1. Islands in Africa: a study of structure in the source population for modern humans Rosalind Harding Depts of Statistics, Zoology & Anthropology, Oxford University Simulations, Genetics and Human Prehistory – A Focus on Islands, The McDonald Institute for Archaeological Research, Cambridge University Gene genealogies from the nuclear genome do not provide clear evidence that modern humans emerged from a small, bottlenecked population. Is there any evidence for diverse ancestry scattered across a subdivided African population and an associated meta-population history of local extinctions, re-colonization and admixture? Methodological problem: how to establish that evidence for structure may date back into the ancestral population, and not arise from recent divergence?

2.  -globin in 1997 suggested population subdivision between African and non-African populations, but not within Africa 2.67 kb sequences from  -globin locus. A/C polymorphism at 357 occurs in the recombination hotspot. Root determined by comparison with chimp, except chimp is not informative at 357. B2 rather than B3 used as root in 1997 study, based on C at 357 in gorilla and gibbon. Harding et al. 1997, Am J Hum Genet 60:772-789 Red: A ‘haplogroup’ Blue: B Yellow: C Green: D

3. San show a different diversity pattern from that seen in 1997. San, n=63 including recombinants Network, median-joining, Fluxus Technology Ltd, 2004 Recombination at hotspot appears to be switching polymorphic sites at 357, 508, and 906 (exon 1, position 6). 11 implied recombinant sequences labelled R. Darker line follows connectivity used in 1997 gene trees, but compare 508 in network with gene tree. Minimum number of recombination events if hotspot not considered is 8 (Beagle program). Red: A Blue: B Yellow: C Green: D Inclusion of San data in African comparisons provides evidence for population structure, but recombination is an issue for further analysis. South African San sample provided by Prof T. Jenkins, sequencing by Y-T Liu

4. Why is recombination an issue for further analysis? Sequences that recombine do not carry the full information needed to reconstruct the order of mutation and recombination events. The number of alternative histories compatible with a set of sequences may be many (even vast!). But, to make any kind of inference about the ancestral population living 100,000 – 250,000 years ago, I need an ordering of events, and to apply a time-scale. I do want to recognize that recombination does increase the uncertainty surrounding any particular reconstruction of events (next slide). Nonetheless, I will argue in favour of a particular reconstruction and proceed using the program genetree, assuming diversity has arisen by a standard coalescent (infinite-sites mutation) process.

5. Recombination for San data increases uncertainty about the order of mutation events One possible history based on the minimum no. of recombination events compatible with San sequences, excluding polymorphisms at 353 & 357. But, I am going to disregard it because these recombination events are not distributed preferentially towards the hotspot. Note 508 in this ordering of events and compare with gene tree for Kenyan Luo. Program: Beagle (Rune Lyngsoe, Statistics Dept, Oxford)

6. An analysis of the migration rates between San and Kenyan Luo based on representative gene trees Random mating, (adjusted for comparison with migration models)  = 3.8 Likelihood of tree: 3.5e-40 Symmetric migration, m=0.5  = 3.2 Likelihood of tree: 5.8e-36 Symmetric migration, m=2.0  = 3.4 Likelihood of tree: 3.0e-33 Symmetric migration, m=4.0  = 3.6 Likelihood of tree: 9.5e-34 Asymmetric migration m=4.0 out of San, m=0.5 in  = 3.7 Likelihood of tree: 6.5e-35 Asymmetric migration m=0.5 out of San, m=4.0 in  = 3.8 Likelihood of tree: 1.3e-32 SanLuo SanLuo Presence of diversity found only in San suggests they were separate and isolated from other African populations, and did not greatly contribute as a source population for other African populations (Kenyan Luo, Gambia, Pygmies). However, the San have been a recipient population for admixture.

7. Population subdivision, two-island model: asymmetric migration (m=0.5 out of San, 4.0 in). ML(  )=3.8 gives an estimate for N e – 15,280 TMRCA=2.02 Program: genetree Under this model, the diversity is old enough to have evolved in the population ancestral to modern humans.

8. Conclusions Question: Is there evidence for ancestral population structure associated with evolution of modern humans? Answer: There is good evidence for structure between San and other African groups, and it is feasible that  - globin data preserve evidence of structure present in the ancestral source population for modern humans. Caveats: many! Aside: asymmetric migration rates suggest a meta- population history of local extinctions, re-colonisation and admixture to me.