The Genom of Homo sapiens.pdf

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EVOLUTION OF EUKARYOTIC GENES AND INTRONS 299Table 3. Dynamics of Intron Evolution in Lineage-specific Gene ExpansionsIntron- Conserved Intron sitesIntron Intron conserving intron withLSEs losses gains duplications a sites gains/lossesH. sapiens 2010 1492 4288 7078 5149 26110A. thaliana 1842 1572 3158 7293 4927 16781D. melanogaster 493 424 879 1648 424 3521C. elegans 1009 1265 2398 3759 1345 15729S. cerevisiae 44 47 38 194 41 46S. pombe 45 33 47 123 45 80a Number of duplications that have not been accompanied by loss or gain of introns.ble with the above hypothesis. In some lineages, particularlythe yeasts, but also insects and nematodes, this deleteriouseffect of intron loss apparently had been overcomeby selective pressure for genome compaction or asa result of retrotransposition sweeps, or both. Absent suchspecific circumstances favoring intron elimination, manyancestral introns might have survived simply because losingthem is costly.Evolution of spliceosomal introns was long consideredin the context of the “intron-early” versus “intron-late”debate. The intron-early hypothesis of Walter Gilbertposits that introns existed before the divergence ofprokaryotes and eukaryotes and had an important role inthe evolution of the very first functional proteins (Gilbert1987; Gilbert and Glynias 1993). In contrast, the intronlatehypothesis holds that introns were inserted into eukaryoticgenes after this primary divergence (Logsdon1998; Lynch and Richardson 2002). Our present observationsdo not bear directly on the outcome of this debate,but they do show that many introns not only emergedshortly after or perhaps concomitantly with the origin ofeukaryotes, but retained their positions at least in someeukaryotic lineages. Thus, the evidence presented hereand elsewhere (Fedorov et al. 2002; Lynch and Richardson2002) appears to be compatible with an “introns extremelyearly in eukaryotic evolution” view. It is eventempting to speculate that invasion of protein-codinggenes by ancestors of introns was part of the dramatic andstill mysterious series of events that led to the origin ofthe eukaryotic cell.DYNAMICS OF INTRON EVOLUTION INPARALOGOUS GENE FAMILIESIn the previous section, we analyzed evolution of intronsin highly conserved sets of orthologous eukaryoticgenes and observed remarkable conservation of many intronpositions, but also substantial lineage-specific loss ofintrons. Of no lesser interest is the dynamics of genestructure evolution in paralogous gene families. Lineagespecificexpansions of paralogs exist in every branch onthe tree of life, but they are particularly prominent in multicellulareukaryotes and, on many occasions, can belinked to the specific biology of the respective groups oforganisms (Lespinet et al. 2002). In the process of constructingthe KOG system, we delineated numerousLSEs, some of which are parts of KOGs, whereas othershave no orthologs in other analyzed species (see above).For all these LSEs, we performed an analysis of the conservationof intron positions using the same strategy asdescribed above for the KOG analysis. The preliminaryresults summarized in Table 3 reveal unexpected fluidityof the gene structure in LSEs, with numerous intronlosses and an even substantially greater number of introngains observed during the evolution of LSEs in each lineage.The great majority of intron sites in the LSEs haveexperienced at least one gain or loss event (Table 3). Ithas been predicted and subsequently supported by empiricalanalysis that gene evolution tends to accelerate afterduplication (Ohno 1970; Lynch and Conery 2000; Kondrashovet al. 2002). Our current observations suggestthat gene duplication also triggers mobilization of introns.Additionally, the