The Genom of Homo sapiens.pdf

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HUMAN-SPECIFIC EVOLUTIONARY CHANGES 483mans (Gilad et al. 2003), which would be expected toshow increased nonsynonymous substitution, we verifiedthat most of the OR genes in our set are bona fide genes(http://bioinformatics.weizmann.ac.il/HORDE). Our results,suggesting that many of the still active OR genesdisplay a signature of positive selection, are supported bythe observation that there is a discordance between levelsof human polymorphisms in many OR genes from interspecificdivergence (Gilad et al. 2003).Genes involved in amino acid catabolism also show evidenceof adaptive evolution. It is possible that the radicalchange in diet between human and chimps might bepartly responsible for this pattern of divergence. Of theeight protein catabolism genes (GSTZ1, HGD, PAH,BCKDHA, PCCB, HAL, ALDH6A1, AMT) with thelowest Model 2 p-values (http://panther.celera.com/appleraHCM_alignments/index.jsp),all have been implicatedin human metabolic disorders. In fact, there is a significanttendency (p < 0.001, Kolmogorov-Smirnov test)for genes implicated in human Mendelian disorders(http://www.ncbi.nlm.nih.gov/htbin-post/Omim/getmorbid)to exhibit significant (p < 0.01) Model 2 p-values.GENES WITH ATYPICAL SEQUENCEDIVERGENCEOf the 667 genes showing evidence of adaptive evolutionunder Model 2 (p < 0.05), there are several categoriesof genes, such as developmental, hearing, and reproductive,that are particularly interesting considering the physiologicaldifferences between humans and chimps (Table4). Considering the importance and general conservationacross evolution of these traits, it is not surprising that theclasses as a whole do not show adaptive evolution (Fig.3). However, given the important functions of genes inthese classes, each one may account disproportionatelyfor specific phenotypic differences.Most of the human developmental genes that appear toTable 4. Selected Genes Showing Evidence of Adaptive Evolution in the Human LineageModel 2Biological process Gene symbol Gene name p-valueDevelopment ALPL alkaline phosphatase, liver/bone/kidney 3.69E-03BMP4 bone morphogenetic protein 4 2.50E-02CDX4 caudal type homeobox transcription factor 4 1.57E-03DIAPH1 diaphanous homolog 1 (Drosophila) 2.01E-02EPHB6 EphB6 3.53E-02EYA1 eyes absent homolog 1 (Drosophila) 6.49E-03EYA4 eyes absent homolog 4 (Drosophila) 3.48E-03FOXI1 forkhead box I1 2.87E-03FOXP2 forkhead box P2 2.67E-03HOXA5 homeobox A5 2.16E-02HOXD4 homeobox D4 4.55E-03MEOX2 mesenchyme homeobox 2 3.45E-02MGP matrix Gla protein 3.94E-02MIXL1 Mix1 homeobox-like 1 (Xenopus laevis) 4.61E-02MMP20 matrix metalloproteinase 20 (enamelysin) 3.18E-02NEUROG1 neurogenin 1 3.57E-02NLGN3 neuroligin 3 2.80E-02NTF3 neurotrophin 3 8.92E-03OTOR otoraplin 3.46E-02PHTF putative homeodomain transcription factor 1 5.24E-02PLXNC1 plexin C1 5.93E-03POU2F3 POU domain, class 2, transcription factor 3 3.34E-02Development SEMA3B Semaphorin 3B 3.57E-03SIM2 single-minded homolog 2 (Drosophila) 4.57E-02SNAI1 snail homolog 1 (Drosophila) 6.74E-03TECTA tectorin alpha 1.57E-05TLL2 tolloid-like 2 3.28E-03TRAF5 TNF receptor-associated factor 5 6.35E-04WHN winged-helix nude 5.57E-04WIF1 WNT inhibitory factor 1 2.71E-02WNT2 wingless-type MMTV integration site family member 2 2.99E-02Amino acid catabolism ALDH6A1 aldehyde dehydrogenase 6 family, member A1 2.72E-02AMT aminomethyltransferase (glycine cleavage system protein T) 3.45E-02branched chain keto acid dehydrogenase E1αBCKDHA polypeptide 4.64E-03GSTZ1 glutathione transferase ζ 1 (maleylacetoacetate isomerase) 9.04E-04HAL histidine ammonia-lyase 7.18E-03HGD homogentisate 1,2-dioxygenase (homogentisate oxidase) 4.39E-03PAH phenylalanine hydroxylase 7.08E-02PCCB propionyl Coenzyme A carboxylase, beta polypeptide 3.93E-02Reproduction GNRHR gonadotropin-releasing hormone receptor 8.48E-03MTNR1A melatonin receptor 1A 3.97E-02PAPPA pregnancy-associated plasma protein A 8.18E-04PGR progesterone receptor 1.05E-03
484 CLARK ET AL.be under adaptive evolution fall into four main categories:skeletal development, neurogenesis, reproduction,and homeotic transcription factor genes (Table 4).For example, the homeotic transcript factor genes CDX4,HOXA5, HOXD4, MEOX2, POU2F3, MIXL1, andPHTF play key roles in early development and haveModel 2 p-values less than 0.05. TRAF5 plays a key rolein osteoclast proliferation and may be implicated in acceleratedgrowth of the long bones in the leg (Kanazawaet al. 2003). TRAF5 shows adaptive evolution along withsix other skeletal developmental genes. At least 10 genesinvolved in neurogenesis processes, including axonalguidance and synapse remodeling, have low Model 2 p-values. For example, the SIM2 transcription factor hasbeen implicated in human Down syndrome and memorydefects in mice (Chrast et al. 2000). FOXN1, or wingedhelix nude, encodes a transcription factor involved in keratingene expression. Mutations in this gene causeathymia, resulting in a severely compromised immunesystem. Developmental defects in Drosophila andCaenorhabditis elegans are also observed when this geneis mutated. A plausible hypothesis is that the relative hairlessnessof humans compared to chimps is in part determinedby FOXNI. Hypotheses like this are generated inabundance by studies such as this, and an exciting aspectof the work is that such hypotheses are amenable to futuretesting.The anatomy and physiology of reproduction are strikinglydifferent between humans and chimpanzees. Severalgenes involved in pregnancy appear to exhibit