Phil. Trans. R. Soc. B (2012) 367, 765769 doi:10.1098/rstb.2011.

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Introduction

Diverse approaches to analysing the history of human and pathogen evolution: how to tell the story of the past 70 000 years
D. M. Altmann1,*, F. Balloux2 and R. J. Boyton1
1

Section of Infectious Diseases and Immunity, Department of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK 2 MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College, St Marys Campus, Norfolk Place, London W2 1PG, UK

The meeting Human evolution, migration and history revealed by genetics, immunity and infection, along with the follow-on satellite meeting at the Kavli Centre over the subsequent two days, brought together diverse talents. The aim was to see if new insights could be gained by bringing together those who have interests in the past 50100 000 years of human history, overlaying the perspectives of palaeogeneticists, anthropologists, human geneticists, pathogen geneticists, immunologists, disease modellers, linguists, immunogeneticists, historians and archaeologists. It rapidly became clear that while all may agree on the broad brush-strokes including out-of-Africa and the general approximations of timelines, diverse approaches may often suggest somewhat different ways of telling the story. Keywords: pathogen; evolution; immunity

1. INTRODUCTION During the temperate days of 6 and 7 June 2011, a diverse group met at the Royal Society, just off the Mall and Buckingham Palace still bedecked in the paraphernalia of a royal wedding, to discuss the human story since migration out-of-Africa. The preamble to the meeting had promised insights into ways in which genetics can teach us about the evolution and migration of humans and the historical impact of infection. This meeting, it was promised, would span molecules to history, with geneticists, immunologists, anthropologists and historians meeting to nurture integration and synthesis. The following pages of this issue contain the manuscripts submitted by the speakers as a formal record of the meeting. That many of the speakers chose to revise their manuscripts substantially as a result of their discussions in the meeting attests to the lively and, occasionally transformative, discussions that ensued. Most of those present at the meeting were familiar with those of the speakers originating in their own academic silos. Few, however, were familiar with each of the silos represented. This made for challenging talks as well as many challenges to commonly held assumptions from those outside their own elds. The meeting Human evolution, migration and history revealed by genetics, immunity and infection, along with the follow-on satellite meeting at the Kavli Centre over the

* Author for correspondence (d.altmann@imperial.ac.uk). One contribution of 14 to a Discussion Meeting Issue Immunity, infection, migration and human evolution.

subsequent two days (gure 1), brought together diverse talents. The aim was to see if new insights could be gained by bringing together those who have interests in the past 50100 000 years of human history, overlaying the perspectives of palaeogeneticists, anthropologists, human geneticists, pathogen geneticists, immunologists, disease modellers, linguists, immunogeneticists, historians and archaeologists. It rapidly became clear that while all may agree on the broad brush-strokes including out-of-Africa and the general approximations of timelines, diverse approaches may often suggest somewhat different ways of telling the story. Our historic sweep for the appraisal of bi-directional evolutionary pressure in host pathogen interactions is one across a changing landscape: this is a story that encompasses the impact of migration and mixing populations, changing lifestyles and population densities, the onset of domestication of livestock and changing exposure to animals and zoonoses as well as changes in nutrition. Mark Jobling red a salutary shot across the boughs of any seeking to tie up easy links between the various elds: on the one hand, we have a fragmentary grasp of the biological history, drawn perhaps from mitochondrial DNA sequences or from amplication of ancient genomic DNA. On the other hand, we have, often, an equally fragmentary account of the historical timeline to which we seek to tether the twists and turns of the biological story [1]. The warning is that we should resist the temptation to link relationships casually through cherry picking those milestones in human history that are best recorded. While it is tempting to look for the correlates in evolutionary selection of the Black Death, the fall 765
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Figure 1. Attendees at the Kavli satellite meeting.

