The Genom of Homo sapiens.pdf

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HUMAN VS. CHIMP CHROMOSOME COMPARISON 457Figure 2. PCR-amplification test of “insertion” and “deletion.” PCR primers were designed according to human sequence, and genomicDNAs of each species were amplified by PCR and analyzed by agarose gel electrophoresis. (Pt) Chimpanzee, (Hs) human, (Gg)gorilla, (Pp) orangutan.moter regions) has some type of genetic change betweenhuman and chimpanzee. An obvious and important questionis, “What are the biological and evolutionary consequencescaused by these genetic changes?” To addressthis question, we checked all the changes in gene regions.Genetic changes that may affect biological functionswere found in more than 30 genes in chimpanzee as comparedwith their human counterparts (Table 2). Thesechanges included premature stop codons, missing startsites, and amino acid insertions or deletions. The biologicalconsequences caused by these changes remain to befurther studied by experimental approaches.Among so many changes, it is of great interest to askwhat types of changes are positively or actively involvedin human (and chimp) evolution. It is known that the ratioof base substitutions that cause amino acid (nonsynonymous)changes (Ka) against base substitutions thatcause synonymous changes (Ks) is correlated to thestrength of evolutionary constraint. A low value of Ka/Ksmeans that the gene evolved under strong constraint. Wecalculated Ka/Ks values of all the genes according to Neiand Gojobori (1986), and found that more than 20 genesshowed high Ka/Ks values of 1.0 or more, suggesting thepossibility that these genes are positively selected duringevolution (Table 3). Interestingly, Table 3 lists three keratin-associatedprotein genes. It is also of interest to notethat 5 out of 10 genes listed in Table 3 are so-called predictedgenes. Those genes may be more free from constraintor poorly predicted. The total number of genes examinedis too small to be statistically significant, but it islikely that some specific types of genes are more freefrom constraint and positively involved in establishingspecies-specific phenotypes.Promoter and Gene ExpressionGenetic changes may cause two types of effects on biologicalprocesses: One is qualitative changes of proteinsand the other is quantitative changes of gene expression(protein production). It has been reported that the geneexpression profiles in human and chimpanzee are significantlydifferent in brain but not so in other tissues examined(Enard et al. 2002). The difference in gene expressionprofiles may be caused by both the difference ofregulatory cis-elements, and the difference of regulatoryTable 3. Genes Showing High Ka/Ks Value (top 10)Minimum Gene LocusKa/Ks name linkvalue (Hs) ID (Hs) * Description3.37 KRTAP23-1 337963 keratin-associatedprotein 23-12.78 C21ohr87 257357 chromosome 21 openreading frame 871.98 C21ohr81 114035 chromosome 21 openreading frame 811.79 FIJ33471 150147 hypothetical proteinFLJ334711.76 C21ohr11 19 not found1.73 RPS5L 54022 ribosomal proteinS5-like1.71 PRED62 not found1.67 KRTAP15-1 254950 keratin-associatedprotein 15-11.57 KRTAP21-1 337977 keratin-associatedprotein 21-11.47 ABCC13 150000 “ATP-binding cassette,sub-family C (CFTR/MRP). Member 13”
458 SAKAKI ET AL.Table 2. Base Substitutions Affecting the Protein StructuresChimp clone Gene Symbol Specific cDNA reference PositionMissing Methionine:PTB-047A24 C21orf18 substitution (5159351806)PTB-084L06 C21orf15 substitution (101445102078)PTB-091H17 C21orf9 substitution (6762567626)PTB-111H18 D21S2056E AY033999 substitution (3197532024)Missing Stop codon:PTB-005B20 PRED5 deletion (6502466013)PTB-034G05 C21orf62 1 nt insertion (4631046359)PTB-034G05 C21orf49 1 nt insertion (4944149490)PTB-061A04 C21orf30 substitution (6528265331)PTB-292C11 TMPRSS3 AB038160 deletion (7982379871)RP43-117B17 C21orf71 substitution (5971559764) (GCA/TCA)Premature Stop codon:CH251-388O03 PCNT2 PCNT2 lots of differences (4848459924)PTB-003F15 PRED75 insertion (120053120102)PTB-013J17 PRED48 XM-071328 1 nt insertion (8610787630)PTB-028I09 PRED78 lots of differencesPTB-045O21 C21orf11 HSA409094 big deletion (7348073519)PTB-047A24 C21orf27 substitution (5500857947)PTB-047A24 C21orf19 2 nt insertion (124956125005)PTB-051O03 KIAA0653 KIAA0653 large deletion (135145135178)PTB-058L13 PRED48 XM-071328 1 nt insertion (4369745220)PTB-099D17 C21orf104 substitution (202361202410)PTB-120M01 LSS AK092334 lots of differences (4920450027)PTB-148P14 PRED61 P704-101D08-model17 deletion (3851438562)PTB-155J22 C21orf79 1 nt insertion (9708497133)PTB-187O16 C21orf104 1 nt insertion (6453264581)PTB-190I13 PRED48 XM-071328 1 nt insertion (135221136744)RP43-001G01 DSCR6 DSCR6 substitution (9821998268)RP43-006A20 PRED42 2 nt insertion (9095191000)RP43-006A20 PRED78 lots of differencesRP43-015P20 PDE9A AF067226 substitution (99938136172)Additional amino acids:PTB-063M23 C21orf96 48 nt deletion (6415764208)PTB-073G05 IFNAR1 IFNAR1 3 nt insertion (4829948348)PTB-083K24 USP16 9 nt insertion (2831828367)PTB-126B09 PRED77 6 nt insertion (191328191398)PTB-153H02 PRED58 AA872876 P704-1023B21-model18-mpi 6 nt insertion (7350073549PTB-196A08 IFNAR1 IFNAR1 3 nt insertion (8779887847)RP43-012J05 SYNJ1 SYNJ1 6 nt insertion (4137141420)trans-acting factors. We examined whether the geneticdifferences found in the present work have any correlationto gene expression. By using Gene-chip technology,the gene expression profiles in brain and liver were comparedbetween human and chimp, and it was found thatseveral among 189 genes examined showed significantdifferences in brain and/or liver (data not shown). For example,IFNAR2, IFNGR2, and ETS2 showed enhancedexpression in chimpanzee brain. On the other hand,C21orf97 was expressed more preferentially in humanbrain. Comparative analysis suggested the presence ofsome significant differences in the promoter regions thatmay affect gene expression. Figure 3 shows differencesin the promoter region of the INFAR2 gene, which is expressedat significantly higher level in chimpanzee brain(and liver). The conclusive view must wait for further experimentalverification, but it is likely that the geneticchanges in intergenic regions also have made considerablecontribution to human evolution through their quantitativeeffects on gene expression.CONCLUSIONSThe present study showed for the first time the chromosome-widesequence comparison between human andnonhuman primates. The study revealed several interestingand important features of the human genome fromevolutionary viewpoints. The overall study showed that asignificant bias in base substitution exists from region toregion and from element to element. These biases mayhave been generated from the regional difference of frequencyof base substitution and the regional difference ofthe strength of constraint. Careful analysis of the basesubstitution rate may reveal the strength of evolutionaryconstraint on each element and region in the genome. Forexample, some CpG islands might be under more strictconstraint than others. Overall comparison also showedtransposable elements seem to have been distributed inspecies-specific manners, suggesting that expansion oftransposable elements occurred discontinuously duringevolution in each species. The most important finding of
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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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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 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
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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: HUMAN-SPECIFIC EVOLUTIONARY CHANGES
Page 492: HUMAN-SPECIFIC EVOLUTIONARY CHANGES
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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