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IDENTIFYING LIVESTOCK QTN 185The fact that the q chromosome of Meishan origin clusterswith the Q clade indicates that the latter is of Asianorigin. The G to A transition either could have been sampledas such during pig domestication in Asia, or couldhave occurred after domestication either in Asia or in Europeafter the importation of Asian germ plasm in the19th century.Functional Analyses Confirm That the QTN Is NotOnly Necessary but Also SufficientGiven the phenotypic effect of the QTL, and the lack ofa structural IGF2 difference between the Q and q alleles,we predicted that the QTN would be a regulatory mutationcausing a postnatal increase in IGF2 levels in striatedmuscle (A.-S.Van Laere et al., in prep.). Indeed, the majoreffect of the QTL was on muscle mass, fat deposition,and heart size, measured at six months of age. There wasno evidence for a perinatal growth effect or a postnatal effecton the size of any other organs (Jeon et al. 1999).Note that in the mouse a deletion involving DMR1, an associatedblock of directly repeated sequences and theCpG island containing the QTN, leads to derepression ofthe maternal allele during fetal development as well ascontinued postnatal expression from the maternal and paternalalleles in mesodermal tissue (Constancia et al.2000). To test the effect of the QTL on IGF2 expressionin vivo, we produced an F 2 population segregating for theQTN. F 2 offspring were slaughtered at five stages of development:fetal, one, two, four, and six months of age.We first demonstrated that the QTL genotype had no effecton the imprinting status of the IGF2 gene. For all analyzablegenotypes (i.e., qq, Qq, and qQ), we found that(1) before birth, IGF2 was expressed exclusively fromthe paternal allele in all examined tissues and (2) afterbirth, IGF2 remained preferentially expressed from thepaternal allele with, however, progressive reactivation ofthe maternal allele in some tissues, including skeletalmuscle. This might explain why in one of the initial QTLmapping experiments muscle growth was found to beslightly superior in q pat /Q mat versus qq animals, and inQQ versus Q pat /q mat animals (Jeon et al. 1999). We thenused northern blot analysis as well as RT-PCR to quantifythe amounts of IGF2 mRNA in different tissues of F 2 animalssorted according to the IGF2 allele inherited fromtheir sire. Before birth, the QTN genotype had no detectableeffect on IGF2 levels in any of the analyzed tissues.This is in agreement with the lack of detectable phenotypiceffect of the QTL at birth. After birth, the QTNgenotype had a very significant effect on IGF2 levels inskeletal muscle (~threefold increase) and heart, althoughnot in liver. This is again in agreement with the postnataleffect of the QTL on skeletal muscle mass and heartsize—resulting probably from a paracrine IGF2 effect—but lack of effect on the size of any other organs. Theseresults thus provided very strong additional support for adirect role of IGF2. To check whether the identified QTNwas sufficient to confer the functional Q status to a chromosome,we performed a series of in vitro experiments.The QTN is the antepenultimate nucleotide of a 16-bpmotif that is perfectly conserved among all tested mammals(eight species) and which contains an 8-bp palindromicsequence susceptible to adopt a hairpin structure.Despite the fact that it does not present any obvious similaritywith known cis-regulatory elements, its remarkableconservation suggested that it might bind a trans-actingfactor. We thus performed electrophoretic mobilityshift assays using 27-mers including the QTN that wereincubated with nuclear extracts from C2C12 myoblastcells. The q allele was clearly able to bind a factor notbound by the Q allele. Competition with cold q but not Qoligonucleotide would effectively displace the q probe.These results suggest that the QTN indeed affects a cisactingsilencer element binding in its wild-type conformationto a trans-acting suppressor. This interactionwould be abrogated in the Q allele, leading to an overexpressionof IGF2 in skeletal muscle and, hence, increasedmuscle mass.To further test this hypothesis, we cloned a 578-bpfragment containing the QTN in front of the luciferase reportergene driven by the IGF2 P3 promoter. We demonstratedin vivo that most of the IGF2 transcript in postnatalskeletal muscle derives from the P3 promoter and thatthe QTN genotype influences the amount of P3-drivenIGF2 transcripts. We clearly demonstrated by transienttransfection in C2C12 cells that including the q