nonneutralevolution (Table 4). For example, the progesterone receptor(PGR) is involved with maintenance of the uterus andmay be involved in the acrosome reaction (Gadkar et al.2003). The reproductive hormone receptors GNRHR andMTNR1A also have significant Model 2 p-values.Several genes associated with the development of hearingappear to have undergone adaptive evolution (Table4). α-Tectorin, which shows the most significant Model 2p-value, plays an important role in the tectorial membraneof the inner ear. When it is mutated, humans showhigh-frequency hearing loss (Mustapha et al. 1999) andmouse knockout mice are deaf. Other genes under human-specificselection, DIAPH1, FOXI1, and EYA4,cause hearing loss in humans when mutated.CONCLUSIONSThere has been considerable interest in obtaining thegenome sequence of the chimpanzee, our closest relative,because of the notion that, by comparing our twogenomes, it might be possible to infer which genetic differencesare responsible for the morphological, physiological,and behavioral factors that differentiate us. At 1%sequence divergence, however, we expect there to beroughly 3 million base pairs of sequence difference, andthe discrimination between substitutions that are totallyunimportant and substitutions that are causal to our biologicaldifferences appears to be a steep challenge. Fortunately,the phylogenetic approach offers a promise tomake progress on this problem. With multiple relatedspecies arranged on a phylogenetic tree, models ofmolecular evolution can place the mutations on particularlineages of the tree. This information can be used to inferwhat DNA sequence changes have occurred specificallyalong the lineage subsequent to the node representing ourcommon ancestry with chimpanzee, and reflectingchanges that occurred in our line of descent since thattime. The challenge that remains is that many of thesechanges will have arisen purely because our populationsize is finite, and because random mutations, providedthey are not too deleterious, may go to fixation by randomdrift. It is humbling to consider that potentially a largeportion of the genomic differences between humans andchimps have arisen by such a purely neutral process. Ifone asks, “What are the genes that make us human?”,these random changes may surely be an important class ofgenes that carry this label.In this paper, we apply methods that have been used bymany others to infer which genes have been undergoingpositive or adaptive evolution. The idea is based on therelative rates of substitution at silent (synonymous) and atreplacement (nonsynonymous) nucleotide positions inthe gene. Strictly neutral genes are expected to have equalrates of substitution for these two classes of sites, whilemost genes have some selective constraint and show considerabledeficit of replacement changes. Formal statisticalapproaches allow us to test the null hypothesis that thechanges are compatible with neutrality, and to make quiteincisive tests of alternative hypotheses about the way thatselection has acted (Yang and Nielsen 2002).The application of this inferential approach identified along list of genes for which it is all too easy to tell an evolutionarystory about how these genes are important forhuman–chimp differences. However, it should be emphasizedthat these approaches are strictly exploratory andthat they really only highlight hypotheses to be tested byadditional data collection at several levels. The finding ofpositive selection in genes such as α-tectorin suggeststhat there may be differences in the hearing acuity of humansand chimpanzees, and the data available on the subjectare too sparse to properly address the issue. This motivatesspecific hearing tests of chimpanzees, with theidea that aspects of vocal speech may place additional requirementson hearing not faced by speechless chimpanzees.For every gene cited in this paper, there are additionalexperiments that must be done to solidify theevidence that these genes may be involved inhuman–chimpanzee differences. In the case of significantdifferences in biological processes, the case based onlyon DNA sequences becomes more compelling, mostlybecause each test involves many genes showing aberrant(nonneutral) behavior. That amino acid catabolismshould be a biological process showing rapid adaptiveevolution suggests further research into the physiology ofdigestion of low- versus high-protein diets, and considerationof the differences among primates in diet. Dietarychanges are not the only thing that might be driving thisdifference. Demands on protein synthesis during braindevelopment might be the driver of this signal of past naturalselection. Despite all these uncertainties, and the
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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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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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Page 452 and 453: Genomic Disorders: Genome Architect
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Page 468 and 469: Novel Transcriptional Units and Unc
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Page 484 and 485: mtDNA VARIATION 477Figure 8. Temper
Page 486 and 487: Positive Selection in the Human Gen
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Page 495 and 496: 488 UNDERHILLorigin episodes, each
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Page 504 and 505: NEW QUANTITATIVE BIOLOGY 497alone.
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