The Human Genome and Human Evolution

1. The Human Genome and Human Evolution Chris Tyler-Smith The Wellcome Trust Sanger Institute

2. Outline • Information from fossils and archaeology • Neutral (or assumed-to-be-neutral) genetic markers • Classical markers • Y chromosome • Demographic changes • Genes under selection • Balancing selection • Positive selection

3. Who are our closest living relatives? Chen FC & Li WH (2001) Am. J. Hum. Genet.68 444-456

4. Phenotypic differences between humans and other apes Carroll (2003) Nature422, 849-857

5. Chimpanzee-human divergence 6-8 million years Hominids or hominins Chimpanzees Humans

6. Origins of hominids • Sahelanthropus tchadensis • Chad (Central Africa) • Dated to 6 – 7 million years ago • Posture uncertain, but slightly later hominids were bipedal ‘Toumai’, Chad, 6-7 MYA Brunet et al. (2002) Nature418, 145-151

7. Hominid fossil summary Found only in Africa Found both in Africa and outside, or only outside Africa

8. Origins of the genus Homo • Homo erectus/ergaster ~1.9 million years ago in Africa • Use of stone tools • H. erectus in Java ~1.8 million years ago Nariokatome boy, Kenya, ~1.6 MYA

9. Additional migrations out of Africa • First known Europeans date to ~800 KYA • Ascribed to H. heidelbergensis Atapueca 5, Spain, ~300 KYA

10. Origins of modern humans (1) • Anatomically modern humans in Africa ~130 KYA • In Israel by ~90 KYA • Not enormously successful Omo I, Ethiopia, ~130 KYA

11. Origins of modern humans (2) • Modern human behaviourstarts to develop in Africa after ~80 KYA • By ~50 KYA, features such as complex tools and long-distance trading are established in Africa The first art? Inscribed ochre, South Africa, ~77 KYA

12. Expansions of fully modern humans • Two expansions: • Middle Stone Age technology in Australia ~50 KYA • Upper Palaeolithic technology in Israel ~47 KYA Lake Mungo 3, Australia, ~40 KYA

13. Routes of migration?archaeological evidence Upper Paleolithic ~130 KYA Middle Stone Age

14. Strengths and weaknesses of the fossil/archaeological records • Major source of information for most of the time period • Only source for extinct species • Dates can be reliable and precise • need suitable material, C calibration required • Did they leave descendants? 14

15. Mixing or replacement?

16. Human genetic diversity is low

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

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

19. Modern human mtDNA is distinct from Neanderthal mtDNA Krings et al. (1997) Cell90, 19-30

20. Classical marker studies Based on 120 protein-coding genes in 1,915 populations Cavalli-Sforza & Feldman (2003) Nature Genet.33, 266-275

21. Phylogeographic studies • Analysis of the geographical distributions of lineages within a phylogeny • Nodes or mutations within the phylogeny may be dated • Extensive studies of mtDNA and the Y chromosome

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

23. An African origin

24. SE Y haplogroups

25. NW Y haplogroups

26. Did both migrations leave descendants? • General SE/NW genetic distinction fits two-migration model • Basic genetic pattern established by initial colonisation • All humans outside Africa share same subset of African diversity (e.g. Y: M168, mtDNA: L3) • Large-scale replacement, or migrations were not independent • How much subsequent change?

27. Fluctuations in climate Ice ages Antarctic ice core data Greenland ice core data

28. Possible reasons for genetic change • Adaptation to new environments • Food production – new diets • Population increase – new diseases

29. Debate about the Paleolithic-Neolithic transition • Major changes in food production, lifestyle, technology, population density • Were these mainly due to movement of people or movement of ideas? • Strong focus on Europe

30. Estimates of the Neolithic Y contribution in Europe • ~22% (=Eu4, 9, 10, 11); Semino et al. (2000) Science290, 1155-1159 • >70% (assuming Basques = Paleolithic and Turks/Lebanese/ Syrians = Neolithic populations); Chikhi et al. (2002) Proc. Natl. Acad. Sci. USA 99, 11008-11013

31. More recent reshaping of diversity • ‘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 Zerjal et al. (2003) Am. J. Hum. Genet. 72, 717-721

32. Is the Y a neutral marker? • Recurrent partial deletions of a region required for spermatogenesis • Possible negative selection on multiple (14/43) lineages Repping et al. (2003) Nature Genet. 35, 247-251

33. Demographic changes • Population has expanded in range and numbers • Genetic impact, e.g. predominantly negative values of Tajima’s D • Most data not consistent with simple models e.g. constant size followed by exponential growth

34. Selection in the human genome time Negative (Purifying, Background) Positive (Directional) Neutral Balancing Bamshad & Wooding (2003) Nature Rev. Genet.4, 99-111