fragmentled to a fourfold reduction in expression level, whereasthe Q fragment reduced the expression level by 1 / 4 only.This confirmed that the evolutionarily conserved segmentcontaining the QTN indeed functions as a silencer elementin myoblastic cells, and that the QTN interferes withthis function leading to a threefold increase in expressionlevels from the Q when compared to the q allele (i.e., noticeablyvery similar to the expression ratios observed invivo). Altogether, these results strongly suggest that theQTN is not only necessary, but also sufficient to determinethe QTL status of the corresponding chromosome(Van Laere et al. 2003).ON THE IMPORTANCE OF SEQUENCINGLIVESTOCK GENOMESIn this paper, we have described the strategies that wereused to successfully identify the causal mutations underlyingtwo QTL in livestock. Given the limited resourcesthat are available in the field of livestock genomics, theseresults are quite remarkable and demonstrate the value oflivestock populations for the molecular dissection ofcomplex traits. We strongly believe, therefore, that amore systematic use of livestock populations could verysignificantly contribute to a fundamental understandingof the molecular architecture of complex inherited traits,as well as to the identification of biochemical pathwaysaffecting phenotypes that are not only of importance foragriculture but have relevance to human health as well.This is well illustrated by the recent identification of amissense mutation in the porcine PRKAG3 gene causingthe RN phenotype associated with a large effect on glycogenstorage in skeletal muscle and direct relevance for thepathogenesis of non-insulin-dependent diabetes mellitus
186 GEORGES AND ANDERSSONin humans (Milan et al. 2000). Other examples abound:The differences in skeletal muscle mass and fat depositionamong pig and poultry breeds as described in this papercan be viewed as models of mild obesity; understandingthe differences in calcium metabolism between junglefowl and leghorn chickens linked to egg production couldreveal pathways relevant to osteoporosis; cystic ovariandisease is a very common complex inherited disease indairy cattle and potentially a good model for polycysticovarian syndrome, one of the most common endocrinedisorders of women.Contrary to previous considerations (Nadeau andFrankel 2000), we believe that QTL mapping and subsequentQTN identification have the potential to make asignificant contribution to narrow the “phenotype gap”;i.e., the lack of functional information from mutation-inducedphenotypes for most mammalian genes. The detectionof the QTN underlying the SSC2 QTL illustrates thisvividly. The Q to q substitution effect corresponds to adifference of 2–3% in muscle mass, which would havebeen virtually impossible to detect in a phenotype-drivenmutagenesis screen. Yet this mutation accounts for 25%of the phenotypic difference in the F 2 generation, and itsidentification revealed a novel cis-acting regulatory elementin IGF2, a gene that has been extensively studiedusing standard molecular biology.The genome sequences of a number of livestockspecies are expected to become available in the not toodistant future. The poultry genome should be completed,at least at eightfold coverage, by the end of 2003(http://genomewustl.edu/projects/chicken/), and the sequencingof the bovine genome should be initiated beforethe end of the year. A onefold coverage of the porcinegenome will be generated by the end of 2003 (M. Fredholm,pers. comm.), and more extensive sequencing ofthe pig genome will hopefully commence soon after thecompletion of the poultry and bovine genomes.So far, the motivation to sequence the genomes of livestockspecies has mainly come from the realization thatcomparison of genome sequences from evolutionarily diversespecies is a powerful approach to identify functionallyimportant genetic elements (see, e.g., Collins et al.2003). Having the sequence of the livestock genomes athand will also immensely facilitate the identification ofadditional QTNs in these species in which—contrary tothe status in the human—large numbers of very convincingQTLs have already been mapped. The potential valueof understanding the molecular architecture of QTLs segregatingin livestock populations not only for agriculturebut, equally importantly, for fundamental biology and thebiomedical science, is an additional reason to ensure thatlivestock genomes are rapidly and completely sequenced.ACKNOWLEDGMENTSResults described in this paper were made possiblethanks to the financial support of the Belgian and WalloonMinistries of Agriculture, the EU, Cr-Delta (Arnhem,The Netherlands), LIC (Hamilton, New Zealand),VLB (Auckland, New Zealand), Gentec (Buggenhout,Belgium), and the Swedish Research Council for Environment,Agricultural Sciences and Spatial Planning. Weare grateful to Dr. Fredholm for critically reviewing thismanuscript.REFERENCESAmarger V., Nguyen M., Van Laere A.S., Nezer C., Georges M.,Andersson L. 2002. Comparative sequence analysis of theINS-IGF2-H19 gene cluster in pigs. Mamm. Genome 13: 388.Andersson L. 2001. Genetic dissection of phenotypic diversityin farm animals. Nat. Rev. Genet. 