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GENETIC EPIDEMIOLOGY 363curate risk information associated with specific alleles atcandidate gene loci. A shift to a risk factor-based epidemiologicapproach in evaluating the roles of candidategenes will be necessary to provide accurate informationregarding the risk associated with particular gene markers(Slooter and van Duijn 1997). For example, differentialpathways to Alzheimer’s disease illustrate the importanceof understanding differences between deterministic genes(β-amyloid precursor, presenilin-1 and -2), and the susceptibilitygenes such as apolipoprotein-E ε-4 (APOEε4), which increase the risk of Alzheimer’s disease in adose-dependent fashion (Tol et al. 1999). Whereas individualswith mutations in deterministic genes appear tohave nearly a 100% chance (i.e., fully penetrant) for thedevelopment of Alzheimer’s disease, those with theAPOE ε4 allele have an increased risk for this disease, butonly in combination with other background genes or environmentalexposures. As research defines specific environmentalexposures, prevention may ultimately be arealistic goal for those individuals who harbor the APOEε4 allele (Farrer et al. 1997; Munoz and Feldman 2000;Kivipelto et al. 2001, 2002).Gap between Health Knowledge and BehaviorOne of the greatest impediments to the application ofgenomics in public health is the gap between healthknowledge and behavior. Even though there iswidespread knowledge regarding the environmental exposuresthat confer increased disease risk and even precipitatemortality, it has been extremely difficult to identifyeffective strategies for inducing changes in negativehealth behaviors. For example, prevention of exposure tocigarettes would have a dramatic effect on the incidenceof respiratory diseases, several forms of cancer, and cardiovasculardisease; yet there is still a substantial proportionof individuals who start to smoke despite this knowledge.An important area of future research will involvestudies of health behavior cognition, behavioral motivation,and effective methods for inducing changes in humanbehavior in order to maximize prevention efforts formalleable risk behaviors.REFERENCESACS. 2003. Cancer facts and figures 2003, p. 1. American CancerSociety, Atlanta, Georgia.Akerblom H.K., Vaarala O., Hyoty H., Ilonen J., and Knip M.2002. Environmental factors in the etiology of type 1 diabetes.Am. J. Med. Genet. 115: 18.Alexander D.R. 2003. Uses and abuses of genetic engineering.Postgrad. Med. J. 79: 249.Altmuller J., Palmer L.J., Fischer G., Scherb H., and Wjst M.2001. Genomewide scans of complex human diseases: Truelinkage is hard to find. Am. J. Hum. 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Power and sample size calculationsfor case-control studies of gene-environment interactionswith a polytomous exposure variable. Am. J. Epidemiol.146: 596.Garcia-Closas M. and Lubin J.H. 1999. Power and sample sizecalculations in case-control studies of gene-environment interactions:Comments on different approaches. Am. J. Epidemiol.149: 689.Glazier A.M., Nadeau J.H., and T.J. Aitman T.J. 2002. Findinggenes that underlie complex traits. Science 298: 2345.Gordis L. 2000. Epidemiology. W.B. Saunders, Philadelphia,Pennsylvania.Guttmacher A.E. and Collins F.S. 2002. Genomic medicine - Aprimer. N. Engl. J. Med. 347: 1512.Hanley A.J., Choi B.C., and Holowaty E.J. 1995. Cancer mortalityamong Chinese migrants: A review. Int. J. Epidemiol.24: 255.Heath A.C., Whitfield J.B., Madden P.A., Bucholz K.K., DinwiddieS.H., Slutske W.S., Bierut L.J., Statham D.B., andMartin N.G. 2001. Towards a molecular epidemiology of alcoholdependence: Analysing the interplay of genetic and environmentalrisk factors. 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The future of genetic studies ofcomplex human disease. An epidemiologic perspective. Epidemiology9: 350.Khoury M.J., Beaty T.H., and Cohen B.H. 1993. Fundamentalsof genetic epidemiology. Oxford University Press, New York.Khoury M.J., McCabe L.L., and McCabe E.R. 2003. Populationscreening in the age of genomic medicine. N. Engl. J. Med.348: 50.King M.C., Lee G.M., Spinner N.B., Thomson G., and WrenschM.R. 1984. Genetic epidemiology. Annu. Rev. Public Health5: 1Kivipelto M., Helkala E.L., Laakso M.P., Hanninen T., HallikainenM., Alhainen K., Soininen H., Tuomilehto J., andNissinen A. 2001. Midlife vascular risk factors andAlzheimer’s disease in later life: Longitudinal, populationbased study. Br. Med. 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364 MERIKANGASPrevention Research Group. Reduction in the incidence oftype II diabetes with lifestyle intervention or metformin. N.Engl. J. Med. 346: 393.Langholz B., Rothman N., Wacholder S., and Thomas D.C.1999. Cohort studies for characterizing measured genes. J.Natl. Cancer Inst. Monogr. 