Human Genetics, part II Liisa Kauppi (Keeney lab) Human populations: origins

1. Human Genetics, part II Liisa Kauppi (Keeney lab) Human populations: origins Implications of population history for disease mapping

2. The first demonstration of world-wide differences in human A, B and O allele frequencies (1919)

3. Human population historyGenetic evidence is always considered alongside linguistic, anthropological and archeological evidencedemic diffusion or cultural diffusion?

4. Two phenomena influencing gene/allele frequencies: Founder effect Bottleneck effect Small number of individuals settles new area, then population grows Population size collapses due to e.g. famine or epidemic  genetic variability decreases

5. Additional forces influencing allele frequencies: ･Genetic drift random effects, stronger when population size is small ･Gene flow between neighboring groups ･Selection For example infectious disease

6. Mixing or replacement?

7. Classical marker studies Differences in allele frequency  genetic distances Genetic diversity outside of Africa is a subset of diversity in Africa Based on 120 protein-coding genes in 1,915 populations Cavalli-Sforza & Feldman (2003) Nature Genet.33, 266-275

8. Human genetic diversity is evenly distributed Most variation between populations Most variation within populations Templeton (1999) Am. J. Anthropol.100, 632-650

9. A large fraction of global human diversity is contained within populations AMOVA (analysis of molecular variance)

10. Father Mother Son Courtesy of Mark Jobling

11. Non-recombining systems Y chromosome “haplogroups” “mitotypes” 1 2 3 4 Molecular clocks Most recent common ancestor

12. mtDNA Maternal - language Y chromosome Paternal - surname Sociocultural factors Patrilocality in most human populations Polygamy Colonizations: mostly males

13. Y chromosome lineages - fathers to sons “Y chromosomal Adam” and “mitochondrial Eve” were not alone! Courtesy of Mark Jobling

14. Phylogenetic trees commonly indicate a recent origin in Africa Y chromosome

15. Y haplogroup distribution Jobling & Tyler-Smith (2003) Nature Rev. Genet.4, 598-612

16. An African origin

17. In Europe, there is a southeast to northwest cline in Y haplogroups Gradients of allele frequencies indicate migration of people

18. Anatomically modern humans arrived in Europe via Asia 35,000 - 40,000 years ago. Europeans are descendants of: Paleolithic hunters and gatherers Neolithic farmers Upper Paleolithic Late Paleolithic Neolithic

19. Modern human mtDNA is distinct from Neanderthal mtDNA Neanderthal people lived in Europe 300,000 - 30,000 years ago Krings et al. (1997) Cell90, 19-30

20. Different genetic marker systems tell different stories Sample from La Plata, Argentina 45.6% native American maternal lineages 10.6% native American paternal lineages Autosomal markers: 68% European, 26% native American, 7% West African Martinez et al., 2004, Hum Biol 76, 543-57

21. More recent reshaping of diversity a cluster ofclosely related lineages • ‘Star cluster’ Y haplotype originated in/near Mongolia ~1,000 (700-1,300) years ago • Now carried by ~8% of men in Central/East Asia, ~0.5% of men worldwide • Suggested association with Genghis Khan (social prestige as a selective force) Zerjal et al. (2003) Am. J. Hum. Genet. 72, 717-721

22. Paternal Clan certificate: Are you a descendant of Genghis Khan? http://www.oxfordancestors.com/genghis_khan.html Matriline service Seven Daughters of Eve certificate

23. Lactase persistence • All infants have high lactase enzyme activity to digest the sugar lactose in milk • In most humans, activity declines after weaning, but in some it persists: LCT*P

24. Population history and mapping of genetic diseases

25. “Unrelated” individuals… All humans are related if you look back far enough …but some are more related than others Founder effect People are on average more related to each other than in an “outbred” population

26. What’s special about isolated populations? In a more “inbred” population, patients suffering from a disease are more likely to share a common ancestor More likely to have just one type of causative mutation (no allelic heterogeneity) In a younger population, LD blocks are longer (less generations - less time for meiotic recombination) Rare recessive diseases maybe much more prevalent

27. The first replicated ABO association study (1954) Mechanism: ABO blood group binding adhesin BabA in H. pylori

28. Admixture Mapping • “Admixed” population is homogeneous but each individual’s genome is a mosaic of segments from different populations • May be used to map disease loci • multiple sclerosis susceptibility (Reich et al. 2005)

29. Admixture Mapping - requirements • Disease has to show a difference in incidence between the two “ancestral” populations, for example: multiple sclerosis  in Africans vs. Europeans, hypertension  in Africans vs. Europeans • Must have polymorphic markers that differ in frequency in the ancestral populations (HapMap SNPs) • Must have at least 10% admixture Smith and O’Brien (2005) Nat Rev Genet 6, 623-632

30. Admixture mapping Disease allele must have different frequencies in populations 1 and 2 Darvasi and Shifman, Nature Genetics37, 118 - 119 (2005)

31. Assigning ancestry of chromosomal segments Smith and O’Brien (2005) Nat Rev Genet 6, 623-632

32. Admixture Mapping • Patient cohort of black Americans with multiple sclerosis (MS) • MS  in Africans vs. Europeans • Admixture: 20% European, 80% African • Assign chromosomal segments (haplotypes) as “African” or “European” • Patients with MS should show an excess of “European” chromosome segments across disease locus

33. Pharmacogenetics “individualized medicine/therapy” Optimize drug efficacy and minimize toxicity Clinical trial: GSK3-beta gene and bipolar disorder SNP (-50 T/C) in promoter region Recurring episodes reduced with lithium in C/C homozygotes and C/T heterozygotes Benedetti et al., (2005) Neurosc Lett 376, 51-55

34. “It is no surprise that skin pigment is a lousy surrogate for drug-metabolism status or most any aspect of human physiology.” McLeod (2001), News and Views commentary on “Population genetic structure of variable drug response”, Nature Genetics  29, 265 - 269 group fluidity and overlap! 14% of black American vs. 49% of White Americans benefiting from angiotensin-converting enzyme inhibitor for heart failure Yet - BiDil is now the first FDA approved drug for use in a specific ethnic group