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

Pongo pygmaeus (orangutan)

Gorilla gorilla (lowland gorilla)

Homo sapiens (human)

Pan troglodytes (common chimpanzee)

Great apes are shown. Gibbons also are apes, (i.e. lesser apes).

Primate classification

Gibbon (lesser ape)

Pygmy loris

Ring tailed lemur

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.

Spider monkey

Tarsier

The beginnings of the study of primate

evolution

• 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’

Charles Darwin

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

Primate Phylogeny

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

Pygmy Loris

Tarsier

Branching order and time-scale for ape phylogeny

Hla: Hylobates lar (gibbon)

Ggo: Gorilla gorilla

Ptr: Pan troglodytes (common chimp)

Ppa: Pan paniscus (bonobo)

Hsa: Homo sapiens (humans)

Ppy: Pongo pygmaeus (orangutan)

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23

4

5

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.

Sanaga R.

Ubangui R.

Ranges of chimp species and subspecies appear bounded by rivers.

Bonobo

Gagneux (2002) TIG 18:327-330

Eastern

Central

Western

Unrooted phylogenetic tree (maximum parsimony) for Y chromosome haplotypes

Gorilla

Human

Bonobo

P.t. verus (Western)

P.t. troglodytes (Central)

P.t. schweinfurthii

(Eastern)

The tree indicates that some nucleotide differences discriminate chimp subspecies.

What does this impIy for FST? Figure from Stone et al. (2002)

Reconstructing haplotypes from the tree

Pp3Pp2Pp1

Bonobo

Ptv1Ptv2 Western

Ptt1Ptt2Ptt4Ptt5

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 (2) 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

Pp3 freq= 2Pp2 freq= 2Pp1 freq= 4

Bonobo

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, .

Unrooted phylogenetic tree (maximum parsimony) for Y chromosome haplotypes

Gorilla

Human

Bonobo

P.t. verus (Western)

P.t. troglodytes (Central)

P.t. schweinfurthii

(Eastern)

The tree indicates that Bonobo and Central chimps have similar levels of diversity, but that Western chimps have less diversity.

Figure from Stone et al. (2002)

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

Haplotypes do not completely discriminate subspecies. What does this imply for FST ?Kaessmann et al. 1999 Science 286:1159-1162

Implications for FST and

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 () taken for Western chimps will be smaller than the average sequence difference between pairs of haplotypes () taken for Central chimps.

Diversity for Central chimps is higher than for Western chimps.

Comparing human and chimp genomes

= 7.51 x 10-4 i.e. 1 SNP per 1,331 bp NIH diversity panel

(including African American, European, Chinese)

= 9.5 x 10-4 for Clint (from West Africa)

= 9.5 x 10-4 among 4 West African chimps

= 17.6 x 10-4 among 3 Central African chimps.

15 Feb 2001

Heterozygosity, estimated by (av. sequence difference between two chromosomes)

West African chimps have similar genomic diversity to humans. Central African chimps have twice as much diversity.

1 Sept 2005

Ne for Chimps (P. troglodytes) ?

Chimpanzee

MtDNA *Nef =41,000;

NRY (3 kb) *Stone et al. (2002) PNAS 99:43-48

*Nem= 21,000

=0.0007; W=0.0011

Xq13.3 (10 kb) Kaessmann et al. (1999)

Ne=35,000

=0.0013;

50 autosomal loci Yu et al. (2003) Genetics 164:1511-1518

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.

% sequence differences

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: Ne = / 4.

• In the model, Ne is inversely proportional to how genetic drift has enhanced or eroded polymorphism.

• In the data, is an estimator of Ne 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

• 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

• 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.

Humans Chimpanzees

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 sub-population 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: 352-345.

• 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 18:327-330