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“Genetics is the science of heredity and variation in living organisms.”Wikipedia (http://en.wikipedia.org/wiki/Genetics)

4DOE Human Genome Project (http://genomics.energy.gov)

TextNational Human Genome Research Institute

James Watson and Francis Crick (1953)

Central Dogmahttp://en.wikipedia.org/wiki/Central_dogma_of_molecular_biology

Genome = Gene + OmeGenome = Whole DNA

Human Genome Project1990? ???????? ??2000? DNA ???? ? 97% ?? 2003? 99.99% ???? ??????? ?? Database : GenBank (http://www.ncbi.nlm.nih.gov/Genbank/)

??? ??Mitosishttp://www.biology.iupui.edu/biocourses/N100/2k4ch8mitosisnotes.html

???? ??Meiosis- 2ndstagehttp://www.biology.iupui.edu/biocourses/n100/2k4ch9meiosisnotes.html

??? ???Crossover & Recombinationhttp://biology200.gsu.edu/houghton/2107%20%2709/lecture15.html

?????Recombination fraction????????(gamete)???(gamete)oror??? O??? 齿1-θ?????：θ

????????Recombination fraction & Distance2 loci???????????????? 0?????2 loci?????????????? 0.5?????

????????Recombination fraction & DistanceL2L3L1

?????(Genetic distance)??: 2??????????????????? : M (morgan)1M?“1?????????? 1???????????”?????????????????: ? 28M, ??: ? 43M?????(Physical distance)??: ????????: bp (base pair)??????????????? : 3x109 bp

?????(θ)??????(x)???Haldane’s map function

??? ???（Darwin,1859）??? ??（Mendel, 1865）??????（???, ?????）????（??, ?????）Galton, Pearson,WeldonBateson, JohannsenModern synthesisFisher, Wright

??? ?????Francis Galton (1822 ~1911)??? ???E(??? ?) = a × ??? ???+ b

Karl Pearson (1857 ~1936) ???? ????

Biometrika, Ann Hum Gene? ???Gregor Johann Mendel (1822 ~1884) Laws of inheritance,18661900? de Vries, Correns, Tschermak????? ???

Battle Round 1???? ????????? ????? ???BatesonGenetics(1905)K. PearsonJohannsenGene (1909)Weldon??????????

Battle Round 2??? ??? ??? !???? ??? ?? !R.A. FisherK. PearsonModern synthesis??? ?????? ??????????（mutation）???? ???（variation）: ?????

R.A Fisher (1890~1962) ???? ?? ??

??（likelihood）? ??, ???? ?? ?? ??? ??? ??　->　Linkage analysis

Additive polygene model??? ??? ??? ??The correlation between relatives on the supposition of Mendelian inheritance.Trans. Roy. Soc, Edinb, 1918

Battle Round 3E. PearsonR.A. Fisher Neyman-Pearson’s lemmaAlternative hypothesisThe most powerful testConfidence intervalOnly null hypothesisFiducial intervalJ. Neyman

??? ??????（eugenics）????? ???? ??? ??- Galton , K. Pearson, R.A Fisher- Adolf Hitler (1931)“??? ??? ?? ?? ??? ?? ?”Lysenko????? ???????? ?? ????, ??? ?? ??? ??

???? ??PolymorphismSNP(Single-nucleotide polymorphism)

STRP (short tandem repeat polymorphism, Microsatellite)

VNTR(variable number of tandem repeat)

STRP? VNTR….ATTCCGATATATAT….….ATTCCGATATATATATATAT….STRPSTRP : 2~5 ??? ??VNTR : 6~ ??? ??

??? ??Insertion/Deletiondeletion….ATTCCGGTACTACT….….ATTCCGGGTACTACT….insertion

?? ?? ??? ???????（trait）?????? ?? ???? ??? ??????（qualitative trait）????（quantitative trait）?????2.16.49.7?? ??????????（phenotype）

ＡaBbＡ or aＡaBbB or b??? ????? ????? ????? ???????(qualitative phenotype)????A/aA or a??? ???? ??? ?? = ??? ??+ ??? ??

??? ??Mendel's law of dominance (1st law)?????（qualitative phenotype）?????（quantitative phenotype）AA or AaaaAAP(D=+|AA)=q+AAP(D=+|Aa)=q+AaAaXAA~N(μ1,σ12)P(D=+|aa)=q+aaaaXAa~N(μ1,σ12)Xaa~N(μ2,σ22)

??????mode of inheritance????（genotype）??（recessive）??（dominant）???? A? ?? ?????? A? ?? ??????AAAaaaaaAaAAAaaaAA

???penetrance?????????AAAaaaAAAaaa10%10%50%90%100%100%100%50%90%??????????

????A/aP(A)=P(a)=1/2A or a??? ??Mendel‘s law of segregation (2nd law)

ＡaBbＡ or aB or b??? ??Mendel's law of independent assortment (3rd law)????A/a B/bAB, Ab, aB, ab

??(?? ??? ??)linkage??? ??recombination fraction??? ??????? 1???? 2

????Mutation??? ????(Germline mutation) ?? :?? ??? ???? ??? ???? ????

