Evolutionary processes shaping genetic structure in Ethiopia and the Sudans

Individuals sampled from across the world show great diversity in their DNA. However the primary features that lead to this diversity are poorly understood. For example, it is well-known that groups residing in close geographic proximity often have similar DNA patterns relative to groups residing further away, but what sorts of anthropological or topographical features best predict these similarities? Do rivers provide gateways for promoting interactions among different groups and thus lead to DNA exchange among these groups throughout history? Do natural features such as mountains provide a major barrier to such interactions, or is not sharing a language or religion a more important barrier? Have the important features that promote genetic diversity changed over time?

The Federal Democratic Republic of Ethiopian, the Republic of Sudan, and the Republic of South Sudan show great cultural diversity, with for example over 100 different languages spoken and over 100 different ethnic groups living within. The history of many of these peoples are poorly understood, with historical records often incomplete or contradictory. Recent studies have shown that the DNA of these groups are also highly diverse. This DNA provides a powerful means of resolving historical inaccuracies, and identifying the aforementioned features that promote intermixing among the different groups that have shaped the genetic landscape of this region for tens of thousands of years.

In this project, we will develop and apply new, state-of-the-art statistical methodology to a novel DNA collection consisting of samples from several hundred Ethiopian and Sudanese individuals. We will identify the features that have shaped the genetic diversity of this unique region of the world, identifying historical events where different ethnic groups within these regions exchanged DNA, as well as DNA contributions from sources outside the countries' borders. Some of this methodology has been successfully used recently to explore the history of the United Kingdom, a part of the world with considerably less cultural and genetic diversity (http://www.peopleofthebritishisles.org/). Elucidating the dynamics of how groups interact genetically will have great implications for understanding how gene flow persists among populations historically and today. Understanding the genetic structure of this diverse region will also help future researchers design sampling strategies for studies testing whether particular regions of the genome are associated with common phenotypes such as height or disease status.

This region of east Africa is also vital for studying human origins, housing the earliest known human fossil remains that confirm a history going back approximately 200,000 years. It is well-established that modern humans first arose in sub-Saharan Africa, and it is believed that Ethiopia and the Sudans were the gateway for the initial migrations of peoples out of sub-Saharan Africa when colonizing the rest of the world. By careful comparison of the DNA of the groups from this region with those outside of sub-Saharan Africa, we may be able to infer the routes taken by these early explorers and map out precisely how the world was colonized by migrating humans.

Although it is well established that DNA differs substantially among different world-wide groups, the principle forces driving human genetic diversity are not well understood. One of the major outstanding questions in human evolution is whether present-day levels of diversity are primarily attributable to recent intermixing among populations (i.e. admixture) or ancient substructure. In addition, we still have only a limited understanding of the impact of factors that influence DNA exchange among populations, such as topography and geographic proximity, access to rivers, or other social factors such as shared language or religion.

With this project, we will genotype 2000 individuals spanning 95 different ethnic, occupational, or regional groups sampled from the Federal Democratic Republic of Ethiopia, the Republic of Sudan, and the Republic of South Sudan. Each Ethiopian and Sudanese sample has information on the donor's birthplace, first and second languages, cultural label, and religion for some samples, plus the equivalent information (excluding religion) for the donor's father, mother, paternal grandfather, and maternal grandmother. We also have cartographical and altitude information on numerous villages across these regions. We will apply novel statistical methodology to these samples to identify recent admixture events among these different groups, as well as DNA contributions from neighboring populations. We will then elucidate the anthropological and topographical features that most strongly determine which groups exchange DNA. We will infer the DNA of the ancestors of these present-day groups by subtracting out the signals of recent admixture we identify, and we will quantify the extent of genetic distinction among these ancient sources. By developing new statistical methods, we also aim to exploit the rich history contained in the DNA of this part of the world to infer details of human origins, including the early migration(s) out of Africa.

Collaborator Endashaw Bekele is Professor at Addis Ababa University and Director of the Human Genetic Variation Center (HGVC) at the Ministry of Health in Ethiopia. The HGVC has a remit from the Ethiopian government to encourage the study of human genetic variation in Ethiopia by overseas researchers, with a view to developing local expertise in undertaking clinical trials that take account of sub-Saharan genetic diversity. For example, Bekele and collaborator Neil Bradman have collected blood and phenotype data from 300 Ethiopian samples, including 25 individuals from each of five distinct Ethiopian groups who are being whole genome sequenced (WGS) by collaborators Luca Pagani and Chris Tyler-Smith. This phenotype information includes height, weight, BMI, standard anthropometric data, blood pressure, spirometer, colorimeter, spirobank, bio-impedance readings, urine analysis, personal disease histories and lifestyle information, as well as sociological data for the subject and the subject's parents and grandparents as recorded in the larger collection described in this study. The proposed study will elucidate the genetic diversity among over 80 additional ethnic and regional groups from Ethiopia and the Sudans, thus defining sampling strategies for forthcoming similar phenotype collections. All samples and our results exploring genetic diversity will be made freely available to researchers upon publication of the first primary manuscript (anticipated at the end of year 1-2). The PI will also visit Addis Ababa University as a guest of Prof Bekele during years 1-3 of the project, explaining the primary results of our studies into the genetic landscape of Ethiopia and the Sudans and advising on sampling strategies for future phenotype collections.

Dr. Bradman is Chairman of Henry Stewart Talks Ltd (http://hstalks.com/), which publishes The Biomedical and Life Sciences Collection of over 1,600 specially prepared online seminars by leading world experts. These seminars are provided for free to over 75 universities in sub-Saharan Africa, including 15 from Ethiopia. Subscribers to the collection includes most of the world's largest pharmaceutical companies as well as research institutes and universities in over 40 countries. We will provide at least one seminar describing our project's findings, anticipated for year 2-3 of the project.

The post-doc employed on this project will develop and apply state-of-the-art statistical techniques to a large-scale genetic data collection, as well as lead an international collaboration. Any new methodology developed during this project will be made freely available to academic researchers upon publication of methods. Visits to Addis Ababa University may lead to collaborations between UCL and Ethiopian PhD students, similar to UCL Prof Dallas Swallow's on-going co-supervision of Tamiru Oljira of Addis Ababa University on projects studying allelic heterogeneity in lactase persistence among Ethiopian groups (e.g. Ingram et al 2009, J Mol Evol 69:579-588).

Finally, understanding human history, including the genetic legacies of known population migrations, is of enormous interest to the wider public. The PI has participated in two public presentations of a similar study to the one proposed here that instead uses United Kingdom samples (POBI). This work featured in both The Royal Society Summer Exhibition 2012 (http://sse.royalsociety.org/2012/exhibits/genetic-maps/) and the Big Bang UK Young Scientists and Engineers Fair 2013 (http://www.thebigbangfair.co.uk/). We anticipate similar interest from the public and media from this project, from our initial publications describing the genetic structure of Ethiopia and the Sudans in years 1-2 of the project to our findings on ancient human demography anticipated for year 3.