Download Human Molecular Evolution Lecture 2

Human Molecular Evolution
Lecture 1
Molecular evolution – Humans as apes
You can download a copy of these slides from
www.stats.ox.ac.uk/~harding
We are apes!
though a unique form of ape
• What makes us different from other apes?
Apes are primates
Great apes are shown.
Gibbons also are apes, (i.e.
lesser apes).
Homo
sapiens
(human)
Pongo pygmaeus
(orangutan)
Gorilla gorilla (lowland
gorilla)
Pan troglodytes
(common
chimpanzee)
Gibbon (lesser ape)
Primate
classification
In 1735 Linneas classified
humans in the same
taxonomic group with
other living primates:
apes, monkeys, lemurs,
lorises, and tarsiers, in his
Anthropomorpha, now
Order: Primates.
Ring tailed lemur
Pygmy loris
Spider monkey
Tarsier
The beginnings of the
study of primate
evolution
Charles Darwin
• 1830s: first discoveries of primate fossils, providing
evidence of a temporal dimension in primate diversity
and biogeography, including extinct species & evidence
that apes once lived in Europe.
• Publication of Darwin’s Origin of Species (1859) and
The Descent of Man and Selection in Relation to Sex
(1871): explaining how evolution could take place.
– ‘much light will be thrown on the origin of man and his history’
Primates: basic
design
• Generalised arboreal anatomy,
but many examples of
specialized adaptations for
locomotion, e.g.
– Knuckle walking by
chimpanzees and gorillas, but
not by humans.
• Stereoscopic vision
• Most have opposability of their
thumbs and/or first toes to
make for a grasping hand
• Many have relatively large
brains for their body size
• Life history traits: variation in
gestation length, age of
weaning, age at sexual maturity
(the high end of which is not
found in other primates of
comparable body size), that
emphasize high investment in
small numbers of offspring,
learned behaviour and sociality.
Primatology as a basis for the
study of human evolution
• By the beginning of the 20th century, primate evolution
had become established as an area of major interest
within anthropology – providing the broad evolutionary
context for studying human origins.
• Classification by morphological similarity is challenged
by phylogenetic methods.
• What was the branching order of these species?
– Chromosomes (karyotypes)
– Molecules (proteins and DNA)
• What was the time scale?
– Fossils
– Molecules
Tarsier
Primate Phylogeny
Pygmy Loris
Higher Primates (including
apes and monkeys) and
Tarsiers are Haplorhines
Divergence between
Haplorhines vs
Strepsirhines
(bushbabies, lorises and
lemurs)
Note the time scales.
Supported by fossils
Estimated from molecular
divergence
Branching order and time-scale for
ape phylogeny
Hla: Hylobates lar
(gibbon)
1
Ggo: Gorilla gorilla
2
Ptr: Pan troglodytes
(common chimp)
3
Ppa: Pan paniscus
(bonobo)
4
5
Hsa: Homo sapiens
(humans)
Ppy: Pongo pygmaeus
(orangutan)
Hacia JG (2001)
What traits distinguish
humans from other
apes?
•
•
•
•
•
•
•
•
•
•
Body shape, S-shaped spine
Relative limb length
Efficient bipedal locomotion
Skull balanced upright on vertebral column
Cranial properties, relative brain size and brain topology
Small canine teeth
Long ontogeny (development time) and lifespan
Reduced body hair
Language
Advanced tool making
How did these traits
evolve? Evidence from
hominin fossils
 Bipedal mode of
location, evident
for earliest
hominins –
australopithecines
 Large brain,
disproportionately
large for body size;
evolved ~2 MYA,
characteristic of
Homo
Our closest living relatives are chimps
Nature 437(7055):17-19, 2005
Chimpanzees: two species
(and several subspecies)
Pan troglodytes
(common chimp)
Pan paniscus (bonobo)
What can we learn from studies
of chimps?
Chimp species (Pan troglodytes and Pan
paniscus) and subspecies are
geographically isolated
Niger R.
Western
Sanaga R.
Ubangui R.
Eastern
Central
Bonobo
Ranges of chimp species and
subspecies appear bounded by rivers.
