The Genom of Homo sapiens.pdf

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High-resolution Human Genome Scanning UsingWhole-genome BAC ArraysJ. LI,* T. JIANG,* B. BEJJANI, † E. RAJCAN-SEPAROVIC, ‡ AND W.-W. CAI**Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030;† Basic Medical Sciences Program, Washington State University Spokane Health Research and EducationCenter, Spokane, Washington 99210-1495; ‡ Department of Pathology, University of British Columbia,Vancouver, V6H 3V4, British ColumbiaConstitutional chromosome abnormalities are a frequentcause of many human syndromes, such as infertility,congenital anomalies, and mental retardation (Gardnerand Sutherland 1996). Cytogenetic analysis ofchromosomal integrity in patients with mental retardation(MR) indicates that 40% of severe (IQ
324 LI ET AL.Figure 1. Array-based CGH to detect copynumber variations. Cloned DNA samples representingdifferent genomic regions are printed onglass surfaces to make microarrays. Test andnormal control genomic DNA is differentiallylabeled with dye-labeled nucleotides and co-hybridizedto the arrays. The copy number variationsalong a chromosome are represented bythe fluorescence ratios of test DNA to controlDNA different from 1 (usually 1.2 is consideredas a cutoff for gain, and 0.8 as a cutoff for loss).Large clones, mostly available as BACs, are preferred formaking CGH arrays because they give good sensitivity,and information on mapped clones is easily accessible inthe human genome databases (http://genome.ucsc.edu/;http://genome.wustl.edu/projects/human/). cDNA arrayshave been demonstrated to be useful for CGH (Pollack etal. 1999; Heiskanen et al. 2000; Beheshti et al. 2003) buthave several limitations which make them less attractivefor detection of DNA copy number changes. First, theydo not generate sufficient sensitivity for complex genomicprobes because of their small size (0.5–3 kb).cDNA clones normally generate hybridization signals30–80 times weaker than BAC clones for human ormouse genomic probes. This lack of sensitivity requiresan additional signal amplification step (Heiskanen et al.2000). Second, large genomic regions sparsely coveredby cDNA clones will give poor resolution, and those genomicregions lacking genes will not be probed at all. Ouranalysis of the complete genomic sequence indicates thata total of 620-Mb euchromatic genomic sequences belongin regions larger than 500 kb without any annotatedgene. These gene-barren regions may contain long-rangegenomic regulatory elements such as locus control regions,the deletion of which will affect multiple genes.Third, for applications that require high-level amplificationof genomic DNA probes, amplification bias willmore likely cause inaccurate copy number detection withcDNA arrays than BAC arrays because the larger size ofBACs is more effective in averaging out amplificationbias.One apparent disadvantage of using BAC clones forCGH-based detection of DNA copy number changes isthat some BACs contain significant amounts of repetitivesequences. Highly repetitive sequences in BACs can usuallybe effectively suppressed by Cot I DNA blocking.The most problematic BAC clones, however, are thosecontaining high levels of low-copy repeats or similarcross-hybridizing sequences. These clones, in theory,will show false-positive or false-negative gains andlosses, respectively (Fig. 2). If, for example, a genomicregion is gained in the patient, false-positive gains arealso caused by cross-hybridization of DNA from this regionto other homologous regions in the genome. On theother hand, cross-hybridization may generate false-negativebut not false-positive loss detection. False-negativeloss detection is a major limitation that reduces the realresolution of BAC arrays, making some small genomicregions noninformative. A complete solution for theFigure 2. Models of false-positive and -negativedetection caused by cross-hybridization. (A)Cross-hybridization causing false-positive gains.Gain of sequences in region a in the test samplecan spill to cross-hybridizing regions b and c,causing false-positive gain detection in b and c.(B) Although real loss of sequences in region aexists, it is not detected due to partial or completecross-hybridization of sequences from regions band c, causing false-negative loss detection in regiona.
