWe are waiting for experim
Page 234 and 235:
Ontologies for Biologists: A Commun
Page 236 and 237:
ONTOLOGIES FOR BIOLOGISTS 229al. 20
Page 238 and 239:
ONTOLOGIES FOR BIOLOGISTS 231TOPIC
Page 240 and 241:
ONTOLOGIES FOR BIOLOGISTS 233a.b.Fi
Page 242:
ONTOLOGIES FOR BIOLOGISTS 2352003.
Page 245 and 246:
238 JOSHI-TOPE ET AL.Figure 1. The
Page 247 and 248:
240 JOSHI-TOPE ET AL.state of knowl
Page 249 and 250:
242 JOSHI-TOPE ET AL.and co-immunop
Page 252 and 253:
The Share of Human Genomic DNA unde
Page 254 and 255:
DNA UNDER SELECTION FROM HUMAN-MOUS
Page 256 and 257:
Page 258 and 259:
Page 260 and 261:
Page 262 and 263:
Detecting Highly Conserved Regions
Page 264 and 265:
DETECTING MULTISPECIES CONSERVED SE
Page 266 and 267:
Page 268 and 269:
Page 270:
Page 273 and 274:
266 ROE ET AL.noncoding regions. On
Page 275 and 276:
268 ROE ET AL.a48 hpf embryos in Mi
Page 277 and 278:
270 ROE ET AL.aNovel gene KIAA0819[
Page 279 and 280:
272 ROE ET AL.aMouseRatAP00354.2 Hu
Page 281 and 282:
274 ROE ET AL.Tautz D. and Pfeifle
Page 283 and 284:
276 JAILLON ET AL.Detection of Evol
Page 285 and 286:
278 JAILLON ET AL.Table 1. Distribu
Page 287 and 288:
280 JAILLON ET AL.Table 3. Distribu
Page 289 and 290:
282 JAILLON ET AL.ecotig is a resul
Page 291 and 292:
284 OVCHARENKO AND LOOTSdivergent r
Page 293 and 294:
286 OVCHARENKO AND LOOTSmodulation
Page 295 and 296:
288 OVCHARENKO AND LOOTSsequencing
Page 297 and 298:
290 OVCHARENKO AND LOOTSments of cl
Page 300 and 301:
Evolution of Eukaryotic Gene Repert
Page 302 and 303:
EVOLUTION OF EUKARYOTIC GENES AND I
Page 304 and 305:
Page 306 and 307:
Page 308:
Page 311 and 312:
304 PENNACCHIO, BAROUKH, AND RUBINA
Page 313 and 314:
306 PENNACCHIO, BAROUKH, AND RUBINh
Page 315 and 316:
308 PENNACCHIO, BAROUKH, AND RUBINA
Page 318:
High-Throughput Mouse Knockouts Pro
Page 321 and 322:
314 FRIDDLE ET AL.screen to lines o
Page 324 and 325:
Identification of Novel Functional
Page 326 and 327:
100 bp ladder68G1168G1168H1168H6100
Page 328 and 329:
FUNCTIONAL ELEMENTS IN HUMAN DNA 32
Page 330 and 331:
High-resolution Human Genome Scanni
Page 332 and 333:
HUMAN GENOME SCANNING 325false-posi
Page 334 and 335:
HUMAN GENOME SCANNING 327affecting
Page 336: HUMAN GENOME SCANNING 329methods fo
Page 339 and 340: 332 MALEK ET AL.Figure 1. The bacte
Page 341 and 342: 334 MALEK ET AL.J., Vincent S., and
Page 343 and 344: 336 HARDISON ET AL.reflect blocks o
Page 345 and 346: 338 HARDISON ET AL.plain the region
Page 347 and 348: 340 HARDISON ET AL.CALIBRATION OF T
Page 349 and 350: 342 HARDISON ET AL.PositionRP2.3noE
Page 351 and 352: 344 HARDISON ET AL.cific chromosoma
Page 353 and 354: 346 WESTON ET AL.these differences
Page 355 and 356: 348 WESTON ET AL.els controlled by
Page 357 and 358: 350 WESTON ET AL.ures prominently i
Page 359 and 360: 352 WESTON ET AL.nal and Bop, which
Page 361 and 362: 354 WESTON ET AL.ablp 1466 bopbcrtB
Page 363 and 364: 356 WESTON ET AL.like fold (Fig. 6)
Page 366 and 367: Implications of Genomics for Public
Page 368 and 369: GENETIC EPIDEMIOLOGY 361lytic epide