2:130.Andersson L., Haley C.S., Ellegren H., Knott S.A., JohanssonM., Andersson K., Andersson-Eklund L., Edfors-Lilja I.,Fredholm M., and Hansson I., et al. 1994. Genetic mapping ofquantitative trait loci for growth and fatness in pigs. Science263:1771.Andersson-Eklund L., Marklund L., Lundstrom K., Haley C.S.,Andersson K., Hansson I., Moller M., and Andersson L. 1998.Mapping quantitative trait loci for carcass and meat qualitytraits in a wild boar x Large White intercross. J. Anim. Sci. 76:694.Arranz J.-J., Coppieters W., Berzi P., Cambisano N., Grisart B.,Karim L., Marcq F., Riquet J., Simon P., Vanmanshoven P.,Wagenaar D., and Georges M. 1998. A QTL affecting milkyield and composition maps to bovine chromosome 20: Aconfirmation. Anim. Genet. 29: 107.Bidanel J.P., Milan D., Iannuccelli N., Amigues Y., BoscherM.Y., Bourgeois F., Caritez J.C., Gruand J., Le Roy P., LagantH., Quintanilla R., Renard C., Gellin J., Ollivier L., andChevalet C. 2001. Detection of quantitative trait loci forgrowth and fatness in pigs. Genet. Sel. Evol. 33: 289.Blott S., Kim J.-J., Moisio S., Schmidt-Küntzel A., Cornet A.,Berzi P., Cambisano N., Ford C., Grisart B., Johnson D.,Karim L., Simon P., Snell R., Spelman R., Wong J., Vilkki J.,Georges M., Farnir F., and Coppieters W. 2003. Moleculardissection of a QTL: A phenylalanine to tyrosine substitutionin the transmembrane domain of the bovine growth hormonereceptor is associated with a major effect on milk yield andcomposition. Genetics 163: 253.Bradley D.G. and Cunningham E.P. 1999. Genetic aspects of domestication.In The genetics of cattle (ed. R. Fries and A. Ruvinsky),p. 15. CAB International, Wallingford, Oxon, UnitedKingdom.Collins F.S., Green E.D., Guttmacher A.E., and Guyer M.S.2003. A vision for the future of genomics research. Nature422: 835.Constancia M., Dean W., Lopes S., Moore T., Kelsey G., andReik W. 2000. Deletion of a silencer element in IGF2 resultsin loss of imprinting independent of H19. Nat. Genet. 26: 203.Coppieters W., Riquet J., Arranz J.-J., Berzi P., Cambisano N.,Grisart B., Karim L., Marcq F., Simon P., Vanmanshoven P.,Wagenaar D., and Georges M. 1998. A QTL with major effecton milk yield and composition maps to bovine chromosome14. Mamm. Genome 9: 540.de Koning D.J., Bovenhuis H., and van Arendonk J.A. 2002. Onthe detection of imprinted quantitative trait loci in experimentalcrosses of outbred species. Genetics 161: 931.de Koning D.J., Rattink A.P., Harlizius B., van Arendonk J.A.,Brascamp E.W., and Groenen M.A. 2000. Genome-wide scanfor body composition in pigs reveals important role of imprinting.Proc. Natl. Acad. Sci. 97: 7947.de Koning D.J., Janss L.L., Rattink A.P., van Oers P.A., de VriesB.J., Groenen M.A., van der Poel J.J., de Groot P.N., BrascampE.W., and van Arendonk J.A. 1999. Detection of quantitativetrait loci for backfat thickness and intramuscular fatcontent in pigs (Sus scrofa). Genetics 152: 1679.Farnir F., Grisart B., Coppieters W., Riquet J., Berzi P., CambisanoN., Karim L., Mni M., Moisio S., Simon P., WagenaarD., Vilkki J., and Georges M. 2002. Simultaneous mining oflinkage and linkage disequilibrium to fine-map QTL in outbredhalf-sib pedigrees: Revisiting the location of a QTL withmajor effect on milk production on bovine chromosome 14.Genetics 161: 275.
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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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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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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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Page 154 and 155: CENTROMERE ANNOTATION 147CONCLUSION
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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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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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