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The Human Genome and Human Evolution

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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

4 Phenotypic differences between humans and other apes
Carroll (2003) Nature 422,

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) Nature 418,

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 behaviour starts 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,

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) Cell 90, 19-30

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

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,

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) Science 290, >70% (assuming Basques = Paleolithic and Turks/Lebanese/ Syrians = Neolithic populations); Chikhi et al. (2002) Proc. Natl. Acad. Sci. USA 99,

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,

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,

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,

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 Divergence (Gibbon) P-value = Mead et al. (2003) Science 300, ‘coding’ ‘non-coding’

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

42 Mutation and evolution of the FOXP2 gene
Chr 7 7q31 Nucleotide substitutions FOXP2 gene silent replacement Enard et al. (2002) Nature 418,

43 Positive selection at the FOXP2 gene
Constant rate of amino-acid replacements? Positive selection in humans? 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 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) Nature 418,

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,

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,

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

47 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 do Carmo Avides and Glover (1999) Science 283, DNA Microtubules asp 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) Science 302,

49 Gene expression differences in human and chimpanzee cerebral cortex
Affymetrix oligonuclotide array (~10,000) genes 91 show human-specific changes, ~90% increases Increased expression Decreased expression Caceres et al. (2003) Proc. Natl. Acad. Sci. USA 100,

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,

51 Selection at the CCR5 locus
CCR532/CCR532 homozygotes are resistant to HIV and AIDS The high frequency and wide distribution of the 32 allele suggest past selection by an unknown agent

52 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

53 Molecular basis of lactase persistence
Lactase level is controlled by a cis-acting element Linkage and LD studies show association of lactase persistence with the T allele of a T/C polymorphism 14 kb upstream of the lactase gene Enattah et al. (2002) Nature Genet. 30,

54 The lactase-persistence haplotype
The persistence-associated T allele occurs on a haplotype (‘A’) showing LD over > 1 Mb Association of lactase persistence and the A haplotype is less clear outside Europe

55 Selection at the G6PD gene by malaria
Reduced G6PD enzyme activity (e.g. A allele) confers some resistance to falciparum malaria Extended haplotype homozygosity at the A allele Sabeti et al. (2002) Nature 419,

56 Final words Is there a genetic continuum between us and our
ancestors and the great apes? If there is, then we can say that these [i.e. microevolutionary] processes are genetically sufficient to fully account for human uniqueness — and that would be my candidate for the top scientific problem solved in the first decade of the new millennium. Nature 427, (2004)

57 Further reading Jobling MA, Hurles ME, Tyler-Smith C (2004) Human Evolutionary Genetics. Garland Science (General textbook) Carroll SB (2003) Genetics and the making of Homo sapiens. Nature, 422, (Broad-ranging review) Paabo S (2003) The mosaic that is our genome. Nature 421, (Review) Cavalli-Sforza LL, Feldman MW (2003) The application of molecular genetic approaches to the study of human evolution. Nature Genet. 33, (Review) Stringer C (2002) Modern human origins. Phil. Trans. R. Soc. Lond. B 357, (Fossils and archaeology) Forster P (2004) Ice Ages and the mitochondrial DNA chronology of human dispersals: a review. Phil. Trans. R. Soc. Lond. B 359, (mtDNA) Jobling MA, Tyler-Smith C (2003) The human Y chromosome: an evolutionary marker comes of age. Nature Rev. Genet. 4, (Y chromosome) Bamshad M, Wooding SP (2003) Signatures of natural selection in the human genome. Nature Rev. Genet. 4,

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