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Lectures on Human Genetics I. History of Disease Gene Mapping II. Statistical Genetics III. Genes and Environment 28 Nov 2013 Jurg Ott, Ph.D. Institute of Psychology Chinese Academy of Sciences, Beijing Rockefeller University, New York Laboratory of Statistical Genetics http://lab.rockefeller.edu/ott/ Aspects of Gene Mapping Scientific Statistical, methodological Computational Commercial Interpersonal Historical J. Ott "Gene Mapping History" 2 1 Gregor Mendel, 1822-1884 Monk at monastery in Brünn Experiments p on g garden pea convince him that phenotypes are determined by inherited “factors” (now called genes) Formulation of the “mendelian” laws of inheritance Inheritance is particulate, not a blending of various forces J. Ott "Gene Mapping History" 3 Mendel’s paper Mendel GJ (1866) Versuche über Pflanzen-Hybriden. Verh Naturforsch Ver Brünn 4:3-47 Ignored until rediscovered in early 1900s J. Ott "Gene Mapping History" 4 2 Mendelian Inheritance of disease Dominant D/N N/N N/N D/N Recessive D/N D/N Large family pedigrees, many generations D/D D/N D/N N/N Tend to occur in single sibships, one generation J. Ott "Gene Mapping History" 5 Chromosomes and Mendel’s laws Sutton & Boveri, years 1902-1904 Theory: Mendel’s Mendel s genes are located on the chromosomes J. Ott "Gene Mapping History" 6 3 “Fly room,” Columbia University Thomas H. Morgan, early 1900s Experiments with fruitfly, Drosophila. Alfred H. Sturtevant, undergraduate student, detected linear arrangement of genes on the X chromosome c o oso e → ge genetic et c linkage, linkage mapping Sturtevant & Lewis (2001) A History of Genetics J. Ott "Gene Mapping History" 7 Heritable Diseases Rare Diseases (prevalence < 1%) Mendelian inheritance, easy to recognize Examples: Color blindness, Huntington disease, cystic fibrosis. 1 disease gene each. Common Diseases Non-mendelian (“complex”) mode of inheritance. Examples: Diabetes, schizophrenia, obesity. Genetically relevant phenotype often unclear Multiple underlying susceptibility genes Traits due to environment To be discussed in lecture 3 J. Ott "Gene Mapping History" 8 4 First assignment of a disease gene to a chromosome E. B. Wilson, 1911. Columbia University, New York Subsequently, ~35 disease genes assigned to X chrom. J. Ott "Gene Mapping History" 9 Genetic Linkage Assumed example Father received AB chromosome from grandma and ab from grandpa. Phase known. When he makes sperm, in meiosis, crossovers occur leading to recombinant offspring, but rarely between two loci close to each other. Recombination fraction θ = measure for genetic distance. Unit: θ = 1% → 1 cM (centimorgan) Direct estimate: ̂ /n, k = number θ=k of recombinants in n meioses J. Ott "Gene Mapping History" 10 5 Estimating θ: y statistics Bernstein (1931) Z Abst Vererb 57:113-138 Grandparents unknown: Number of recombinants and nonrecombinants depends p on p phase. Can use 2-generation g data. Define k = number of recombinants for a given phase. No direct estimate of θ possible. But y = k (n – k) is the same for each phase; y = 0 for θ = 0, and is largest for θ = ½. Here y = 3. Here, 3 Fisher (later): y statistics do not make use of all information in data. J. Ott "Gene Mapping History" 11 Penrose’s sibpair method Penrose (1935) Ann Eugen 6:133-138 Idea: Given two traits with a genetic basis, siblings concordant for the trait are genetically similar (share susceptibility alleles); if so for two traits traits, these traits are genetically linked. Linkage analysis possible on the basis of a single generation: sibpairs. J. Ott "Gene Mapping History" 12 6 Penrose’s sibpair method Ott (2011) Ann Hum Genet 75:344 (review on linkage papers in Annals) Potential problem: Sibpairs i larger in l sibships ib hi are nott independent. Method inefficient, contains much useless information. Nonetheless, became wildly popular. Large numbers of linkage studies published, mostt with ith negative ti results. lt Example: Boyd & Boyd (Ann Eugen [1941] 11:1-9) scored 500 sibpairs for such phenotypes as presence of hair in the mid-digital regions of the fingers, ability to taste phenyl-thiocarbamide (PTC), and various blood types. J. Ott "Gene Mapping History" 13 First autosomal linkage Mohr (1951) Acta Pathol Microbiol Scand 28:207-210 Penrose (1946) Ann Eugen 13:25-29 Jan Mohr U Using i sibpair ib i data d analyzed l db by P Penrose’s ’ extended method, Jan Mohr (1921-2009) detected linkage between the Lutheran blood group (LU) and the Secretor locus (Se), but chromosomal location as yet unknown. In 1954, he reported a linkage of myotonic dystrophy with the above loci. Linkage relations between various loci on the X chromosome had been found earlier by the maximum likelihood method… J. Ott "Gene Mapping History" 14 7 Maximum likelihood estimation