The Human Genome and Human Evolution

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The Human Genome and Human Evolution

• Chris Tyler-Smith
• The Wellcome Trust Sanger Institute

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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

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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) Nature 422, 849-857
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Chimpanzee-human divergence
6-8 million years
Hominids or hominins
Chimpanzees
Humans
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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, 145-151
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Hominid fossil summary
Found only in Africa
Found both in Africa and outside, or only outside
Africa
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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
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Additional migrations out of Africa

• First known Europeans date to 800 KYA
• Ascribed to H. heidelbergensis

Atapueca 5, Spain, 300 KYA
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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
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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
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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
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Routes of migration?archaeological evidence
Upper Paleolithic
130 KYA
Middle Stone Age
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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?

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Mixing or replacement?
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Human genetic diversity is low
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Human genetic diversity is evenly distributed
Most variation between populations
Most variation within populations
Templeton (1999) Am. J. Anthropol. 100, 632-650
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Phylogenetic trees commonly indicate a recent
origin in Africa
Y chromosome
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Modern human mtDNA is distinct from Neanderthal
mtDNA
Krings et al. (1997) Cell 90, 19-30
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Classical marker studies
Based on 120 protein-coding genes in 1,915
populations Cavalli-Sforza Feldman (2003)
Nature Genet. 33, 266-275
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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

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Y haplogroup distribution
Jobling Tyler-Smith (2003) Nature Rev. Genet.
4, 598-612
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An African origin
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SE Y haplogroups
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NW Y haplogroups
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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?

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Fluctuations in climate
Ice ages
Antarctic ice core data
Greenland ice core data
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Possible reasons for genetic change

• Adaptation to new environments
• Food production new diets
• Population increase new diseases

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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

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Estimates of the Neolithic Y contribution in
Europe

• 22 (Eu4, 9, 10, 11) Semino et al. (2000)
  Science 290, 1155-1159
• gt70 (assuming Basques Paleolithic and
  Turks/Lebanese/ Syrians Neolithic populations)
  Chikhi et al. (2002) Proc. Natl. Acad. Sci. USA
  99, 11008-11013

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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
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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
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Demographic changes

• Population has expanded in range and numbers

• Genetic impact, e.g. predominantly negative
  values of Tajimas D
• Most data not consistent with simple models e.g.
  constant size followed by exponential growth

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

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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) Science 300, 640-643
coding
non-coding
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Balancing selection at PRNP

• Excess of intermediate-frequency SNPs e.g.
  Tajimas 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
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Effect of positive selection
Neutral
Selection
Derived allele of SNP
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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

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How do we find such changes?

• Chance
• fhHaA type I hair keratin gene inactivation in
  humans
• Identify phenotypic changes, investigate genetic
  basis
• Identify genetic changes, investigate functional
  consequences

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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
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Mutation and evolution of the FOXP2 gene
Chr 7
7q31
Nucleotide substitutions
FOXP2 gene
silent
replacement
Enard et al. (2002) Nature 418, 869-872
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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 (Tajimas D
  -2.20)
• Excess of high-frequency derived alleles (Fay
  Wus 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 (Plt0.001)
Enard et al. (2002) Nature 418, 869-872
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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
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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 (Plt0.03)
Evans et al. (2004) Hum. Mol. Genet. 13, 489-494
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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
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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

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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, 1960-1963
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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. USA
100, 13030-13035
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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
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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

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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

LCTP
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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
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The lactase-persistence haplotype

• The persistence-associated T allele occurs on a
  haplotype (A) showing LD over gt 1 Mb

• Association of lactase persistence and the A
  haplotype is less clear outside Europe

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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, 832-837
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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)
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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.
  Nature 421, 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