Human Population Genomics ACGTTTGACTGAGGAGTTTACGGGAGCAAAGCGGCGTCATTGCTATTCGTATCTGTTTAG

Cost Killer apps Roadblocks? How soon will we all be sequenced? Time 2013? 2018? Cost Applications

The Hominid Lineage

Human population migrations Out of Africa, Replacement –Single mother of all humans (Eve) ~190,000yr –Single father of all humans (Adam) ~340,000yr –Humans out of Africa ~50000 years ago replaced others (e.g., Neandertals) Multiregional Evolution –Generally debunked, however, –~5% of human genome in Europeans, Asians is Neanderthal, Denisova

Coalescence Y-chromosome coalescence

Why humans are so similar Out of Africa Oppenheimer S Phil. Trans. R. Soc. B 2012;367:

Some Key Definitions Mary: AGCCCGTACG John: AGCCCGTACG Josh: AGCCCGTACG Kate: AGCCCGTACG Pete: AGCCCGTACG Anne: AGCCCGTACG Mimi: AGCCCGTACG Mike: AGCCCTTACG Olga: AGCCCTTACG Tony: AGCCCTTACG Mary: AGCCCGTACG John: AGCCCGTACG Josh: AGCCCGTACG Kate: AGCCCGTACG Pete: AGCCCGTACG Anne: AGCCCGTACG Mimi: AGCCCGTACG Mike: AGCCCTTACG Olga: AGCCCTTACG Tony: AGCCCTTACG Alleles: G, T Major Allele: G Minor Allele: T G/G G/T G/G T/T T/G G/G G/T G/G T/T T/G Recombinations: At least 1/chromosome On average ~1/100 Mb Linkage Disequilibrium: The degree of correlation between two SNP locations MomDad

Human Genome Variation SNP TGCTGAGA TGCCGAGA Novel Sequence TGCTCGGAGA TGC GAGA Inversion Mobile Element or Pseudogene Insertion TranslocationTandem Duplication Microdeletion TGC - - AGA TGCCGAGA Transposition Large Deletion Novel Sequence at Breakpoint TGC

The Fall in Heterozygosity H – H POP F ST = H H – H POP F ST = H

From bones, compared genomes of three different Neanderthals with five genomes from modern humans from different areas of the world The Neanderthal Genome Figure 1- R. E. Green et al., Science 328, (2010)

Neanderthal Genome

Denisovan – Another human relative

Denisovan/Human Comparison

Aboriginal Australian

Benefits of Admixture

Out of Africa Revisited Ann Gibbons Science 28 January 2011: “Human uniqueness?”

The HapMap Project ASWAfrican ancestry in Southwest USA 90 CEUNorthern and Western Europeans (Utah) 180 CHBHan Chinese in Beijing, China 90 CHDChinese in Metropolitan Denver100 GIHGujarati Indians in Houston, Texas100 JPTJapanese in Tokyo, Japan 91 LWKLuhya in Webuye, Kenya100 MXLMexican ancestry in Los Angeles 90 MKKMaasai in Kinyawa, Kenya180 TSIToscani in Italia100 YRIYoruba in Ibadan, Nigeria100 Genotyping: Probe a limited number (~1M) of known highly variable positions of the human genome

Linkage Disequilibrium & Haplotype Blocks pApA pGpG Linkage Disequilibrium (LD): D = P(A and G) - p A p G Linkage Disequilibrium (LD): D = P(A and G) - p A p G Minor allele: A G

Population Sequencing – 1000 Genomes Project 1000 Genomes Project Population Sequencing – 1000 Genomes Project 1000 Genomes Project

Population Sequencing – 1000 Genomes Project 1000 Genomes Project Population Sequencing – 1000 Genomes Project 1000 Genomes Project

Association Studies Control Disease A/G G/G A/G G/G A/A A/G A/A A/G A/A AA04 AG33 GG40 p-value

Wellcome Trust Case Control Nature 447, (7 June 2007) Nature 464, (1 April 2010) Many associations of small effect sizes (<1.5)

Heritability & Environment Bienvenu OJ, Davydow DS, & Kendler KS (2011). Psychological medicine, 41 (1), PMID:

Disease Clustering RA vs. ATD RA vs. MS –No recorded co-occurrence of RA and MS SNP - Allele Gene Symbol Genetic Variation Score (GVS) RA (NARAC) RAAST1DATDMS (IMSGC)MS rs CZSCAN rs ACDSN rs GHLA-DMB rs TTAP rs GVARS rs CCDSN rs ANOTCH rs GBTNL rs TTRIM

Global Ancestry Inference Nature November 6; 456(7218): 98–101.

Ancestry Painting Danish French Spanish Mexican ALLOY: A factorial HMM for ancestry painting

Fixation, Positive & Negative Selection Neutral Drift Positive Selection Negative Selection How can we detect negative selection? How can we detect positive selection?

Conservation and Human SNPs CNSs have fewer SNPs SNPs have shifted allele frequency spectra CNSs have fewer SNPs SNPs have shifted allele frequency spectra Neutral CNS

How can we detect positive selection? Ka/Ks ratio: Ratio of nonsynonymous to synonymous substitutions Very old, persistent, strong positive selection for a protein that keeps adapting Examples: immune response, spermatogenesis Ka/Ks ratio: Ratio of nonsynonymous to synonymous substitutions Very old, persistent, strong positive selection for a protein that keeps adapting Examples: immune response, spermatogenesis

How can we detect positive selection?

Long Haplotypes –iHS test Less time: Fewer mutations Fewer recombinations