results are compatible with thehypothesis that many duplications occurred via reversetranscription, with introns reinserting into new sites.CONCLUSIONS: CONGRUENT TRENDSIN THE EVOLUTION OF GENEREPERTOIRE AND GENE STRUCTUREIn the previous sections, we described the parsimoniousscenarios of evolution for the eukaryotic generepertoire and, separately, for the exon–intron structureof a set of highly conserved eukaryotic genes. Distincttrends of gene and intron loss and gain were detected fordifferent eukaryotic lineages. To determine whether ornot the loss and gain of genes and introns occurred in parallel,we plotted the respective values for each speciesand for the internal branches against each other. Extremelystrong correlations were observed between thenumbers of gene and intron gains (Fig. 5A) and gene andintron losses (Fig. 5B). To avoid confusion, it should beemphasized that the gain and loss of introns were measuredfor a set of highly conserved genes (KOGs), whichhave not experienced any gene loss or gain. Accordingly,the observed correlations were not trivial and appeared toindicate that genes and introns are gained and lost in parallel,reflecting the same, lineage-specific trends ingenome evolution. Some eukaryotic lineages, such asfungi and, to a lesser extent, arthropods and nematodes,seem to be under strong selection for genome compaction,which is achieved through loss of dispensablegenes, introns (even in the most conserved, housekeepinggenes), and, probably, intergenic DNA. Other lineages,
300 ROGOZIN ET AL.gene lossgene gain1000800600400200Correlation between the loss ofgenes and introns00 200 400 600 800 1000intron lossCorrelation between gain of genesand introns15000100005000such as vertebrates and plants, seem not to experience thisselective pressure and are much more tolerant to variousforms of apparently dispensable DNA, or even tend toexpand their genomes. Understanding the deeper biologicalreasons behind these lineage-specific evolutionarytrends is a fascinating task for the next generation of comparative-genomicstudies.ACKNOWLEDGMENTWe thank Roman Tatusov for his contribution to theconstruction of the KOGs.REFERENCESR=0.9300 500 1000 1500 2000-5000intron gainR=0.96Figure 5. Comparative dynamics of evoluton of gene repertoiresand gene structure. (Top) Gene (KOG) gain vs. intron gain. (Bottom)Gene (KOG) loss vs. intron loss. Data for gene and introngain and loss are for each species, with the exception of Encephalitozooncuniculi (intron data not analyzed since thisgenome contains practically no introns), Anopheles gambiae, andPlasmodium falciparum (two species not included in the KOGs),and for internal branches of the phylogenetic tree (Figs. 3 and 4).Aravind L., Watanabe H., Lipman D.J., and Koonin E.V. 2000.Lineage-specific loss and divergence of functionally linkedgenes in eukaryotes. Proc. Natl. Acad. Sci. 97: 11319.Blair J.E., Ikeo K., Gojobori T., and Hedges S.B. 2002. The evolutionaryposition of nematodes. BMC Evol. Biol. 2: 7.Boudet N., Aubourg S., Toffano-Nioche C., Kreis M., andLecharny A. 2001. Evolution of intron/exon structure ofDEAD helicase family genes in Arabidopsis, Caenorhabditis,and Drosophila. Genome Res. 11: 2101.Dacks J.B. and Doolittle W.F. 2001. Reconstructing/deconstructingthe earliest eukaryotes: How comparative genomicscan help. Cell 107: 419.Dibb N.J. 1991. Proto-splice site model of intron origin. J.Theor. Biol. 151: 405.Doolittle W.F. 1999. Lateral genomics. Trends Cell Biol. 9: M5.Farris J.S. 1977. Phylogenetic analysis under Dollo’s Law. Syst.Zool. 26: 77.Fedorov A., Merican A.F., and Gilbert W. 2002. Large-scalecomparison of intron positions among animal, plant, and fungalgenes. Proc. Natl. Acad. Sci. 99: 16128.Fitch W.M. 1970. Distinguishing homologous from analogousproteins. Syst. Zool. 19: 99.Gaasterland T. and Ragan M.A. 1998. Microbial genescapes:Phyletic and functional patterns of ORF distribution amongprokaryotes. Microb. Comp. Genomics 3: 199.Galperin M.Y. and Koonin E.V. 2000. Who’s your neighbor?New computational approaches for functional genomics. Nat.Biotechnol. 