Gagneux (2002) TIG 18:327-330
Gorilla
Bonobo
P.t. schweinfurthii
(Eastern)
Human
P.t. troglodytes
(Central)
P.t. verus
(Western)
Figure from Stone et al. (2002)
Unrooted
phylogenetic
tree (maximum
parsimony) for
Y chromosome
haplotypes
The tree indicates that
some nucleotide
differences
discriminate chimp
subspecies.
What does this impIy
for FST?
Reconstructing haplotypes from the tree
Pp3
Pp2
Pp1
Bonobo
Ptv1
Ptv2
Western
Ptt1
Ptt2
Ptt4
Ptt5
Central
The actual locations of variable sites are unknown,
but we have some information about how variable
sites are shared between haplotypes.
Estimating FST from Y haplotypes
 FST = 0 (min value) when allele / haplotype lineages
frequencies are the same across subpopulations, ie
variance (s2) is zero.
 FST = 1 (max value) when alternative alleles / haplotype
lineages are fixed (100% freq) in different
subpopulations.
 The Y haplotype tree indicates that chimp
subpopulations have diverged and do not share
haplotype lineages.
FST ~ 1
 The Western and Central common chimpanzee (P.
troglotydes) subpopulations have diverged nearly as
much from each other as from P. paniscus (bonobo).
 MtDNA likewise discriminates chimp sub-’species’.
Estimating diversity from average
pairwise sequence difference
Bonobo
Pp3 freq= 2
Pp2 freq= 2
Pp1 freq= 4
Pp1 Pp1 Pp1 Pp1 Pp2 Pp2 Pp3 Pp3
Pp1
Pp1
Pp1
Pp1
Pp2
Pp2
Pp3
Pp3
0
0
0
0
3
3
3
3
0
0
0
0
3
3
3
3
0
0
0
0
3
3
3
3
0
0
0
0
3
3
3
3
3
3
3
3
0
0
1
1
3
3
3
3
0
0
1
1
3
3
3
3
1
1
0
0
3
3
3
3
1
1
0
0
Av = 104/64
= 1.625
Divide Av by the
length of
sequence to give
nucleotide
diversity, p.
Gorilla
Bonobo
P.t. schweinfurthii
(Eastern)
Human
P.t. troglodytes
(Central)
P.t. verus
(Western)
Figure from Stone et al. (2002)
Unrooted
phylogenetic
tree (maximum
parsimony) for
Y chromosome
haplotypes
The tree indicates that
Bonobo and Central
chimps have similar
levels of diversity, but
that Western chimps
have less diversity.
Phylogenetic tree
(maximum likelihood)
of chimpanzee and
bonobo Xq13.3
haplotypes
B: Bonobo, Pan paniscus
C: Central African, P. t. t.
W: Western, P. t. verus E:
Eastern, P. t.
schweinfurthii
Kaessmann et al. 1999 Science 286:1159-1162
Haplotypes do not
completely discriminate
subspecies. What does
this imply for FST ?
Implications for FST and p
 The tree shows incomplete lineage sorting for
Xq13.3 haplotypes.
 There is a high level of population divergence but
some Central chimp haplotypes are mixed in with
the Western chimp haplotypes, so FST <1
 Note that the average sequence difference
between pairs of haplotypes (p) taken for
Western chimps will be smaller than the average
sequence difference between pairs of
haplotypes (p) taken for Central chimps.
 Diversity for Central chimps is higher than for
Western chimps.
Comparing human and
chimp genomes
15 Feb 2001
Heterozygosity, estimated by p
(av. sequence difference between
two chromosomes)
 p = 7.51 x 10-4
 i.e. 1 SNP per 1,331 bp
 NIH diversity panel
(including African
American, European,
Chinese)
1 Sept 2005
 p = 9.5 x 10-4 for Clint
(from West Africa)
 p = 9.5 x 10-4 among 4
West African chimps
 p = 17.6 x 10-4 among 3
Central African chimps.
West African chimps have similar genomic diversity to humans.
Central African chimps have twice as much diversity.
