8Genetic properties of human populations Genetic variantsTypeChromosomal abnormalitiesVariable length repeatsSingle Nucleotide Polymorphisms (SNP)Copy Number Variants (CNV)Allele frequenciesLDHaplotypes
9Genetic properties of human populations Genetic variantsLarge scale rearrangementsRareDe novoStrong, penetrant, environment independent and early onset phenotypesNot where the action is in behavioral genetics
10University of Wisconsin Comprehensive Cancer Center
11Genetic properties of human populations Genetic variantsVariable stretches of sequenceLow genome-wide densityUnstable/mutable
12Exon 1 IT-15 gene 167bp 92bp HD allele (>40) cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag…HD allele (>40)cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagReduced penetrance HD allele (36-39)cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagMutable normal (27-35)cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagNormal (26)Exon 1IT-15 gene167bp92bpPotter et al (2006) AMERICAN COLLEGE OF MEDICAL GENETICS, Standards and Guidelines for Clinical Genetics Laboratories
13Genetic properties of human populations Genetic variants:SNPs
14Genetic properties of human populations Genetic variants:SNPs13x106 SNPs defined from comparing genomes of several individuals1 common SNP per 500 bp
21Genetic properties of human populations Allele frequenciesFrequencies of variants differ across populationsSome variants only exist in some and not other populations (founder effects, selection, etc)
22Human Migration History Dpt Genet. Genomics, Boston U.
2325-50 million deaths in Europe 30%-60% of European population
24Genetic properties of human populations LD – “linkage disequilibrium”Human genetic polymorphisms are not independent from each otherAlleles of polymorphisms that are close to each other travel together (recombination does not separate them)
33ACACACGTACATACGCACATATACACGCACATACGTACACACACACATACGTACATATACACGCATATACACACGCACACACACACACACATACACACGTATGTIndividuals in this pedigree will contain chromosome that will have all possible combinations of the polymorphisms A C, G T, A T and G C.
34ACACACGTACATACGCACATATACACGCACATACGTACACACACACATACGTACATATACACGCATATACACACGCACACACACACACACATACACACGTATGTIndividuals in this pedigree will contain chromosome that will have all possible combinations of the polymorphisms A C, G T, A T and G C.
35Genetic properties of human populations HaplotypesHaplotype is a block of alleles that travel together through recombination eventsAlleles within a block predict each other (D’, r^2)
38Human genetic traits Traits = phenotypes How are the above related Examples:EthnicityDiseaseBehavioralHow are the above related
39Human genetic traits Ethnicity Defined by a set of polymorphic alleles inherited from ancestorsThe set is shaped by the history of the populationPigmentation, hair type, etc
40Human genetic traits Disease Some variants will affect function or regulation of proteins and genes (many genes at once)Selection (positive, negative, balanced)
41Human genetic traits Behavioral Some variants may result in predisposing individuals to react differently to outside stimuliPersonality traits and their inheritanceCognitive ability (IQ)Psychiatric disorders
42Human genetic traits Traits (phenotypes) How are the above related EthnicityDiseaseBehavioralHow are the above related
43Human genetic traitsSome traits were selected for in certain environments and when those environments ceased to exist, the traits persisted since they were not selected against (eg eyesight, athletic ability etc)Some traits may consist of components that are beneficial for survival/reproductive ability of an individual, although the entire trait may not be desirable/beneficial (novelty seeking – substance abuse).Some LD blocks may have variants contributing to different traits, one desirable and one not, there is a constant evolutionary tug-of-war between those.Some variants may be good for one thing and bad for the other (sickle cell anemia/resistance to malaria).1/2
45How to identify genes responsible for human genetic traits? Family studies (genes + environment)Twin studiesLinkage and Mendelian traitsComplex traitsAssociation analysisWhole genome association
46How to identify genes responsible for human genetic traits? Family studies (genes + environment)Familiality is prerequisite for a trait to be genetic.However, a familial trait may be purely environmental (respiratory phenotypes in families living in polluted areas)
47How to identify genes responsible for human genetic traits? Twin studiesMonozygous twins share ALL genomic variantsDizygotic (fraternal) twins share some of the genomic variantsAll twins share early environmental influences
48How to identify genes responsible for human genetic traits? Twin studiesConcordance (twins have same phenotype) of twins, difference in concordance of MZ and DZ twinsCorrelation between quantitative traits, difference in correlation of MZ and DZ twins
49Is height heritable?David Duffy, Queensland Inst Med Res,
50Are levels of Total Serum Immunoglobulin E heritable?David Duffy, Queensland Inst Med Res,
51Hurd et al, Department of Psychology University of Alberta
52Hurd et al Department of Psychology University of Alberta
58Wallace et al (2006) Journal of Child Psychology and Psychiatry 47:987-993
59How to identify genes responsible for human genetic traits? Linkage analysis and Mendelian traitsPatterns of inheritance in extended familyCorrelation between genotype and phenotype segregation
60How to identify genes responsible for human genetic traits? Complex traitsOligogenicPolygenicGenetic heterogeneityPenetranceEnvironmental effectsEpigenetics
61How to identify genes responsible for human genetic traits? Failure of linkage analysis (complex traits)Many loci, small effectLinkage areas very large, containing hundreds of genesFindings relevant to particular pedigree, not population
62How to identify genes responsible for human genetic traits? Association analysisCasesControlsMeasure allele frequency of selected polymorphisms and compare the cases group with the control group. Difference can be attributed to the difference in phenotype.Association regions usually contain one or few genes.
63How to identify genes responsible for human genetic traits? Association analysisCasesControlsIssues: population stratification, relatedness
64Human Migration History Dpt Genet. Genomics, Boston U.
65How to identify genes responsible for human genetic traits? Genome Wide AssociationProbing large amount of genetic polymorphisms at once“Hypothesis free”
66How to identify genes responsible for human genetic traits? Genetic variantsSNPs13 x 10^6 SNPs defined from comparing genomes of many individuals1 common SNP per 500 bpCNVs12,000 in 5000 loci
80Each spot represents a hybridization intensity of a SNP or a CNV probe. These can be used in binary mode to identify presence or absence of an allele in an individual, or in a quantitative mode to assay SNP/CNV allele frequency in a pool of individuals.
81Pool with 25% A and 75% G gacgcactacatgtatcTagcgctgtattgtcgtacta cagcgtgatgtacatagAtcgcgacataacagcatgatgacgcactacatgtatcTagcgctgtattgtcgtactacagcgtgatgtacatagGtcgcgacataacagcatgatgacgcactacatgtatcCagcgctgtattgtcgtactacagcgtgatgtacatagGtcgcgacataacagcatgatgacgcactacatgtatcCagcgctgtattgtcgtactacagcgtgatgtacatagGtcgcgacataacagcatgatgacgcactacatgtatcCagcgctgtattgtcgtactaPool with 25% A and 75% G