The Genom of Homo sapiens.pdf

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TRANSCRIPTIONAL UNITS AND GENE PAIRS 463ABCFigure 1. (A) Genomic complexity at human 5q31: the case of 38I10.TU1. The solid horizontal line at top represents the genomic sequence.5cen is on the left. Arrows indicate the directions of transcription. The complete exon–intron structure is shown only for theTU, not for the known genes. Solid red boxes indicate antisense overlaps. The green vertical line indicates a putative bidirectional promoter.The magenta box indicates same-strand exon sharing. The region between the blue lines is the homology to the 10q21 myopalladingene within the 5q31 genomic sequence. The dotted red box highlights an exon of 38I10.TU1 which is cis-antisense to anupstream ORF homologous to the myopalladin amino terminus and absent from the known TTID sequence. The figure was derivedfrom our SeqHelp-aided manual annotation of genomic clones AC004021, AC073206, AC004820, and AC006084. The ESTs originallyused to define the TU are AL707026, BI755671, AI822067, AI822069, BF238994, BI462983, BF217923, BF977167,AA459981, N66667, N98951, AA805667, BX097833, and BG704696. To allow maximum detail, the drawing is not to scale, althoughrelative coordinates of feature boundaries along the 415-kb genomic interval are indicated. (B) A 1,580-kb interval of 5q31enriched in unconventional gene pairs. 5cen is to the left. Arrows indicate the direction of transcription. Known genes are in blue,EST-supported TUs are in orange, cis-antisense overlaps are in green, and putative bidirectional promoters are in red. To allow maximumdetail, the drawing is not to scale. (C) The distribution of unconventional gene pairs along human chr. 22. The horizontal lineat the bottom represents the chromosome. Each short colored horizontal line represents an island (a region enriched in a particular typeof UGP, as defined by the presence of at least two UGPs and a distance of
464 LIPOVICH AND KINGto-tail antisense to the LOC51306 gene. The KLHL3gene shared two exons in the sense orientation with38I10.TU1 (Fig. 1A). Although the multiple UGPs associatedwith 38I10.TU1 and other genes in the locus wereevident from manual curation of EST-to-genomic alignments,no mention of these UGPs, or of the existence of38I10.TU1, is seen in published analyses of the genomicstructures of genes which we show to be adjacent to oroverlapped by the TU (Godley et al. 1999; Guo et al.2000; Lai et al. 2001).Comparative annotation of the syntenic region in themouse genome was undertaken to determine whether38I10.TU1 has a direct homolog or a positional equivalentin the mouse. The mouse Ttid and Pkd2l2 genes werefound to be 10 Mb from each other due to a local inversionwithin a larger syntenic stretch. This sharply contrastswith the 2-kb distance separating the human orthologsof these genes and precludes the existence of amouse TU that would connect or span the two genes.Along with the major contribution of expressed primatespecificrepeats to the definition of splice junctions andhence exons of 38I10.TU1, these results indicate that theTU, along with its potential impact on expression regulationand structural modification of its multiple overlappingand adjacent coding genes, is likely primate-specific.If true, this would not be the only case of alineage-specific TU simultaneously involved in multipleUGPs (Ohinata et al. 2003).Example 2 was discovered during our annotation of the5q31 protocadherin (PCDH) gene cluster. PCDHs aremembers of the cadherin superfamily, known to representmajor structural and functional components of synapses.Cell-specific combinations of PCDHs are expressed atsynaptic junctions. PCDHs likely account for some of theneuronal combinatorial complexity in both developingand adult brain, affecting brain development and possiblymemory formation (Noonan et al. 2003). Open questionsregarding the mechanism of cell specificity and splicingregulation of PCDH expression remain (Wang et al.2002). Our annotation demonstrated EST support for 8TUs cis-antisense to human PCDH exons (Table 1). In allcases, ESTs comprising the TUs were erroneouslygrouped by UniGene together with the sense-strandPCDH ESTs from the appropriate locus, even thoughtheir antisense nature is clear from a distinct pattern ofEST-to-genomic alignments coupled with unambiguousassignment of GT-AG splice sites and/or canonicalpolyadenylation signals to the strand opposite that fromwhich the PCDH exons are transcribed.Two of the eight anti-PCDH TUs overlap newly pseudogenicPCDH exons inactivated during mammalianevolution, in a fashion reminiscent of that exhibited by38I10.TU1 in its overlap of TTID’s apparently silencedamino-terminal-coding exon. Specifically, the humanPCDHβΨ5 pseudogene, which has an antisense TU, andthe human PCDHβ15 gene are the putative products of alineage-specific duplication of the ancestral PCDHβVgene, which is single-copy in mouse (Vanhalst et al.2001). Similarly, the human PCDHγ variable exon Ψ3,which also has an antisense TU, is pseudogenic, but itsmouse ortholog, Pcdhγ variable exon b8, has an intactORF (Wu et al. 2001). This again suggests a role for cisantisensein gene structure evolution.Lineage specificity of such gene-structure evolution isaccentuated by the absence of equivalents of any humananti-PCDH TUs in the mouse, revealed by manual annotationof all mouse ESTs representing true orthologs ornearest homologs of human PCDH exons. It is highly intriguingthat not only are PCDHs directly relevant to neuronaland behavioral complexity (which is more extensivein mammals, and especially primates, than in anyother animals), but they may also be subject to an antisense-mediatedregulatory mechanism that arose after theprimate–rodent divergence. Such a mechanism would bein agreement with suggestions of species-specific evolutionarypressures