Ne for Chimps (P. troglodytes) ?
Chimpanzee
MtDNA
NRY (3 kb)
*Stone et al. (2002)
PNAS 99:43-48
Xq13.3 (10 kb)
Kaessmann et al.
(1999)
50 autosomal
loci
Yu et al. (2003)
Genetics 164:15111518
% sequence
differences
*Nef =41,000;
*Nem= 21,000
p=0.0007; qW=0.0011
Ne=35,000
p=0.0013;
Ne=20,900 (P. troglodytes)
Ne = 20,100 (P.t.t.)
Ne = 14,600 (P.t.s.)
Ne = 13,000 (P.t.v.)
~3-7 times
higher in
chimps than in
humans for
mtDNA, NRY
and Xq13.3
~1-2 times
higher in
chimps than in
humans for
autosomal loci.
Differences between loci
• Why are there greater sequence differences among
chimps in Y haplotypes and mtDNA compared with
autosomal genomes?
• Isolation between chimp subpopulations leads to
genetic divergence, lineage sorting and accumulation
of fixed differences. This effect has added sequence
differences in addition to polymorphism in Y
haplotypes and mtDNA but not to autosomal loci.
• The estimates of Ne for chimps from Y haplotypes
and mtDNA are incorrect because they should be
based only on polymorphism, not on fixed
differences.
What is effective population size, Ne?
• An estimate of Ne from autosomal genetic diversity:
N^e = p / 4.m
• In the model, Ne is inversely proportional to how
genetic drift has enhanced or eroded polymorphism.
• In the data, p is an estimator of Nem provided that it is
based on polymorphism.
• Two issues for interpreting sequence diversity:
– Size (Ne) – diversity shared by larger numbers of breeding
individuals in a population is less subject to erosion by
genetic drift.
– Structure – a number of individuals in a structured population
(island model) may present more sequence differences than
the same number in a randomly-mating population.
Comparing humans with chimps:
population structure
Humans
• Diversity in racial
phenotypes does not mark
genetic divergence.
• A moderate level of
structure: FST ~0.15 between
populations, across most
classes of polymorphism,
though lower than this for
(microsatellites) and higher
(~0.33-0.38) for Y
haplotypes.
• Largest genetic distances
are between populations
within sub-Saharan Africa
not between populations on
different continents
Chimpanzees
• Diversity in phenotypes does
mark genetic divergence
between bonobo and
common chimps but not
divergence between chimp
subpopulations.
• A high level of structure and
isolation leading to
divergence. Even higher for
Y chromosomes than for
autosomal loci.
• Genetic distances between
subpopulations almost as
large as between species.
Comparing humans with chimps:
differential selective pressures?
• Morphological diversity is low in chimps compared with
humans. Is this due to strong differential selection in
humans.
• Classical polymorphisms (blood groups) and enzyme
polymorphisms have higher diversity in humans than in
chimps.
• MHC diversity, for HLA-A in particular, is lower in chimps
than in humans.
• Levels of polymorphism at VNTRs, dinucleotide
microsatellites in particular, seem reduced in chimps
compared with humans. Ascertainment bias is a partial
but incomplete explanation.
• How have patterns of selection differed in humans
compared with chimps? Local adaptations to climate?
And to pathogens?
Conclusions
• One feasible assumption is that hominins during the
Pleistocene were a highly structured species, with
species and sub-species differentiation like in
chimps today.
• Then from contemporary levels and patterns of
genetic diversity we can suggest that modern
humans descend from a single regional subpopulation and reject the multiregional hypothesis.
• The estimates of ~10,000 for Ne for humans and for
western chimps implies that neutral diversity is
being lost by genetic drift as expected in long term
small populations
• The estimate of 20,000 for Ne for central chimps
implies a larger long term evolutionary size.
References
• Bramble DM and Lieberman DE (2004) Endurance
running and the evolution of Homo. Nature 432: 352345.
• Hacia JG (2001) Genome of the apes. Trends in
Genetics 17(11): 645-637
• Gagneux P (2002) The genus Pan: population genetics
of an endangered outgroup. Trends in Genetics 18:327330