of the Roman Empire or the colonization of South America, how many equally or more dramatic bottlenecks have been imposed in the past millennia by pathogens, climate change or natural disasters for which we lack a good historical record (or any awareness at all)? An honourable exception here is the very rigorous appraisal in this issue from Mark Achtman [2] of Yersinia pestis, the causative agent in plague and thus the Black Death, and its origins in China. Genetically monomorphic pathogens of this type are relatively easy to analyse by comparative genomics precisely because their recent origins allow easier reconstructions of their history than is possible with most other microbes. For part of the narrative, it is clearly important that we delve back further than out-of-Africa. As Marta Lahr (University of Cambridge) pointed out, three quarters of our history as a species resides exclusively in Africa during the 150 kyr prior to the successful migrations that populated the other continents. One of the biggest obstacles to reconstructing our story is the very fragmentary evidence we have from palaeontology or archaeological artefacts of either our own species during that period or indeed of the related species. This became apparent during debate over a high-prole presentation from Peter Parham, described in this issue [3] and since published in detail in Science [4]. The premise is that since some human leucocyte antigen (HLA) class allelic sequences found in modern Europeans are found in European Neanderthal and Denisova genomic DNA but not among the extensive HLA polymorphisms found in Africa, these were selected following interbreeding post-Africa, and confer advantage in the new setting. This provocative notion led to a burst of activity among
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medical artists commissioned by the press to present the concept accessibly with reconstructions of lascivious Neanderthals ogling coy Homo sapiens. One of the most evident areas in which this meeting cultivated debate was in the ways we measure genetic antecedence and calibrate our timelines. The issue of precise calibration over such a long timespan remains key, and receives signicant attention in the following pages. The message is that genetic dating, archaeology (a point emphasized at the Kavli meeting by Paul Mellars (University of Cambridge), geology, climatology, carbon-based and evoked luminescence dating, language studies and palaeoanthropology must be used in concert. Indeed, one of the attendees, Quentin Atkinson, made the case for the parallels between tracking language and genetic evolution in identifying the origins of the proto-Indo-European language. Within this issue and in the transcripts of the meeting are those relying on mitochondrial DNA, Y chromosome DNA, HLA polymorphisms and whole genome sequencing. We were privileged at the Royal Society meeting to have a presentation by Stephen Oppenheimer, and at the Kavli satellite meeting by Brenna Henn (Stanford University), the proponent of an out-of-Southwestern Africa origin [5] and Andrea Manica who stressed the likely importance of past climate in triggering past human migrations. Oppenheimers excellent contribution to this issue [6] encapsulates the key unknowns of the early peopling of the planet. The key questions of the exodus are: how many founding exits of modern humans were there as seen in the fossil or

Introduction. Human and pathogen co-evolution archaeological record, to what extent can we gather evidence for this from genetics of modern populations, and which routes were taken, when and why? To this challenging list, we can add further questions based on the contributions to this issue from other participants: what evidence can we nd for the impact of selection on subsequent populations by infection, and to what extent can this part of the story be told through tracking the immunogenetics of the migrations and the phylogenetics of the pathogens themselves? Through the London and Kavli meetings, Eske Willerslev offered a masterclass in the rigours of analysing and sequencing ancient DNA from human samples, ora and fauna, including their studies of ancient bacterial and plant DNA from silty ice sediments dating to before glaciation more than 2.5 Mya. Human faeces (coprolites) from the Paisley Caves in Oregon were used by them to recalibrate the timing of the peopling of North America to 14 000 ya. HLA genes are most polymorphic in the genome. While there are more than 250 loci in the HLA region, the key functional gene products involved in the presentation of antigen peptides for priming adaptive immunity, HLA-A, HLA-B and HLA-DRB1, can potentially be tracked with respect to human migration and pathogen selection pressure. In this issue, contributions from Fernandez Vina and colleagues, Thorsby, and Sanchez-Mazas and colleagues each offer case studies of this type [79]. Many tribes of Amerindians show high levels of HLA heterozygosity despite a reduced number of alleles in the population and, notably, encompass a number of novel HLA-B variants. These are presumed to have arisen in relatively recent history (after the outof-Africa migration) through recombination between the existing alleles. As Alicia Sanchez-Mazas and colleagues [9] explain, HLA variation often deviates signicantly from neutral expectations towards an excess of genetic diversity, an observation best accounted for by pathogen-driven-balancing selection. They show a positive correlation between HLA polymorphism and geographical distance from East Africa for several populations from all continents. Thorsbys contribution [8] uses HLA polymorphisms to revisit the specic issue of the peopling of Polynesia. In contrast to the popular works of Thor Heyerdahl, it is widely accepted that Polynesia was settled from southeast Asia. Thus, the alternative view that parts of Polynesia were rst inhabited by Amerindians has retained sparse support. Thorsby conducted genomic HLA typing as well as typing for mitochondrial DNA and Y chromosome markers of samples from Easter Islanders. Some individuals carried HLA alleles previously seen only in Amerindians. Furthermore, the studies suggest that these Amerindian alleles were introduced before the Peruvian slave trades in the area, probably in prehistoric times. The potentially supportive evidence that Easter Islanders eat a type of sweet potato normally considered indigenous to South America suggests further opportunities for phylogenetic comparisons of vegetables. Peter Parhams contribution [3] for the most part focuses on the evolutionary expansion and signicance of an HLA interaction that long predates the
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speciation of H. sapiensthat is, the expansion of HLA-C alleles and their corresponding receptors, the killer immunoglobulin-like receptors (KIRs). The HLA/KIR interaction is part of a complex positive and negative cell activation balance determining the level of activity of an innate immunity mechanism mediated by natural killer (NK) cells [10]. While many components of adaptive immunity are relatively conserved in phylogenetic history through mammals and sometimes back to cartilaginous sh, this is a modern part of immune system recognition, unique to primates: the single KIR gene in lemurs is a pseudogene and is rst seen as an expressed gene in the dusky titi (Callicebus moloch). The expansion of HLA-C alleles is seen from around orang-utans, 14 18 Mya. The HLA/KIR interaction, it is argued, has exerted its inuence through a balance between its role in host defence and in survival of the foetus in utero. For example, Parham makes the case that the HLA-C-like allele, HLA-B*46, has arisen from a gene conversion event between HLA-C*07 and HLA-B15 and has been strongly selected for through its utility for KIR activation of NK cells, specically in an area of southeast Asia centred on Hunang Province. The hypothesis is that the selective sweep of HLA-B*46 could have been driven by epidemic infection caused by hepatitis C virus [11]. Clearly, studies of these and other polymorphic systems will be replaced, as costs continue to come down, by whole genome sequencing. Chris TylerSmith (Wellcome Trust Sanger Institute, Cambridge) spoke at the Kavli meeting about ndings to date from the 1000 Genomes Project, sequencing across 27 different populations and giving the full picture of genome diversity [12]. An example is the selective sweep of IL-29 in Europe and southeast Asia, presumably related to a strong phenotype in antiviral immunity. The contribution from Nina Jablonski and George Chaplin in this issue [13] makes the case for the complex relationship that there has been since out-ofAfrica between UV-radiation exposure, vitamin D3 function and normal immune development and function. Human skin pigmentation must balance the conicting physiological demands of protection against the effects of ultraviolet radiation and the photosynthesis of UVB-dependent vitamin D3. Ancestral H. sapiens had skin rich in protective eumelanin, but the migrations from Africa to low UVB regions were associated with positive selection for depigmentation, and then subsequent selection in some regions such as Australia for repigmentation. Much of the richness of this Royal Society meeting came from the juxtaposition of two academic communities who rarely get the opportunity to engage sufciently with each other, the human geneticists and the pathogen geneticists. The piece from Adrian Hill [14] bridges this divide. As he explains, studies on the genetics of infectious disease susceptibility are motivated by the need to understand the evolutionary history, by the potential benets from the identication of new drug targets, and by the potential insights into high-risk groups to target for new vaccines or treatments. It is a given in the eld that it should be