18: 609.Gilbert W. 1987. The exon theory of genes. Cold Spring HarborSymp. Quant. Biol. 52: 901.Gilbert W. and Glynias M. 1993. On the ancient nature of introns.Gene 135: 137.Gogarten J.P., Doolittle W.F., and Lawrence J.G. 2002. Prokaryoticevolution in light of gene transfer. Mol. Biol. Evol. 19: 2226.Hedges S.B. 2002. The origin and evolution of model organisms.Nat. Rev. Genet. 3: 838.Huynen M.A. and Bork P. 1998. Measuring genome evolution.Proc. Natl. Acad. Sci. 95: 5849.Katinka M.D., Duprat S., Cornillot E., Metenier G., ThomaratF., Prensier G., Barbe V., Peyretaillade E., Brottier P.,Wincker P., Delbac F., El Alaoui H., Peyret P., Saurin W.,Gouy M., Weissenbach J., and Vivares C.P. 2001. Genomesequence and gene compaction of the eukaryote parasite Encephalitozooncuniculi. Nature 414: 450.Kondrashov F.A., Rogozin I.B., Wolf Y.I., and Koonin E.V.2002. Selection in the evolution of gene duplications. GenomeBiol. 3: RESEARCH0008.Koonin E.V. and Galperin M.Y. 2002. Sequence - evolution -function: Computational approaches in comparative genomics.Kluwer Academic, Boston, Massachusetts.Koonin E.V., Makarova K.S., and Aravind L. 2001. Horizontalgene transfer in prokaryotes: Quantification and classification.Annu. Rev. Microbiol. 55: 709.Lespinet O., Wolf Y.I., Koonin E.V., and Aravind L. 2002. Therole of lineage-specific gene family expansion in the evolutionof eukaryotes. Genome Res. 12: 1048.Levesque M., Shasha D., Kim W., Surette M.G., and Benfey P.N.2003. Trait-to-gene. A computational method for predictingthe function of uncharacterized genes. Curr. Biol. 13: 129.Logsdon J.M., Jr. 1998. The recent origins of spliceosomal intronsrevisited. Curr. Opin. Genet. Dev. 8: 637.Logsdon J.M., Jr., Stoltzfus A., and Doolittle W.F. 1998. Molecularevolution: Recent cases of spliceosomal intron gain?Curr. Biol. 8: R560.Logsdon J.M., Jr., Tyshenko M.G., Dixon C., D-Jafari J., WalkerV.K., and Palmer J.D. 1995. Seven newly discovered intronpositions in the triose-phosphate isomerase gene: Evidencefor the introns-late theory. Proc. Natl. Acad. Sci. 92: 8507.Long M., de Souza S.J., and Gilbert W. 1995. Evolution of theintron-exon structure of eukaryotic genes. Curr. Opin. Genet.Dev. 5: 774.Lynch M. and Conery J.S. 2000. The evolutionary fate and consequencesof duplicate genes. Science 290: 1151.Lynch M. and Richardson A.O. 2002. The evolution of spliceosomalintrons. Curr. Opin. Genet. Dev. 12: 701.Marchionni M. and Gilbert W. 1986. The triosephosphate isomerasegene from maize: Introns antedate the plant-animal divergence.Cell 46: 133.Mirkin B.G., Fenner T.I., Galperin M.Y., and Koonin E.V. 2003.Algorithms for computing parsimonious evolutionary scenariosfor genome evolution, the last universal common ancestorand dominance of horizontal gene transfer in the evolution ofprokaryotes. BMC Evol. Biol. 3: 2.Montague M.G. and Hutchison C.A., III. 2000. Gene contentphylogeny of herpesviruses. Proc. Natl. Acad. Sci. 97: 5334.Moran N.A. 2002. Microbial minimalism: Genome reduction inbacterial pathogens. Cell 108: 583.Myllykallio H., Lipowski G., Leduc D., Filee J., Forterre P., and
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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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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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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 501ceded,
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