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,