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Introduction. Human and pathogen co-evolution amplication and sequencing of ancient DNA and in molecular immunology. Meanwhile, one of the clear lessons of the meeting is that high-tech molecular biology needs to recount this story alongside strong archaeological ndings to ll the yawning gaps in our historic and phylogenetic evidence. Why does it matter so much? To reconstruct the story of who we are and how we got here is sufcient in itself. However, understanding our survival in the face of massive selection pressure from microbial pathogens also offers prospective benets for the future with respect to our response to pandemics and our design of therapeutics through the study of disease resistance.
The authors would like to thank the Royal Society and especially Christine Phillips for their enthusiastic support of this meeting as well as the speakers, chairs and discussants who helped to make this grouping so productive.

possible to identify signatures of natural selection in the human genome driven by serious disease-causing pathogens. While there have been notable successes from candidate gene studies including both HLA and innate immunity genes, the complexities of phenotypes and of sample collection have made genome-wide association studies (GWAS) considerably more challenging for infectious than for the relatively rich pickings of autoimmune disease studies. In this context, the contribution to this issue from Kristian Andersen, Pardis Sabeti and others [15] is noteworthy. They have previously proposed that Lassa virus may have been a driver of natural selection in West African populations where Lassa haemorrhagic fever is endemic. By applying tests for selection to genomewide data they found positive selection in LARGE and IL21, both genes implicated in either infection by or immunity to Lassa virus. In evolutionary genetics, hard sweeps are the outcome of a single advantageous mutation arising and spreading through a population, while soft sweeps involve the occurrence of the advantageous mutation on several haplotypes. As John Novembre and Eunjung Han [16] point out, a signicant issue for the study of human adaptive evolution is that soft sweeps may play a larger role than hard sweeps, so that the ability to detect loci that have undergone recent adaptive evolution can be severely compromised. While the global disease burden from Mycobacterium tuberculosis is massive, it is difcult to build the picture of the extent to which this pathogen may have exerted selection pressure on human populations, but is perhaps easier to describe how M. tuberculosis variants have been selected in different parts of the world. The coevolution of modern humans and M. tuberculosis is described here by Sebastian Gagneux [17]. While tuberculosis has sometimes been considered a zoonotic transmission of relatively recent millennia, we now believe that it emerged as a human pathogen in Africa and spread across the globe with migrations of modern humans. Evolutionarily modern lineages of M. tuberculosis expanded in these new settings and as a consequence of growing populations. The modern lineages are more successful in terms of their geographical spread compared with the ancient. This could possibly be explained by differences in the immune subversion strategies they have developed [17]. An innovative approach to tracking the interplay between selective pressure on both the human and the parasite is offered here in the contribution from Williams-Blangero and colleagues [18].

