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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


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


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

6-8

million

years

Hominids or hominins

Chimpanzees

Humans


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

~130

KYA

Middle

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?

14


Mixing or replacement?


Human genetic diversity is low


Human genetic diversity is evenly distributed

Most variation

between

populations

Most variation

within

populations

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

Antarctic

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

time

Negative

(Purifying,

Background)

Positive

(Directional)

Neutral

Balancing

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

N S

Diversity 5 1

Divergence

(Gibbon) 2 13

P-value = 0.0055

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

‘coding’

‘non-coding’


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


Effect of positive selection

Neutral

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

7q31

Nucleotide substitutions

FOXP2 gene

silent

replacement

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?

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


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


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


Evolution of the ASPM gene (2)

McDonald-Kreitman test

Sequence ASPM coding region

from 40 diverse individuals and

one chimpanzee

NS

Diversity 610

Divergence 19 7

P-value = 0.025

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


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


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:

LCT*P


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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