35. The Prion protein gene and human disease • Prion protein gene PRNP linked to ‘protein-only’ diseases e.g. CJD, kuru • A common polymorphism, M129V, influences the course of these diseases: the MV heterozygous genotype is protective • Kuru acquired from ritual cannibalism was reported (1950s) in the Fore people of Papua New Guinea, where it caused up to 1% annual mortality • Departure from Hardy-Weinberg equilibrium for the M129V polymorphism is seen in Fore women over 50 (23/30 heterozygotes, P = 0.01)

36. Non-neutral evolution at PRNP McDonald-Kreitman test Resequence coding region in ? humans and apes N S Diversity 5 1 Divergence (Gibbon) 2 13 P-value = 0.0055 Mead et al. (2003) Science300, 640-643 ‘coding’ ‘non-coding’

37. Observed Expected Balancing selection at PRNP • Excess of intermediate-frequency SNPs: e.g. Tajima’s D = +2.98 (Fore), +3.80 (CEPH families) • Deep division between the M and V lineages, estimated at 500,000 years (using 5 MY chimp-human split) 24 SNPs in 4.7 kb region, 95 haplotypes

38. Effect of positive selection Neutral Selection Derived allele of SNP

39. What changes do we expect? • New genes • Changes in amino-acid sequence • Changes in gene expression (e.g. level, timing or location) • Changes in copy number

40. How do we find such changes? • Chance • φhHaA type I hair keratin gene inactivation in humans • Identify phenotypic changes, investigate genetic basis • Identify genetic changes, investigate functional consequences

41. Inheritance of a language/speech defect in the KE family Autosomal dominant inheritance pattern Lai et al. (2000) Am. J. Hum. Genet. 67, 357-367

42. Mutation and evolution of the FOXP2 gene Chr 7 7q31 Nucleotide substitutions FOXP2 gene silent replacement Enard et al. (2002) Nature418, 869-872

43. Positive selection at the FOXP2 gene • Resequence ~14 kb of DNA adjacent to the amino-acid changes in 20 diverse humans, two chimpanzees and one orang-utan • No reduction in diversity • Excess of low-frequency alleles (Tajima’s D = -2.20) • Excess of high-frequency derived alleles (Fay & Wu’s H =-12.24) • Simulations suggest a selective sweep at 0 (0 – 200,000) years Constant rate of amino-acid replacements? Positive selection in humans? replacement (non-synonymous) dN silent (synonymous) dS Orang Gorilla Chimp Human Human-specific increase in dN/dS ratio (P<0.001) Enard et al. (2002) Nature418, 869-872

44. A gene affecting brain size Microcephaly (MCPH) • Small (~430 cc v ~1,400 cc) but otherwise ~normal brain, only mild mental retardation • MCPH5 shows Mendelian autosomal recessive inheritance • Due to loss of activity of the ASMP gene ASPM-/ASPM- control Bond et al. (2002) Nature Genet. 32, 316-320

45. Evolution of the ASPM gene (1) Summary dN/dS values Sliding-window dN/dS analysis 0.62 0.52 0.53 1.44 0.56 0.56 Orang Gorilla Chimp Human Human-specific increase in dN/dS ratio (P<0.03) Evans et al. (2004) Hum. Mol. Genet.13, 489-494

46. Evolution of the ASPM gene (2) McDonald-Kreitman test Sequence ASPM coding region from 40 diverse individuals and one chimpanzee N S Diversity 6 10 Divergence 19 7 P-value = 0.025 Evans et al. (2004) Hum. Mol. Genet.13, 489-494

47. asp Microtubules DNA do Carmo Avides and Glover (1999) Science283, 1773-1735 What changes? • FOXP2 is a member of a large family of transcription factors and could therefore influence the expression of a wide variety of genes • The Drosophila homolog of ASPM codes for a microtubule-binding protein that influences spindle orientation and the number of neurons • Subtle changes to the function of well-conserved genes

48. Genome-wide search for protein sequence evolution • 7645 human-chimp-mouse gene trios compared • Most significant categories showing positive selection include: • Olfaction: sense of smell • Amino-acid metabolism: diet • Development: e.g. skeletal • Hearing: for speech perception Clark et al. (2003) Science302, 1960-1963

49. Increased expression Decreased expression Gene expression differences in human and chimpanzee cerebral cortex • Affymetrix oligonuclotide array (~10,000) genes • 91 show human-specific changes, ~90% increases Caceres et al. (2003) Proc. Natl. Acad. Sci. USA100, 13030-13035

50. Copy number differences between human and chimpanzee genomic DNA Human male reference genomic DNA hybridised with female chimpanzee genomic DNA Locke et al. (2003) Genome Res. 13, 347-357