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Topics in genetics of complex human traits

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1 Topics in genetics of complex human traits
Tomas Drgon National Institute on Drug Abuse NIH, Baltimore MD, USA

2 Complex Genetics As opposed to “simple genetics” describing Mendelian, single gene traits Phenotype is determined by more than one gene Environmental influence

3 Human Migration History
Dpt Genet. Genomics, Boston U.

4 Human Migration History
Dpt Genet. Genomics, Boston U.

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6 25-50 million deaths in Europe
30%-60% of European population

7 Human Migration Today

8 Genetic properties of human populations
Genetic variants Type Chromosomal abnormalities Variable length repeats Single Nucleotide Polymorphisms (SNP) Copy Number Variants (CNV) Allele frequencies LD Haplotypes

9 Genetic properties of human populations
Genetic variants Large scale rearrangements Rare De novo Strong, penetrant, environment independent and early onset phenotypes Not where the action is in behavioral genetics

10 University of Wisconsin Comprehensive Cancer Center

11 Genetic properties of human populations
Genetic variants Variable stretches of sequence Low genome-wide density Unstable/mutable

12 Exon 1 IT-15 gene 167bp 92bp HD allele (>40)
cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag… HD allele (>40) cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag Reduced penetrance HD allele (36-39) cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag Mutable normal (27-35) cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag Normal (26) Exon 1 IT-15 gene 167bp 92bp Potter et al (2006) AMERICAN COLLEGE OF MEDICAL GENETICS, Standards and Guidelines for Clinical Genetics Laboratories

13 Genetic properties of human populations
Genetic variants: SNPs

14 Genetic properties of human populations
Genetic variants: SNPs 13x106 SNPs defined from comparing genomes of several individuals 1 common SNP per 500 bp

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16 Mapviewer example

17 Genetic properties of human populations
Genetic variants: CNVs 12,000 in 5000 loci

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19 Legend: Blue bars indicate reported CNVs; Red bars indicate reported inversion breakpoints; Green bars to the left indicate segmental duplications.

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21 Genetic properties of human populations
Allele frequencies Frequencies of variants differ across populations Some variants only exist in some and not other populations (founder effects, selection, etc)

22 Human Migration History
Dpt Genet. Genomics, Boston U.

23 25-50 million deaths in Europe
30%-60% of European population

24 Genetic properties of human populations
LD – “linkage disequilibrium” Human genetic polymorphisms are not independent from each other Alleles of polymorphisms that are close to each other travel together (recombination does not separate them)

25 Linkage disequilibrium
C G T

26 Linkage disequilibrium
T A C

27 Linkage disequilibrium
T A C Marker Functional allele

28 A C A C A C G T A C A C A C G T A C A C A C A C A C G T A C A C A C G T A C A C A C A C A C A C A C G T A C A C A C A C A C G T A C A C A C A C A C G T A C A C A C A C A C A C A C A C A C A C A C G T A C G T All individuals in this pedigree will contain chromosomes that will have either AC or GT.

29 A C A C A C G T A C A C A C G T A C A C A C A C A C G T A C A C A C G T A C A C A C A C A C A C A C G T A C A C A C A C A C G T A C A C A C A C A C G T A C A C A C A C A C A C A C A C A C A C A C G T A C G T All individuals in this pedigree will contain chromosomes that will have either AC or GT.

30 Linkage disequilibrium
C G T

31 Linkage disequilibrium
T G C

32 Linkage disequilibrium
T G C Marker Functional allele

33 A C A C A C G T A C A T A C G C A C A T A T A C A C G C A C A T A C G T A C A C A C A C A C A T A C G T A C A T A T A C A C G C A T A T A C A C A C G C A C A C A C A C A C A C A C A T A C A C A C G T A T G T Individuals in this pedigree will contain chromosome that will have all possible combinations of the polymorphisms A C, G T, A T and G C.

34 A C A C A C G T A C A T A C G C A C A T A T A C A C G C A C A T A C G T A C A C A C A C A C A T A C G T A C A T A T A C A C G C A T A T A C A C A C G C A C A C A C A C A C A C A C A T A C A C A C G T A T G T Individuals in this pedigree will contain chromosome that will have all possible combinations of the polymorphisms A C, G T, A T and G C.

35 Genetic properties of human populations
Haplotypes Haplotype is a block of alleles that travel together through recombination events Alleles within a block predict each other (D’, r^2)

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38 Human genetic traits Traits = phenotypes How are the above related
Examples: Ethnicity Disease Behavioral How are the above related

39 Human genetic traits Ethnicity
Defined by a set of polymorphic alleles inherited from ancestors The set is shaped by the history of the population Pigmentation, hair type, etc

40 Human genetic traits Disease
Some variants will affect function or regulation of proteins and genes (many genes at once) Selection (positive, negative, balanced)

41 Human genetic traits Behavioral
Some variants may result in predisposing individuals to react differently to outside stimuli Personality traits and their inheritance Cognitive ability (IQ) Psychiatric disorders

42 Human genetic traits Traits (phenotypes) How are the above related
Ethnicity Disease Behavioral How are the above related

43 Human genetic traits Some 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

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45 How to identify genes responsible for human genetic traits?
Family studies (genes + environment) Twin studies Linkage and Mendelian traits Complex traits Association analysis Whole genome association