on PCDH genes (Vanhalst et al. 2001).Major Properties of UGPs and TUs at 5q31The results of our 5q31 annotation can be summarizedin four major trends. First, the number of EST-supportednovel TUs approximately equals that of known genes.Second, certain genes and TUs are simultaneously involvedin multiple UGPs. Third, UGPs occur more frequentlyin specific genomic intervals and may be nonran-Table 1. Putative Novel Transcriptional Units (TUs) cis-Antisense to Protocadherin (PCDH) Genes at 5q31Human PCDH Mouse Expression Antisense ESTs Exons in humangene or exon Characteristics ortholog human/mouse human/mouse antisense transcriptPCDHα9 variable exon Pcdhα7 + + 10 0 1PCDHα11 variable exon Pcdhα11 + + 1 0 1PCDHα12 variable exon none + na 2 na 1PCDHαc1 variable exon Pcdhαc1 + + 1 0 1PCDHβ3 single-exon gene Pcdhβ3 + + 6 0 2PCDHβ16 single-exon gene Pcdhβ16 + + 4 0 1PCDHΨ5 single-exon unprocessed β-class none – na 16 na 3pseudogenePCDHΨ3 unprocessed γ-class pseudogenic Pcdhγb8 – + 2 0 1variable exonTable was derived from our SeqHelp-aided manual annotation of genomic clones AC005609, AC010223, AC025436, AC008727,AC005618, and AC005366.(na) Not applicable.
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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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272 ROE ET AL.aMouseRatAP00354.2 Hu
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274 ROE ET AL.Tautz D. and Pfeifle
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276 JAILLON ET AL.Detection of Evol
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278 JAILLON ET AL.Table 1. Distribu
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280 JAILLON ET AL.Table 3. Distribu
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282 JAILLON ET AL.ecotig is a resul
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284 OVCHARENKO AND LOOTSdivergent r
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286 OVCHARENKO AND LOOTSmodulation
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288 OVCHARENKO AND LOOTSsequencing
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290 OVCHARENKO AND LOOTSments of cl
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Evolution of Eukaryotic Gene Repert
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EVOLUTION OF EUKARYOTIC GENES AND I
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304 PENNACCHIO, BAROUKH, AND RUBINA
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306 PENNACCHIO, BAROUKH, AND RUBINh
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308 PENNACCHIO, BAROUKH, AND RUBINA
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High-Throughput Mouse Knockouts Pro
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314 FRIDDLE ET AL.screen to lines o
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Identification of Novel Functional
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100 bp ladder68G1168G1168H1168H6100
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FUNCTIONAL ELEMENTS IN HUMAN DNA 32
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High-resolution Human Genome Scanni
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HUMAN GENOME SCANNING 325false-posi
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HUMAN GENOME SCANNING 327affecting
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HUMAN GENOME SCANNING 329methods fo
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332 MALEK ET AL.Figure 1. The bacte
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334 MALEK ET AL.J., Vincent S., and
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336 HARDISON ET AL.reflect blocks o
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338 HARDISON ET AL.plain the region
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340 HARDISON ET AL.CALIBRATION OF T
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342 HARDISON ET AL.PositionRP2.3noE
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344 HARDISON ET AL.cific chromosoma
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346 WESTON ET AL.these differences
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348 WESTON ET AL.els controlled by
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350 WESTON ET AL.ures prominently i
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352 WESTON ET AL.nal and Bop, which
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354 WESTON ET AL.ablp 1466 bopbcrtB
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356 WESTON ET AL.like fold (Fig. 6)
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Implications of Genomics for Public
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GENETIC EPIDEMIOLOGY 361lytic epide
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GENETIC EPIDEMIOLOGY 363curate risk
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A Model System for Identifying Gene
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PTC TASTE GENETICS 367Figure 2. Hap
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PTC TASTE GENETICS 369Table 2. Hapl
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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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Page 422: α-SYNUCLEIN EXPRESSION AND PD 415g
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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
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Page 452 and 453: Genomic Disorders: Genome Architect
Page 454 and 455: GENOME ARCHITECTURE AND GENOMIC DIS
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 472 and 473: TRANSCRIPTIONAL UNITS AND GENE PAIR
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
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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,
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