understanding human evolution through genetic dataibg · 2013-02-06 · understanding human...
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Understanding Human Evolution throughGenetic Data
Daniel P. HowriganMatthew A. SimonsonMatthew C. KellerDepartment of Psychology, University ofColorado at Boulder, U.S.A.Institute of Behavioral Genetics,University of Colorado at Boulder, U.S.A.
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An overview of…• What our current genetic variation can tell us
about
• Directional Selection
• Balancing Selection
• Mutation-Selection Balance
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Genetic Variation• Unrelated individuals share roughly 99% of their DNA
with each other (although slowly falling)
• Yet almost every trait studied to date is heritable tosome degree
• Main question: How does evolution explain existinggenetic variation?
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Genetic Variation• Single Nucleotide Polymorphisms (SNPs)
www.science.marshall.edu
• Allele = Variant
• Locus (loci) = Location
• Common and rare variants
• Genome-wide coverage ofcommon variants (GWAS)
• Deletions and duplications
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Inferring Directional Selectionfrom genetic variation• Fisherʼs fundamental theorem (1930) - any trait under selection pressure
should become fixed and show no variation
• But…
• In general, more recent selection seen in patterns of genetic variation atthe population level. After the the variant reaches 100%, the patterns startto disappear
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Evidence of recent selection• Variant under
positive selection
• High frequency
• Long “Haplotype”
• High homozygosity Sabeti, Varilly et al., Nature, 2007
Findings so far
• Skin pigmentation (Sabeti, Varilly et al., 2007, Pickrell et al., 2009)• Lactose tolerance (Bersaglieri et al., 2004)• Hypertension and Alcohol susceptibility (Voight et al., 2006)• Numerous others with little or no known function….
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Population differentiationSLC24A5 skin pigmentation variant
anthropology.net
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Directional SelectionBut beware…
Multiple confounding demographic variables
• Population Bottlenecks
• Population Expansion
• Genetic drift within sub-populations
Multiple tests and exceptionally strong signals needed to overcomefalse positives
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Inferring Balancing Selectionfrom genetic variation• Balancing selection occurs when common variants are
maintained at equilibrium via selection
• The fitness of the variant depends on its frequency
Candidate Examples• Immune system genes (MHC) - host-pathogen defense
• Sickle-cell / Malaria resistance - ex. of heterozygote advantage
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Balancing Selection
• Indirect evidence - Common variants not explaining a largeproportion of susceptibility in complex disease
Confounds and difficulties• Weak balancing-selection hard to distinguish from neutral drift• Recent balancing selection may just be a snapshot of directional
selection• High-standards of evidence to infer antagonistic pleiotropy
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Inferring Mutation-SelectionBalance from genetic variation• Fisherʼs fundamental theorem again…
• But complex traits rely on a multitude of genes
• New mutations arising (Keighley Keighley & Eyre-Walker, 2000& Eyre-Walker, 2000)
• Old mutations yet to disappear (Fay et al, 2001; Fay et al, 2001; Sunyaev Sunyaev et al, 2001)et al, 2001)
• Genetic variation is a result of mutations appearing and being selected out
• What we expect• Common variation explains little or no individual differences• Genome-wide burden of rare variants, most of small effect, will
correlate to trait variation
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Transcription factors
Cortical neural firing
Pre-frontal cortex function
intelligence
• Upstream processes directly affected
• Downstream processes altered
• Complex emergent trait shows heritable continuous distribution
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Extended Homozygosityburden on IQ
• Recessive mutation
• Ex. Inbreeding depression
• Genome-wide burden
M.C. Keller, unpublished data
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Mutations and Schizophrenia• Schizophrenia - high heritability, but no strong candidate genes
• Walsh et al., Science, 2008
• Other rare deletions found in large case/control studies (ISC, 2008;Stefansson et al., 2008; Xu et al., 2008)
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Mutation-Selection balance• Large scale studies of common variants (GWAS) and
disease have not ruled out role of mutation-selectionbalance
Issues• Mutation is a factor in all heritable traits, so the effect of mutation-
selection balance is a matter of degree• Sequencing data from large sample (e.g. 1000 genomes project)
necessary to fully test mutation-selection predictions
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The future…• More sequencing data• Gene expression studies• Epigenetics• Proteomics
This presentation is a precis to an upcoming chapter for Evolution ofPersonality and Individual Differences (Eds. Patricia Hawley and DavidBuss)
The author is supported by NIH training grant 5 T32 HD007289 andthe Institute for Behavioral Genetics
Youʼll be able to download this presentationat: http://ibgwww.colorado.edu/~howrigan
Or just google: Daniel Howrigan
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References
Positive selection
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References
Mutation-selection balance
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References
Schizophrenia