REFERENCES
1 Jobling, M. A. 2012 The impact of recent events on human genetic diversity. Phil. Trans. R. Soc. B 367, 793 799. (doi:10.1098/rstb.2011.0297) 2 Achtman, M. 2012 Insights from genomic comparisons of genetically monomorphic bacterial pathogens. Phil. Trans. R. Soc. B 367, 860 867. (doi:10.1098/rstb. 2011.0303) 3 Parham, P., Norman, P. J., Abi-Rached, L. & Guethlein, L. A. 2012 Human-specic evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules. Phil. Trans. R. Soc. B 367, 800811. (doi:10.1098/rstb.2011.0266) 4 Abi-Rached, L. et al. 2011 The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 334, 8994. (doi:10.1126/ science.1209202) 5 Henn, B. M. et al. 2012 Hunter-gatherer genomic diversity suggests a southern African origin for modern humans. Proc. Natl Acad. Sci. USA 108, 5154 5162. (doi:10.1073/pnas.1017511108) 6 Oppenheimer, S. 2012 Out-of-Africa, the peopling of continents and islands: tracing uniparental gene trees across the map. Phil. Trans. R. Soc. B 367, 770784. (doi:10.1098/rstb.2011.0306) 7 Fernandez Vina, M. A. et al. 2012 Tracking of human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations. Phil. Trans. R. Soc. B 367, 820 829. (doi:10.1098/rstb.2011.0320) 8 Thorsby, E. 2012 The Polynesian gene pool: an early contribution by Amerindians to Easter Island. Phil. Trans. R. Soc. B 367, 812 819. (doi:10.1098/rstb.2011. 0319) 9 Sanchez-Mazas, A., Lematre, J.-F. & Currat, M. 2012 Distinct evolutionary strategies of human leucocyte antigen loci in pathogen-rich environments. Phil. Trans. R. Soc. B 367, 830 839. (doi:10.1098/rstb.2011. 0312) 10 Cheent, K. & Khakoo, S. I. 2009 Natural killer cells: integrating diversity with function. Immunology 126, 449 457. (doi:10.1111/j.1365-2567.2009.03045.x) 11 Abi-Rached, L., Moesta, A. K., Rajalingam, R., Guethlein, L. A. & Parham, P. 2010 Human-specic evolution and adaptation led to major qualitative differences in the variable receptors of human and chimpanzee natural killer cells. PLoS Genet. 6, e1001192. (doi:10.1371/journal. pgen.1001192)

2. CONCLUDING REMARKS What happened at this meeting, and hopefully in the subsequent pages of this issue, was that a highly accomplished and diverse collection of academics learnt and exchanged the stories of the past 70 000 years of human survival. Because the story was told in so many different wayswith diverse perspectives, paradigms and scientic syntax, it was constantly challenged and reappraised, emerging perhaps a little more robust. This comes at a time when the technologies themselves of course offer a quantum leap through the impact of human whole genome sequencing, high-throughput pathogen sequencing, advances in
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12 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061 1073. (doi:10.1038/nature.09534) 13 Jablonski, N. G. & Chaplin, G. 2012 Human skin pigmentation, migration and disease susceptibility. Phil. Trans. R. Soc. B 367, 785 792. (doi:10.1098/rstb.2011. 0308) 14 Hill, A. V. S. 2012 Evolution, revolution and heresy in the genetics of infectious disease susceptibility. Phil. Trans. R. Soc. B 367, 840849. (doi:10.1098/rstb.2011.0275) 15 Andersen, K. G., Shylakhter, I., Tabrizi, S., Grossman, S. R, Happi, C. T. & Sabeti, P. C. 2012 Genome-wide scans provide evidence for positive selection of genes

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implicated in Lassa fever. Phil. Trans. R. Soc. B 367, 868 877. (doi:10.1098/rstb.2011.0299) 16 Novembre, J. & Han, E. 2012 Human population structure and the adaptive response to pathogen-induced selection pressures. Phil. Trans. R. Soc. B 367, 878 886. (doi:10.1098/rstb.2011.0305) 17 Gagneux, S. 2012 Hostpathogen coevolution in human tuberclosis. Phil. Trans. R. Soc. B 367, 850859. (doi:10. 1098/rstb.2011.0316) 18 Williams-Blangero, S. et al. 2012 Host genetics and population structure effects on parasitic disease. Phil. Trans. R. Soc. B 367, 887894. (doi:10.1098/ rstb.2011.0296)

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