topics in genetics of complex human traits tomas drgon national institute on drug abuse nih,...
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Topics in genetics of complex human traits
Tomas Drgon
National Institute on Drug Abuse
NIH, Baltimore MD, USA
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Complex Genetics
• As opposed to “simple genetics” describing Mendelian, single gene traits
• Phenotype is determined by more than one gene
• Environmental influence
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Dpt Genet. Genomics, Boston U. http://gmed.bu.edu/about/images/human_migration.jpg
Human Migration History
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Dpt Genet. Genomics, Boston U. http://gmed.bu.edu/about/images/human_migration.jpg
Human Migration History
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25-50 million deaths in Europe30%-60% of European population
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Human Migration Today
www.mapsofworld.com
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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
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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
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University of Wisconsin Comprehensive Cancer Center
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Genetic properties of human populations
• Genetic variants
– Variable stretches of sequence• Low genome-wide density• Unstable/mutable
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Exon 1
cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag
Normal (26)
cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag
Mutable normal (27-35)
cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag
Reduced penetrance HD allele (36-39)
cagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcagcag…
HD allele (>40)
IT-15 gene
167bp
92bp
Potter et al (2006) AMERICAN COLLEGE OF MEDICAL GENETICS, Standards and Guidelines for Clinical Genetics Laboratories
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Genetic properties of human populations
• Genetic variants: – SNPs
http://fig.cox.miami.edu/~cmallery/150/gene/sf12x16.jpg
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Genetic properties of human populations
• Genetic variants: – SNPs
• 13x106 SNPs defined from comparing genomes of several individuals
• 1 common SNP per 500 bp
• http://www.ncbi.nlm.nih.gov/SNP/
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Mapviewer example
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Genetic properties of human populations
• Genetic variants:
– CNVs
• 12,000 in 5000 loci
• http://projects.tcag.ca/variation/
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Legend: Blue bars indicate reported CNVs; Red bars indicate reported inversion breakpoints; Green bars to the left indicate segmental duplications.
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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)
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Dpt Genet. Genomics, Boston U. http://gmed.bu.edu/about/images/human_migration.jpg
Human Migration History
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25-50 million deaths in Europe30%-60% of European population
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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)
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Linkage disequilibrium
A
G
C
T
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Linkage disequilibrium
A
G
C
T
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Linkage disequilibrium
A
G
C
T
Marker Functional allele
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All individuals in this pedigree will contain chromosomes that will have either AC or GT.
ACGT
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACGT
ACGT
ACGT
ACGT
ACGT
ACGT
ACGT
ACGT
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All individuals in this pedigree will contain chromosomes that will have either AC or GT.
ACGT
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACAC
ACGT
ACGT
ACGT
ACGT
ACGT
ACGT
ACGT
ACGT
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Linkage disequilibrium
A
G
C
T
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Linkage disequilibrium
A
G C
T
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Linkage disequilibrium
A
G C
T
Marker Functional allele
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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.
ACGT
ACAC
ACAT
ACAT
ATAC
ACAT
ACAC
ACAC
ACAT
ACAT
ATAC
ATAT
ACAC
ACAC
ACAC
ACAC
ACAT
ACAC
ACGC
ACGC
ACGT
ACGT
ACGC
ACGC
ACGT
ATGT
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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.
ACGT
ACAC
ACAT
ACAT
ATAC
ACAT
ACAC
ACAC
ACAT
ACAT
ATAC
ATAT
ACAC
ACAC
ACAC
ACAC
ACAT
ACAC
ACGC
ACGC
ACGT
ACGT
ACGC
ACGC
ACGT
ATGT
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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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www.hapmap.org
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Human genetic traits
• Traits = phenotypes– Examples:
• Ethnicity• Disease• Behavioral
• How are the above related
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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
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Human genetic traits
• Disease
– Some variants will affect function or regulation of proteins and genes (many genes at once)
– Selection (positive, negative, balanced)
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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
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Human genetic traits
• Traits (phenotypes)– Ethnicity– Disease– Behavioral
• How are the above related
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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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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
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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)
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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
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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
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David Duffy, Queensland Inst Med Res, http://www.qimr.edu.au/davidD/Talks/twins2002/twin_asthma_talk.html
Is height heritable?
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David Duffy, Queensland Inst Med Res, http://www.qimr.edu.au/davidD/Talks/twins2002/twin_asthma_talk.html
Are levels of Total Serum Immunoglobulin E
heritable?
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Hurd et al, Department of Psychology University of Alberta
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Hurd et al Department of Psychology University of Alberta
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Kendler et al
Heritability of schizophrenia
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Koenig et al (2005) Journal of Personality 73:2
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Bouchard et al (2002) Journal of Neurobiology 54:4-45
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Thompson PM (2001) Nature Neuroscience 4:1253-1258
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Thompson PM (2001) Nature Neuroscience 4:1253-1258
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Wallace et al (2006) Journal of Child Psychology and Psychiatry 47:987-993
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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
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How to identify genes responsible for human genetic traits?
• Complex traits– Oligogenic– Polygenic– Genetic heterogeneity– Penetrance– Environmental effects– Epigenetics
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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
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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.
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How to identify genes responsible for human genetic traits?
• Association analysis
Cases Controls
Issues: population stratification, relatedness
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Dpt Genet. Genomics, Boston U. http://gmed.bu.edu/about/images/human_migration.jpg
Human Migration History
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How to identify genes responsible for human genetic traits?
• Genome Wide Association
– Probing large amount of genetic polymorphisms at once
– “Hypothesis free”
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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
• http://www.ncbi.nlm.nih.gov/SNP/
– CNVs
• 12,000 in 5000 loci
• http://projects.tcag.ca/variation/
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Hubble telescope of genetics
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gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
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gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
cagcgtgatgtacatagAtcgcgacataacagcatgat
cagcgtgatgtacatagAtcgcgacataacagcatgat
cagcgtgatgtacatagAtcgcgacataacagcatgat
AA homozygote
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gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
cagcgtgatgtacatagGtcgcgacataacagcatgat
cagcgtgatgtacatagGtcgcgacataacagcatgat
cagcgtgatgtacatagGtcgcgacataacagcatgat
GG homozygote
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gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
cagcgtgatgtacatagGtcgcgacataacagcatgat
cagcgtgatgtacatagGtcgcgacataacagcatgat
cagcgtgatgtacatagGtcgcgacataacagcatgat
cagcgtgatgtacatagAtcgcgacataacagcatgat
cagcgtgatgtacatagAtcgcgacataacagcatgat
cagcgtgatgtacatagAtcgcgacataacagcatgat
AG heterozygote
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HuSNP, 1500 SNPs
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10k chip10 000 SNPs
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100K chip100 000 SNPs
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500K chip500 000 SNPs
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1M chip1 000 000 SNPs1 000 000 CNVs
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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.
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gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcTagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
gacgcactacatgtatcCagcgctgtattgtcgtacta
cagcgtgatgtacatagGtcgcgacataacagcatgat
cagcgtgatgtacatagGtcgcgacataacagcatgat
cagcgtgatgtacatagGtcgcgacataacagcatgat
cagcgtgatgtacatagAtcgcgacataacagcatgat
Pool with 25% A and 75% G
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Analytical issues
• Multiple testing issues, Bonferroni correction
• Sensitivity vs specificity
• Bayesian approaches
• PCA, HCA
• Monte Carlo Modelling
• Philosophy, epistemology
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