46 How 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)

47 How to identify genes responsible for human genetic traits?
Twin studies Monozygous twins share ALL genomic variants Dizygotic (fraternal) twins share some of the genomic variants All twins share early environmental influences

48 How to identify genes responsible for human genetic traits?
Twin studies Concordance (twins have same phenotype) of twins, difference in concordance of MZ and DZ twins Correlation between quantitative traits, difference in correlation of MZ and DZ twins

49 Is height heritable? David Duffy, Queensland Inst Med Res,

50 Are levels of Total Serum Immunoglobulin E
heritable? David Duffy, Queensland Inst Med Res,

51 Hurd et al, Department of Psychology University of Alberta

52 Hurd et al Department of Psychology University of Alberta

53 Heritability of schizophrenia
Kendler et al

54 Koenig et al (2005) Journal of Personality 73:2

55 Bouchard et al (2002) Journal of Neurobiology 54:4-45

56 Thompson PM (2001) Nature Neuroscience 4:1253-1258

57 Thompson PM (2001) Nature Neuroscience 4:1253-1258

58 Wallace et al (2006) Journal of Child Psychology and Psychiatry 47:987-993

59 How to identify genes responsible for human genetic traits?
Linkage analysis and Mendelian traits Patterns of inheritance in extended family Correlation between genotype and phenotype segregation

60 How to identify genes responsible for human genetic traits?
Complex traits Oligogenic Polygenic Genetic heterogeneity Penetrance Environmental effects Epigenetics

61 How to identify genes responsible for human genetic traits?
Failure of linkage analysis (complex traits) Many loci, small effect Linkage areas very large, containing hundreds of genes Findings relevant to particular pedigree, not population

62 How to identify genes responsible for human genetic traits?
Association analysis Cases Controls Measure 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.

63 How to identify genes responsible for human genetic traits?
Association analysis Cases Controls Issues: population stratification, relatedness

64 Human Migration History
Dpt Genet. Genomics, Boston U.

65 How to identify genes responsible for human genetic traits?
Genome Wide Association Probing large amount of genetic polymorphisms at once “Hypothesis free”

66 How to identify genes responsible for human genetic traits?
Genetic variants SNPs 13 x 10^6 SNPs defined from comparing genomes of many individuals 1 common SNP per 500 bp CNVs 12,000 in 5000 loci

67 Hubble telescope of genetics

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71 gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta gacgcactacatgtatcCagcgctgtattgtcgtacta gacgcactacatgtatcCagcgctgtattgtcgtacta

72 AA homozygote cagcgtgatgtacatagAtcgcgacataacagcatgat
gacgcactacatgtatcTagcgctgtattgtcgtacta cagcgtgatgtacatagAtcgcgacataacagcatgat gacgcactacatgtatcTagcgctgtattgtcgtacta cagcgtgatgtacatagAtcgcgacataacagcatgat gacgcactacatgtatcTagcgctgtattgtcgtacta gacgcactacatgtatcCagcgctgtattgtcgtacta gacgcactacatgtatcCagcgctgtattgtcgtacta gacgcactacatgtatcCagcgctgtattgtcgtacta AA homozygote

73 GG homozygote gacgcactacatgtatcTagcgctgtattgtcgtacta
cagcgtgatgtacatagGtcgcgacataacagcatgat gacgcactacatgtatcCagcgctgtattgtcgtacta cagcgtgatgtacatagGtcgcgacataacagcatgat gacgcactacatgtatcCagcgctgtattgtcgtacta cagcgtgatgtacatagGtcgcgacataacagcatgat gacgcactacatgtatcCagcgctgtattgtcgtacta GG homozygote

74 AG heterozygote cagcgtgatgtacatagAtcgcgacataacagcatgat
gacgcactacatgtatcTagcgctgtattgtcgtacta cagcgtgatgtacatagAtcgcgacataacagcatgat gacgcactacatgtatcTagcgctgtattgtcgtacta cagcgtgatgtacatagAtcgcgacataacagcatgat gacgcactacatgtatcTagcgctgtattgtcgtacta cagcgtgatgtacatagGtcgcgacataacagcatgat gacgcactacatgtatcCagcgctgtattgtcgtacta cagcgtgatgtacatagGtcgcgacataacagcatgat gacgcactacatgtatcCagcgctgtattgtcgtacta cagcgtgatgtacatagGtcgcgacataacagcatgat gacgcactacatgtatcCagcgctgtattgtcgtacta AG heterozygote

75 HuSNP, 1500 SNPs

76 10k chip SNPs

77 100K chip SNPs

78 500K chip SNPs

79 1M chip SNPs CNVs

80 Each 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.

81 Pool with 25% A and 75% G gacgcactacatgtatcTagcgctgtattgtcgtacta
cagcgtgatgtacatagAtcgcgacataacagcatgat gacgcactacatgtatcTagcgctgtattgtcgtacta cagcgtgatgtacatagGtcgcgacataacagcatgat gacgcactacatgtatcCagcgctgtattgtcgtacta cagcgtgatgtacatagGtcgcgacataacagcatgat gacgcactacatgtatcCagcgctgtattgtcgtacta cagcgtgatgtacatagGtcgcgacataacagcatgat gacgcactacatgtatcCagcgctgtattgtcgtacta Pool with 25% A and 75% G

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86 Analytical issues Multiple testing issues, Bonferroni correction
Sensitivity vs specificity Bayesian approaches PCA, HCA Monte Carlo Modelling Philosophy, epistemology

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