???? : ???(??,??), ???, ???????? ????

??? ??? ??, ??? ????? ????(Somatic mutation) ??: ??? ?? ??? ???? ???? ???? ??

????? ??? ???? ???Down’s syndromeTrisomy 21

????American Family Physician: Aug 15, 2000

???? ??????? ?? ??????? ?? ??????PMS

????? ?? ????? ??? ??? ? ? ???????(linkage analysis)? ?? ??? ??? ??

Marker locus????(linkage analysis)Marker locus???? ??????(?????)? ??

??????? ????Parametric linkage analysis?? ????? ????? ????????? ????? 2?? ???? A, N? ???, ????A? ?? ?? ??, ?????? ??

??????????? ??(θ)=0.5??? ??(θ)< 0.5

????? ???? 1? diplotype?：A-X/T-N? ??

?? 1? diplotype?：A-N/T-X? ??

LOD(log of odds) Score????? ????????? ??

Map distance (cM)LOD scoreUMOD#118#238D16S3041D16S3046D16S3045D16S3036#123D16S499D16S501D16S773D16S772D16S401D16S537D16S410D16S412D16S420D16S417D16S3056D16S3113D16S3133ac002299a3ac002302a4ac002299a4連鎖解析によるFamilial Juvenile Hyperuricemic Nephropathy (FJHN)疾患関連座位の探索 (鎌谷直之　数学セミナー 517, 40, 2004)

????? ?? ??Case-control studyCohort studyIntervention study????????? ???? A?? B?????????? ????????Case groupControl group

AATT+TA????????? ??(??? ??)＋＋AATT+TA????TT+TA?? ???????AA?? ????????(relative risk)

???? ??(Case-Control ??)Case groupAATT+TAOdds?????(Odds ratio)???Odds???? ? ? ??Control group

??? ??Test of associationPearson’s chi-square testorFisher’s exact test

Hardy-Weinberg ????Law of Hardy-Weinberg Equilibrium??? ????? ??(p)???＝??trandom mating＝??t+1

Hardy-Weinberg ????Law of Hardy-Weinberg Equilibriumthenif

HWE??? ???? ?? ??Random Mating ??? ?????????? (assortative mating)??? ??????? ??(Typing miss)

??????? ??（1）??（2）??（3）????(4) Risk allele? ?(5)allele? ?

??? ??Cochran-Armigate test for trendBalding (2006), Nat. Rev. Genet

????? ??? ???????????? ????? ??AA=0, Aa=1, aa=2??? ?, ????? 0?? ???? ????? ??????Kendall’s tauSpearman? ?????????????? ?????a? ??Balding (2006), Nat. Rev. Genet

CTAhaplotypeand diplotypeGTGDiplotype configuration??? ??? haplotype： C-T-A??? ??? haplotype： G-T-G?? ????C/G-T/T-A/GCGTTAG

?????linkage disequilibrium?? ?? ???? ??? ???2 ?????2 ?????1 ?????1 ????

???????DCoefficient of linkage disequilibrium??????? D’

?? ?? ?????? ?? ???absolute LD & complete LD ?? ?? ????? ?? ????? ??

?? ??? ??r2Haplotype??? ??????? ????? ????? ???? ???? ??? ????? ??2nd locusfreq?2 ????b? 1????BAa1st locus

Linkage Disequilibrium map (LD map)

Absolute LDComplete LDLinkage equilibrium?? ??? ?? D’?r2D’=1D’=1D’=0r2=1r2=0.28r2=0

LD? ?????? ??D’θ=0.001θ=0.01θ=0.05generation

????? ????(Genome-Wide Association Study, GWAS)??? ???? ???? ????? ??1,000? SNP? ??? ??30~100? SNP chip（Invader, Illumina, Affymetrix）

“??? ?? ??? ??? ????? ??? ??? ??? ???? ??? ??? ?? ????? ??”Common Disease Common Variant ??

????? ????Direct association & Indirect associationKruglyak (2008), Nat. Rev. Genet

??? ???Population structureBalding (2006), Nat. Rev. Genet

EIGENSTRAT?????? ??? ??? ??? ??1. ???? ???３．?SNP?? ???Binom(2,MAF)２．????? ????????? ??? ??? ??? ?? ?? minor allele? MAF? ??? ???

EIGENSTRAT? ?HapMap???? ???? ???

???? ??The multiple testing problemBalding (2006), Nat. Rev. Genet

“… 789 publications reporting on 802 different polymorphismsin 277 genes .”…“We systematically meta-analyzed 127 polymorphisms across69 different putative Alzheimer disease risk genes.” ???? ??

????? ?? 3? ????? ??????? ??????????Cohort studysample sizeRR=3alpha =0.05power=0.8

????? (???? ?????)PowerSample size (#case=#control)100

100100GWASControlCasePower??????? ????????：1.38×10-08ControlCase????：0.012nd stage ? ?????2 ?? ????2 Stage association study????? ????：1×10-7

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