Julia Bell & J.B.S. Haldane (1937) Proc Roy Soc B 123:119 General statistical method, introduced by R.A. Fisher, for estimating ti ti parameters t such h as θ. θ Compute C t L(θ) = P(data;θ) P(d t θ) and vary θ between 0 and ½ until L(θ) is maximized. Bell & Haldane: Exact calculation of L(θ) for colorblindness versus hemophilia, considered “unduly cumbrous.” J. Ott "Gene Mapping History" 15 Colorblindness vs. hemophilia Haldane & Smith (1947) Ann Eugen 14:10-31 H Here too, t exactt calculation of L(θ) and L ratio, L(θ)/L(½). Easier to work with lod score, Z(θ) = log10[L(θ)/L(½)]. No possibility yet to do these calculations for autosomal family pedigrees. J. Ott "Gene Mapping History" 16 8 Autosomal linkage in small families Newton E. Morton (1955) Am J Hum Genet 7:277-318 F Famous publication; bli ti 1,234 1 234 citations it ti For small family types, developed lod scores at fixed θ values, published in tables. Recommendation: Researchers should publish their own lod scores at θ = 0.01, 0.05, 0.10, …, 0.40. Significance test: Implemented Wald’s sequential probability ratio test of θ = 0.20 versus θ = 0.50. Rule: C Combine bi lod l d scores over families f ili and… d stop and declare linkage if Z(θ) > 3 stop and declare no linkage if Z(θ) < -2 otherwise, continue sampling families J. Ott "Gene Mapping History" 17 Newton E. Morton D.C. Rao (2012) Genet Epidemiol 37:131-135 Morton’s 1955 work was the foundation for the next 20 years of linkage g analysis. y Worked in Hawaii, New York, University of Southampton. Stephanie Sherman, Michael Conneally, Newton Morton, James Crow Morton’s 70th birthday in 1999 J. Ott "Gene Mapping History" 18 9 Newton E. Morton http://www.jurgott.org/linkage/ Morton’s 70th birthday in 1999 J. Ott "Gene Mapping History" 19 MIM – Mendelian Inheritance of Man McKusick (1966) Johns Hopkins University Press, Baltimore Catalog of heritable human diseases Maintained on computer since 1964 Put online as OMIM in 1987 Highly recommended: McKusick (2006) “A 60-year tale of spots, maps, and genes” Annu Rev Genomics Hum Genet 7:1-27 Contains various stories, for example, about Renwick’s linkage program, written in machine code J. Ott "Gene Mapping History" Victor A. McKusick 20 10 First assignment of a gene to an autosome Roger Donahue et al (1968) Proc Natl Acad Sci USA 61:949-955 Linkage analysis of Duffy (Fy) blood group locus with the “uncoiler” chromosomal polymorphism on chromosome 1, 1 which segresegre gated in Donahue’s family as a heritable secondary constriction. J. Ott "Gene Mapping History" 21 Maps ““Map”” generally ll 2-dimensional Human genetics: Linear arrangement of genes Different (types of) maps, depending on metric Linkage map, unit of centimorgan (cM) = 1% recombination bi ti fraction f ti (at ( t small ll distance) di t ) Physical map, unit of 1 megabase (MB) = 1 mio basepairs. Very roughly, 1 MB = 1 cM LD map in units of linkage disequilibrium, radiation hybrid maps,etc. J. Ott "Gene Mapping History" 22 11 Human Gene Mapping workshops HGM1 in New Haven, Haven 1973 Many more workshops over the years. Committees compiled results and recommended procedures and rules for nomenclature. Genes to be mapped: Mostly blood groups (ABO, Rh, …) and enzyme polymorphisms. J. Ott "Gene Mapping History" 23 Linkage in general pedigrees Elston & Stewart (1971) Hum Hered 21:523-542 Robert C. Elston Method for calculating likelihood in large family pedigrees; 1,166 citations. Numerical recursive calculation, “receipe” rather than formula. ES algorithm. Opened possibilities for linkage analysis in large pedigrees J. Ott "Gene Mapping History" 24 12 The LIPED program Ott (1974) Am J Hum Genet 26:588-597 Ott (1976) Am J Hum Genet 28:528-529 Implemented the ES algorithm in a FORTRAN IV program for li k linkage analysis; l i 1 1,263 263 citations. it ti For the next 10 years, LIPED was the only generally available program for linkage analysis in large families. Used worldwide to genetically map disease genes. Initially used with 16 enzyme polymorphisms and blood groups. J. Ott "Gene Mapping History" 25 Familial Hypercholesterolemia Ott et al (1974) Am J Hum Genet 26:598-603 Alaska kindred with many affected iindividuals. di id l Cholesterol Ch l t l level l l > 95th %ile of normal → affected LIPED program showed mild evidence of linkage to C3 polymorphism Later confirmed by Elston, Berg. This demonstrated existence of a disease gene in the vicinity of C3 (chrom. 