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ForewordIn 2001, as we considered t
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The Finished Genome Sequence of Hom
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4 ROGERSFigure 2. Accumulation of h
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6 ROGERSFigure 4. Sequencing center
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8 ROGERSabcFigure 5. Ensembl view o
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10 ROGERS2000. Analysis of vertebra
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The Human Genome: Genes, Pseudogene
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VARIATION ON CHROMOSOME 7 15rived f
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VARIATION ON CHROMOSOME 7 17DNAs an
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VARIATION ON CHROMOSOME 7 19expecte
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VARIATION ON CHROMOSOME 7 21Drosoph
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Mutational Profiling in the Human G
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HUMAN MUTATIONAL PROFILING 25Anothe
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HUMAN MUTATIONAL PROFILING 27Figure
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HUMAN MUTATIONAL PROFILING 29Rieder
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32 SCHMUTZ ET AL.algorithm itself,
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34 SCHMUTZ ET AL.Figure 2. Genomic
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36 SCHMUTZ ET AL.compared. Some of
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Human Subtelomeric DNAH. RIETHMAN,
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HUMAN SUBTELOMERIC SEQUENCES 41The
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HUMAN SUBTELOMERIC SEQUENCES 43cate
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HUMAN SUBTELOMERIC SEQUENCES 45Figu
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HUMAN SUBTELOMERIC SEQUENCES 47pres
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50 COLLINSand expand the genomics r
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52 COLLINSFigure 2. A public-sector
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54 COLLINSdefine all the parts of t
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56 BENTLEYmon over many generations
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58 BENTLEYTable 1. Genetic Disease
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60 BENTLEY(Clark et al. 1998; Reich
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62 BENTLEYACKNOWLEDGMENTSThe author
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SNP Genotyping and Molecular Haplot
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GENETIC ANALYSIS OF DNA POOLS 67gen
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70 FAN ET AL.matrix is then mated t
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72 FAN ET AL.Figure 3. Views of gen
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74 FAN ET AL.including 32 duplicate
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76 FAN ET AL.Figure 7. Allele-speci
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78 FAN ET AL.microsphere-based assa
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80 BERTRANPETIT ET AL.function, may
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82 BERTRANPETIT ET AL.diversity in
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84 BERTRANPETIT ET AL.gree of block
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86 BERTRANPETIT ET AL.Figure 1. Dec
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88 BERTRANPETIT ET AL.1999. Populat
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90 WINDEMUTH ET AL.Expression data.
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92 WINDEMUTH ET AL.Table 1. A Summa
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94 WINDEMUTH ET AL.Table 2. Signifi
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96 WINDEMUTH ET AL.Table 3. Summary
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98 WINDEMUTH ET AL.Table 6. List of
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100 WINDEMUTH ET AL.Table 6. (Conti
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102 WINDEMUTH ET AL.Table 6. (Conti
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104 WINDEMUTH ET AL.much of a surpr
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106 WINDEMUTH ET AL.Given our resul
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Genetic Variation and the Control o
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GENETIC CONTROL OF TRANSCRIPTION 11
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GENETIC CONTROL OF TRANSCRIPTION 11
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Genome-wide Detection and Analysis
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RECENT SEGMENTAL DUPLICATIONS 117Fi
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RECENT SEGMENTAL DUPLICATIONS 119St
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RECENT SEGMENTAL DUPLICATIONS 121Co
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RECENT SEGMENTAL DUPLICATIONS 123Ho
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The Effects of Evolutionary Distanc
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EVOLUTIONARY DISTANCE AND GENE PRED
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EVOLUTIONARY DISTANCE AND GENE PRED
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Lineage-specific Expansion of KRAB
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EVOLUTION OF ZNF GENES 133Figure 2.
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EVOLUTION OF ZNF GENES 135Figure 4.
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EVOLUTION OF ZNF GENES 137get gene,
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EVOLUTION OF ZNF GENES 139Y., Goodw
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Sequence Organization and Functiona
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CENTROMERE ANNOTATION 143THE CENTRO
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CENTROMERE ANNOTATION 145Figure 4.
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CENTROMERE ANNOTATION 147CONCLUSION
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CENTROMERE ANNOTATION 149Schueler M
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152 PARKHILL AND THOMSONFigure 1. T
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154 PARKHILL AND THOMSONshow very h
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156 PARKHILL AND THOMSONGene Loss a
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158 PARKHILL AND THOMSONYersinia ad
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160 MCKAY ET AL.Choosing Candidate
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162 MCKAY ET AL.new comparative too
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164 MCKAY ET AL.rich. Based on a th
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166 MCKAY ET AL.Embryonic Muscle an
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168 MCKAY ET AL.native polyadenylat
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Building Comparative Maps Using 1.5
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HUMAN CHROMOSOME 1p IN THE DOG 1731
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HUMAN CHROMOSOME 1p IN THE DOG 175(
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HUMAN CHROMOSOME 1p IN THE DOG 177l
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180 GEORGES AND ANDERSSON5. There i
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182 GEORGES AND ANDERSSONplied to r
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184 GEORGES AND ANDERSSONbe common
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186 GEORGES AND ANDERSSONin humans
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Evolving Methods for the Assembly o
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ASSEMBLING LARGE GENOMES 191Figure
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ASSEMBLING LARGE GENOMES 193tant ad
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Mouse Genome Encyclopedia ProjectY.
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MOUSE GENOME ENCYCLOPEDIA PROJECT 1
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DNA Sequence Assembly and Multiple
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EULERIAN ASSEMBLY AND MULTIPLE ALIG
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Ensembl: A Genome InfrastructureE.