Page 370 and 371: GENETIC EPIDEMIOLOGY 363curate risk
Page 372 and 373: A Model System for Identifying Gene
Page 374 and 375: PTC TASTE GENETICS 367Figure 2. Hap
Page 376 and 377: PTC TASTE GENETICS 369Table 2. Hapl
Page 378: PTC TASTE GENETICS 371the emergence
Page 381 and 382: 374 MCCALLION ET AL.Figure 1. Schem
Page 383 and 384: 376 MCCALLION ET AL.lier (Carrasqui
Page 385: 378 MCCALLION ET AL.Table 3. HSCR A
Page 390 and 391: Genetics of Schizophrenia and Bipol
Page 392 and 393: SCHIZOPHRENIA AND BIPOLAR AFFECTIVE
Page 402 and 403: The Genetics of Common Diseases: 10
Page 404 and 405: GENETICS OF COMMON DISEASES 397with
Page 406 and 407: GENETICS OF COMMON DISEASES 399SELE
Page 408: GENETICS OF COMMON DISEASES 401F.,
Page 411 and 412: 404 CHEUNG ET AL.netic analysis. Ex
Page 413 and 414: 406 CHEUNG ET AL.Figure 3. The expr
Page 416 and 417: Regulation of α-Synuclein Expressi
Page 418 and 419: α-SYNUCLEIN EXPRESSION AND PD 411T
Page 420 and 421: 1. The levels of α-synuclein prote
Page 422: α-SYNUCLEIN EXPRESSION AND PD 415g
Page 425 and 426: 418 BOTSTEINFigure 1. (A) Blectron
Page 427 and 428: 420 BOTSTEINFigure 3. Cluster diagr
Page 429 and 430: 422 BOTSTEINFigure 6. Kaplan-Meier
Page 431 and 432: 424 BOTSTEINGarber M.E., Troyanskay
Page 433 and 434: 426 ANTONARAKIS ET AL.1316192225283
Page 435 and 436: 428 ANTONARAKIS ET AL.Figure 5. Sam
Page 437 and 438:
430 ANTONARAKIS ET AL.POPULATION VA
Page 439 and 440:
432 JORGENSEN ET AL.tive small mole
Page 441 and 442:
434 JORGENSEN ET AL.FLAG-tagged pro
Page 443 and 444:
436 JORGENSEN ET AL.visualization t
Page 445 and 446:
438 JORGENSEN ET AL.AArp2/3 Complex
Page 447 and 448:
Pathway40S440 JORGENSEN ET AL.ANutr
Page 449 and 450:
442 JORGENSEN ET AL.Giaever G., Chu
Page 452 and 453:
Genomic Disorders: Genome Architect
Page 454 and 455:
GENOME ARCHITECTURE AND GENOMIC DIS
Page 456 and 457:
Page 458 and 459:
Page 460 and 461:
Page 462 and 463:
Human Versus Chimpanzee Chromosome-
Page 464 and 465:
HUMAN VS. CHIMP CHROMOSOME COMPARIS
Page 466 and 467:
HUMAN VS. CHIMP CHROMOSOME COMPARIS
Page 468 and 469:
Novel Transcriptional Units and Unc
Page 470 and 471:
TRANSCRIPTIONAL UNITS AND GENE PAIR
Page 472 and 473:
Page 474 and 475:
Page 476 and 477:
Page 478 and 479:
mtDNA Variation, Climatic Adaptatio
Page 480 and 481:
mtDNA VARIATION 473Figure 3. Region
Page 482 and 483:
ANALYSIS OF ADAPTIVE SELECTION FORR
Page 484 and 485:
mtDNA VARIATION 477Figure 8. Temper
Page 486 and 487:
Positive Selection in the Human Gen
Page 488 and 489:
HUMAN-SPECIFIC EVOLUTIONARY CHANGES
Page 490 and 491:
Page 492:
Page 495 and 496:
488 UNDERHILLorigin episodes, each
Page 497 and 498:
490 UNDERHILLhaplogroups C through
Page 499 and 500:
492 UNDERHILLO (Fig. 2e) that share
Page 502 and 503:
The New Quantitative BiologyM.V. OL
Page 504 and 505:
NEW QUANTITATIVE BIOLOGY 497alone.
Page 506 and 507:
NEW QUANTITATIVE BIOLOGY 499There w
Page 508 and 509:
NEW QUANTITATIVE BIOLOGY 501ceded,
show all

The Genom of Homo sapiens.pdf

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?