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

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The Human Genome and Human Evolution

Chris Tyler-Smith

The Wellcome Trust Sanger Institute


  • 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

Who are our closest living relatives?

Chen FC & Li WH (2001) Am. J. Hum. Genet.68 444-456

Phenotypic differences between humans and other apes

Carroll (2003) Nature422, 849-857

Chimpanzee-human divergence




Hominids or hominins



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

Hominid fossil summary

Found only in Africa

Found both in Africa and outside, or only outside Africa

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

Additional migrations out of Africa

  • First known Europeans date to ~800 KYA

  • Ascribed to H. heidelbergensis

Atapueca 5, Spain,

~300 KYA

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

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

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

Routes of migration?archaeological evidence

Upper Paleolithic




Stone Age

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?


Mixing or replacement?

Human genetic diversity is low

Human genetic diversity is evenly distributed

Most variation



Most variation



Templeton (1999) Am. J.

Anthropol.100, 632-650

Phylogenetic trees commonly indicate a recent origin in Africa

Y chromosome

Modern human mtDNA is distinct from Neanderthal mtDNA

Krings et al. (1997) Cell90, 19-30

Classical marker studies

Based on 120 protein-coding genes in 1,915 populations

Cavalli-Sforza & Feldman (2003) Nature Genet.33, 266-275

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

Y haplogroup distribution

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

An African origin

SE Y haplogroups

NW Y haplogroups

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?

Fluctuations in climate

Ice ages


ice core data

Greenland ice core data

Possible reasons for genetic change

  • Adaptation to new environments

  • Food production – new diets

  • Population increase – new diseases

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

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

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

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

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

Selection in the human genome









Bamshad & Wooding (2003) Nature Rev. Genet.4, 99-111

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)

Non-neutral evolution at PRNP

McDonald-Kreitman test

Resequence coding region

in ? humans and apes


Diversity 5 1


(Gibbon) 2 13

P-value = 0.0055

Mead et al. (2003) Science300, 640-643





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

Effect of positive selection



Derived allele of SNP

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

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

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

Mutation and evolution of the FOXP2 gene

Chr 7


Nucleotide substitutions

FOXP2 gene



Enard et al. (2002) Nature418, 869-872

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?











Human-specific increase in dN/dS ratio (P<0.001)

Enard et al. (2002) Nature418, 869-872

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



Bond et al. (2002) Nature Genet. 32, 316-320

Evolution of the ASPM gene (1)

Summary dN/dS values

Sliding-window dN/dS analysis











Human-specific increase in dN/dS ratio (P<0.03)

Evans et al. (2004) Hum. Mol. Genet.13, 489-494

Evolution of the ASPM gene (2)

McDonald-Kreitman test

Sequence ASPM coding region

from 40 diverse individuals and

one chimpanzee


Diversity 610

Divergence 19 7

P-value = 0.025

Evans et al. (2004) Hum. Mol. Genet.13, 489-494




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

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

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

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

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

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:


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, 233-237

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

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) Nature419, 832-837

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, 208-209 (2004)

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, 849-857 (Broad-ranging review)

  • Paabo S (2003) The mosaic that is our genome. Nature421, 409-412 (Review)

  • Cavalli-Sforza LL, Feldman MW (2003) The application of molecular genetic approaches to the study of human evolution. Nature Genet.33, 266-275 (Review)

  • Stringer C (2002) Modern human origins. Phil. Trans. R. Soc. Lond. B 357, 563-579 (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, 255-264 (mtDNA)

  • Jobling MA, Tyler-Smith C (2003) The human Y chromosome: an evolutionary marker comes of age. Nature Rev. Genet.4, 589-612 (Y chromosome)

  • Bamshad M, Wooding SP (2003) Signatures of natural selection in the human genome. Nature Rev. Genet.4, 99-111

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