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ENSEMBL 215projects often submit th
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218 ZHANGthe majority of these are
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220 ZHANGFigure 2. Demonstration of
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222 ZHANG(G.X. Chen et al., in prep
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224 ZHANGWe are waiting for experim
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Ontologies for Biologists: A Commun
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ONTOLOGIES FOR BIOLOGISTS 229al. 20
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ONTOLOGIES FOR BIOLOGISTS 231TOPIC
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ONTOLOGIES FOR BIOLOGISTS 233a.b.Fi
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ONTOLOGIES FOR BIOLOGISTS 2352003.
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238 JOSHI-TOPE ET AL.Figure 1. The
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240 JOSHI-TOPE ET AL.state of knowl
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242 JOSHI-TOPE ET AL.and co-immunop
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The Share of Human Genomic DNA unde
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DNA UNDER SELECTION FROM HUMAN-MOUS
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Detecting Highly Conserved Regions
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DETECTING MULTISPECIES CONSERVED SE
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266 ROE ET AL.noncoding regions. On
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268 ROE ET AL.a48 hpf embryos in Mi
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270 ROE ET AL.aNovel gene KIAA0819[
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Page 283 and 284: 276 JAILLON ET AL.Detection of Evol
Page 285 and 286: 278 JAILLON ET AL.Table 1. Distribu
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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
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Page 302 and 303: EVOLUTION OF EUKARYOTIC GENES AND I
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Page 311 and 312: 304 PENNACCHIO, BAROUKH, AND RUBINA
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Page 318: High-Throughput Mouse Knockouts Pro
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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 332 and 333: HUMAN GENOME SCANNING 325false-posi
Page 334 and 335: HUMAN GENOME SCANNING 327affecting
Page 336: HUMAN GENOME SCANNING 329methods fo
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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
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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
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374 MCCALLION ET AL.Figure 1. Schem
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376 MCCALLION ET AL.lier (Carrasqui
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378 MCCALLION ET AL.Table 3. HSCR A
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380 MCCALLION ET AL.Figure 3. Trans
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Genetics of Schizophrenia and Bipol
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SCHIZOPHRENIA AND BIPOLAR AFFECTIVE
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The Genetics of Common Diseases: 10
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GENETICS OF COMMON DISEASES 397with
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GENETICS OF COMMON DISEASES 399SELE
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GENETICS OF COMMON DISEASES 401F.,
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404 CHEUNG ET AL.netic analysis. Ex
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406 CHEUNG ET AL.Figure 3. The expr
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Regulation of α-Synuclein Expressi
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α-SYNUCLEIN EXPRESSION AND PD 411T
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1. The levels of α-synuclein prote
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α-SYNUCLEIN EXPRESSION AND PD 415g
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418 BOTSTEINFigure 1. (A) Blectron
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420 BOTSTEINFigure 3. Cluster diagr
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422 BOTSTEINFigure 6. Kaplan-Meier
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424 BOTSTEINGarber M.E., Troyanskay
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426 ANTONARAKIS ET AL.1316192225283
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428 ANTONARAKIS ET AL.Figure 5. Sam
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430 ANTONARAKIS ET AL.POPULATION VA
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432 JORGENSEN ET AL.tive small mole
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434 JORGENSEN ET AL.FLAG-tagged pro
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436 JORGENSEN ET AL.visualization t
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438 JORGENSEN ET AL.AArp2/3 Complex
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Pathway40S440 JORGENSEN ET AL.ANutr
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442 JORGENSEN ET AL.Giaever G., Chu
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Genomic Disorders: Genome Architect
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GENOME ARCHITECTURE AND GENOMIC DIS
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Human Versus Chimpanzee Chromosome-
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HUMAN VS. CHIMP CHROMOSOME COMPARIS
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HUMAN VS. CHIMP CHROMOSOME COMPARIS
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Novel Transcriptional Units and Unc
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TRANSCRIPTIONAL UNITS AND GENE PAIR
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mtDNA Variation, Climatic Adaptatio
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mtDNA VARIATION 473Figure 3. Region
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ANALYSIS OF ADAPTIVE SELECTION FORR
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mtDNA VARIATION 477Figure 8. Temper
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Positive Selection in the Human Gen
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HUMAN-SPECIFIC EVOLUTIONARY CHANGES
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488 UNDERHILLorigin episodes, each
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490 UNDERHILLhaplogroups C through
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492 UNDERHILLO (Fig. 2e) that share
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The New Quantitative BiologyM.V. OL
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NEW QUANTITATIVE BIOLOGY 497alone.
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NEW QUANTITATIVE BIOLOGY 499There w
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NEW QUANTITATIVE BIOLOGY 501ceded,
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