26: 39.Merikangas K.R. 2002. Genetic epidemiology: Bringing geneticsto the population—The NAPE Lecture 2001. Acta Psychiatr.Scand. 105: 3.Merikangas K.R. and Risch N. 2003. Genomic priorities andpublic health. Science 302: 599.Merikangas K.R., Chakravarti A., Moldin S.O., Araj H.,Blangero J., Burmeister M., Crabbe J.C.J., DePaulo J.R.J.,Foulks E., Freimer N.B., Koretz D.S., Lichtenstein W.,Mignot E., Reiss A.L., Risch N.J., and Takahashi J. 2002. Futureof genetics of mood disorders research: Workgroup ongenetics for NIMH strategic plan for mood disorders. Biol.Psychiatry 52: 457.Michael N.L. 1999. Host genetic influences on HIV-1 pathogenesis.Curr. Opin. Immunol. 11: 466.Munoz D.G. and Feldman H. 2000. Causes of Alzheimer’s disease.Can. Med. Assoc. J. 162: 65.Nebert D.W., Ingelman-Sundberg M., and Daly A.K. 1999. Geneticepidemiology of environmental toxicity and cancer susceptibility:Human allelic polymorphisms in drug-metabolizingenzyme genes, their functional importance, andnomenclature issues. Drug Metab. Rev. 31: 467.Ottman R. 1990. An epidemiologic approach to gene-environmentinteraction. Genet. Epidemiol. 7: 177.Ravussin E., Valencia M.E., Esparza J., Bennett P.H., andSchulz L.O. 1994. Effects of a traditional lifestyle on obesityin Pima Indians. Diabetes Care 17: 1067.Renegar G., Rieser P., and Manasco P. 2001. Family consent andthe pursuit of better medicines through genetic research. J.Contin. Educ. Health Prof. 21: 265.Rewers M.R. and Hamman R.F. 1995. Risk factors for non-insulin-dependentdiabetes. In Diabetes in America, 2nd edition,p. 179. National Diabetes Data Group, National Institutesof Health, National Institute of Diabetes and Digestiveand Kidney Diseases, NIH Publication No. 95-1468.Risch N. 1990. Linkage strategies for genetically complex traits.I. Multilocus models. Am. J. Hum. Genet. 46: 222._______ . 2000. Searching for genetic determinants in the new millenium.Nature 405: 847._______ . 2001. The genetic epidemiology of cancer: Interpretingfamily and twin studies and their implications for molecular geneticapproaches. Cancer Epidemiol. Biomark. Prev. 10: 733.Risch N. and Merikangas K.R. 1996. The future of genetic studiesof complex human diseases. Science 273: 1516.Sadovnick A.D. 2002. The genetics of multiple sclerosis. Clin.Neurol. Neurosurg. 104: 199.Shaper A.G. and Elford J. 1991. Place of birth and adult cardiovasculardisease: The British Regional Heart Study. Acta Paediatr.Scand. Suppl. 373: 73.Slooter A. and van Duijn C. 1997. Genetic epidemiology ofAlzheimer disease. Epidemiol. Rev. 19: 107.Smith P.G. and Day N.E. 1984. The design of case-control studies:The influence of confounding and interaction effects. Int.J. Epidemiol. 13: 356.Sobngwi E., Boudou P., Mauvais-Jarvis F., Leblanc H., VelhoG., Vexiau P., Porcher R., Hadjadj S., Pratley R., TataranniP.A., Calvo F., and Gautier J.-F. 2003. Effect of a diabetic environmentin utero on predisposition to type 2 diabetes.Lancet 361: 1861.Thomas D.C. 2000. Genetic epidemiology with a capital “E”.Genet. Epidemiol.19: 289.Tol J., Roks G., Slooter A.J., and van Duijn C.M. 1999. Geneticand environmental factors in Alzheimer’s disease. Rev. Neurol.(suppl. 4) 155: S10.Trevisan R., Vedovato M., and Tiengo A. 1998. The epidemiologyof diabetes mellitus. Nephrol. Dial. Transplant. (suppl. 8)13: 2.Wacholder S., Chatterjee N., and Hartge P. 2002. Joint effect ofgenes and environment distorted by selection biases: Implicationsfor hospital-based case-control studies. Cancer Epidemiol.Biomark. Prev. 11: 885.Weiss R. 2003. Science Notebook, May 19, p. 7. In The WashingtonPost, Washington, D.C.WHO. 2002. Reducing risks, promoting healthy life. In WorldHealth Report 2002: Preventing risks and taking action,chapter 7. World Health Organization.Yang Q. and Khoury M.J. 1997. Evolving methods in geneticepidemiology III. Gene-environment interaction in epidemiologicresearch. Epidemiol. Rev. 19: 33.Yang Q., Khoury M.J., Coughlin S.C., Sun F., and FlandersW.D. 2000. On the use of population-based registries in theclinical validation of genetic tests for disease susceptibility.Genet. Med. 2: 186.
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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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Page 366 and 367: Implications of Genomics for Public
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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 499There w
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NEW QUANTITATIVE BIOLOGY 501ceded,
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