19) Work by Joe Goldstein and Michael Brown (Nobel prize in 1985) identified disease as defect in LDL receptor; located on chromosome 19. Now drugs (statins) have been developed for lowering cholesterol level. J. Ott "Gene Mapping History" Alaska kindred with familial hypercholesterolemia (Schrott et al 1972) 26 13 Genetic markers Before 1980 1980, up to 60 blood groups and enzyme polymorphisms used Botstein et al (1980): DNA polymorphisms, RFLPs, 2 alleles each VNTRs, highly polymorphic, panel of 800 markers used SNPs, origin in single mutation, very stable, several million known, 2 alleles each Ultimate resolution: Basepairs from DNA sequencing J. Ott "Gene Mapping History" 27 Huntington Disease Gusella et al (1983) Nature 306:234 Bates (2005) Nat Rev Genet 6:766 Dominant inheritance, average age at onset 35 years. Venezuela pedigree (Nancy Wexler) Wexler), 18,000 18 000 individuals over 10 generations Using RFLPs and the LIPED program, Gusella et al (1983) mapped HD to a location on chromosome 4. Duyao et al (1993) Nat Genet 4:387 – HD caused by CAG repeats. Normal range: up to 35 repeats; HD: 40+ repeats Potential legal issues (insurance) 1983: HD Foundation donated IBM PC to me for multipoint mapping. mapping American HD family J. Ott "Gene Mapping History" 28 14 Human Gene Maps Lathrop/Lalouel/Julier/Ott (1984) Proc Natl Acad Sci USA 81:3443. Multilocus linkage analysis with LINKAGE programs. First map: Helen Donis-Keller et al (1987) Cell 51:319. 403 markers, mostly RFLPs Dausset et al (1990) Genomics 6:575. CEPH families for collaborative mapping NIH/CEPH Collaborative Mapping Group (1992) Science 258:6786. “A genetic linkage map of the human genome was g 279 genes g and constructed that consists of 1416 loci,, including expressed sequences. The loci are represented by 1676 polymorphic systems genotyped with the CEPH reference pedigree resource. A total of 339 microsatellite repeat markers assayed by PCR are contained within the map.” J. Ott "Gene Mapping History" 29 Breast Cancer Hall, …, King (1990) Science 250:1684 http://www.google.com/patents/US5837492 Linkage of early onset disease gene, gene BRCA1 BRCA1, to chromosome 17q 21 Used LIPED and LINKAGE programs Mary-Claire King Mark Skolnick, CEO of Myriad Genetics in Salt Lake City, Utah, wins race to find BRCA2 on chromosome 18 17 Nov 1998: Patent for “methods and materials used to i l isolate and d detect d a human h breast b cancer predisposing di i gene (BRCA2), some mutant alleles of which cause susceptibility to cancer, in particular breast cancer” 13 June 2013: U.S. Supreme court strikes down Myriad Genetics’ patent J. Ott "Gene Mapping History" 30 15 Mapping methods McKusick (1991) FASEB J 5:12-20 Linkage analysis predominant through 1980 Risch & Merikangas (1996) Science 273:1516. Association analysis more powerful than linkage analysis for variants of small effect on disease; complex traits. Case-control studies GWAS. Now, sequence data are again obtained preferentially in human families; re-emergence of linkage analysis J. Ott "Gene Mapping History" 31 First genomewide screen with SNP chips Science 308, 358-389 15 Apr 2005 Josephine Hoh Genome-wide screen, n = 116,204 SNPs, strong association of a variant and AMD. Robert Klein J. Ott "Gene Mapping History" 32 16 GWAS misguided? McClellan & King (2010) Cell 141:210 “Strong evidence suggests that rare mutations of severe effect are responsible for a substantial portion of complex human disease” “new alleles constantly arise, at an estimated rate of approximately 175 per diploid human genome per generation” “common disease-common variant model … genome-wide association studies (GWAS) have published hundreds of common variants whose allele frequencies are statistically correlated with various illnesses and traits. However, the vast majority of such variants have no established biological relevance to disease or clinical utility for prognosis or treatment” “A Time to Sequence— Genome-wide screening for mutations remains the most effective and unbiased way to discover genes involved in complex illnesses” J. Ott "Gene Mapping History" 33 Sequencing the Human Genome J. Craig Venter. 984-92 Researcher at NIH. S NIH Sequenced d 1000s 1000 off human h gene fragments. NIH filed for patents. 1992: Set up The Institute for Genomic Research (TIGR). May 1998: Joined forces with ABI /Perkin-Elmer to sequence human genome in three years. Direct competition with NIH sequencing effort. “It was the methods, not the machines” Time magazine 2007 and 2008: Among the 100 most influential people in the world. Autobiography, A life decoded. Shows how scientists really work… J. Ott "Gene Mapping History" Venter et al (2001) The sequence of th human the h genome. Science 291, 1304-51 34 17 Nat Rev Genet J. Ott "Gene Mapping History" 35 Nat Rev Genet J. Ott "Gene Mapping History" 36 18 Acknowledgments http://lab.rockefeller.edu/ott/associates Research grants from NIH and Chinese government My former students and faculty members Former students in Beijing now in U.S.: Zhe Liu, U Chicago Yuanyuan Shen, Shen Harvard U, U Boston Gao Wang, Rice U, Houston Xu Shu, U Michigan, Ann Arbor J. Ott "Gene Mapping History" 37 19