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) Nature 422, 849-857
Chimpanzee-human divergence
6-8
million
years
Chimpanzees
Hominids or hominins
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) Nature 418, 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 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
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
39 KYA
40 KYA
47 KYA
~130
KYA
50 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, 14C calibration required
• Did they leave descendants?
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
90 (50 - 130) KYA, Hammer and Zegura
59 (40 - 140) KYA, Thomson et al.
90
69 (56 - 81) KYA, Hammer and Zegura
40 (35 - 89) KYA, Thomson et al.
80
KYA
70
60
50
40
30
20
10
0
A
B C D E F* G H
I
J K* L M N O P* Q R
Y chromosome
Modern human mtDNA is distinct
from Neanderthal mtDNA
Krings et al. (1997) Cell 90, 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
A
B C D E F* G H
I
J K* L M N O P* Q R
Jobling & Tyler-Smith (2003) Nature Rev. Genet. 4, 598-612
An African origin
A
B C D E F* G H
I
J K* L M N O P* Q R
SE Y haplogroups
A
B C D E F* G H
I
J K* L M N O P* Q R
NW Y haplogroups
A
B C D E F* G H
I
J K* L M N O P* Q R
Did both migrations leave
descendants?
• General SE/NW genetic distinction fits twomigration 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
4
Ice ages
0
-2
-4
-6
Antarctic
ice core data
-8
-10
100
90
80
70
60
50
Greenland ice core data
KYA
40
30
20
10
0
Temperature difference (C)
2
Possible reasons for genetic change
• Adaptation to new environments
• Food production – new diets
• Population increase – new diseases
Debate about the PaleolithicNeolithic 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)
Science 290, 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
Neutral
Negative
(Purifying,
Background)
Balancing
Positive
(Directional)
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
Divergence
(Gibbon)
N
5
S
1
2
13
P-value = 0.0055
‘coding’
‘non-coding’
Mead et al. (2003) Science 300, 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)
Observed
Expected
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) Nature 418, 869-872
Positive selection at the FOXP2 gene
Constant rate of amino-acid replacements?
Positive selection in humans?
•
replacement
(non-synonymous)
silent
dN
(synonymous)
•
•
dS
•
•
Orang
Gorilla
Chimp
Human
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
Human-specific increase in dN/dS ratio (P<0.001)
Enard et al. (2002) Nature 418, 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
Orang
Gorilla
0.56
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
N
Diversity
6
Divergence 19
S
10
7
P-value = 0.025
Evans et al. (2004) Hum. Mol. Genet. 13, 489-494
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
asp
Microtubules
DNA
do Carmo Avides and Glover (1999) Science 283, 1773-1735
• 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) Science 302, 1960-1963
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, 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 persistenceassociated 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) Nature 419, 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. 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