Yuffayur
01-18-2015, 01:14 PM
African Genome Variation project paper
Published online 03 December 2014.
Abstract
Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.
http://www.nature.com/nature/journal/v517/n7534/images/nature13997-f1.jpg
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Formal tests for admixture (the three population test or f3 statistic)11, confirmed widespread Eurasian and HG admixture in SSA (Supplementary Tables 2 and 3). Quantification of admixture (Supplementary Table 4, Supplementary Methods and Supplementary Notes 3 and 4) indicated substantial Eurasian ancestry in many African populations (ranging from 0% to 50%), with the greatest proportion in East Africa (Fig. 2 and Supplementary Table 4). Similarly, HG admixture ranged from 0% to 23%, being greatest among Zulu and Sotho (Fig. 2 and Supplementary Table 5).
We found evidence for historically complex and regionally distinct admixture with multiple HG and Eurasian populations across SSA (Fig. 2 and Supplementary Note 5). Specifically, ancient Eurasian admixture was observed in central West African populations (Yoruba; ~7,500–10,500 years ago), old admixture among Ethiopian populations (~2,400–3,200 years ago) consistent with previous reports10, 12, and more recent complex admixture in some East African populations (~150–1,500 years ago) (Fig. 2, Extended Data Fig. 7 and Supplementary Note 5). Our finding of ancient Eurasian admixture corroborates findings of non-zero Neanderthal ancestry in Yoruba, which is likely to have been introduced through Eurasian admixture and back migration, possibly facilitated by greening of the Sahara desert during this period13, 14.
http://www.nature.com/nature/journal/v517/n7534/images/nature13997-f2.jpg
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We also find evidence for complex and regionally distinct HG admixture across SSA (Fig. 2, Extended Data Figs 7 and Supplementary Note 5), with ancient gene flow (~9,000 years ago) among Igbo and more recent admixture in East and South Africa (multiple events ranging from 100 years ago to 3,000 years ago), broadly consistent with historical movements reflecting the Bantu expansion. An exploration of the likeliest sources of admixture in our data suggested that HG admixture in Igbo was most closely represented by modern day Khoe-San populations rather than by rainforest HG populations (Supplementary Note 5). Given limited archaeological and linguistic evidence for the presence of Khoe-San populations in West Africa, this extant HG admixture might represent ancient populations, consistent with the presence of mass HG graves from the early Holocene period comprising skeletons with distinct morphological features15, and with evidence of HG rock art dating to this period in the western Sahara16, 17. In East Africa, our analyses suggested that Mbuti rainforest HG populations most closely represented ancient HG mixing populations (Supplementary Note 5), with admixture dating to ~3,000 years ago, suggesting that HG ancestry here is likely to be older than previously reported18. The primary source of HG admixture in Zulu and Sotho populations was from Khoe-San populations (Fig. 2 and Supplementary Note 5), consistent with linguistic assimilation of click consonants among these populations.
The marked haplotype diversity within Africa has important implications for the design of large-scale medical genomics studies across the region, as well as studies of population history and evolution. In this context, the AGVP is a resource that will facilitate a broad range of genomic studies in Africa and globally.
Although Africa is the most genetically diverse region in the world, we provide evidence for relatively modest differentiation among populations representing the major sub-populations in SSA, consistent with recent population movement and expansion across the region beginning around 5,000 years ago—the Bantu expansion8. Although the history of the Bantu expansion is probably complex, assessments of population admixture can provide new insights. We note historically complex and regionally distinct admixture with multiple HG and Eurasian populations across SSA, including ancient HG and Eurasian ancestry in West and East Africa and more recent complex HG admixture in South Africa. As well as explaining genetic differentiation among modern populations in SSA, these admixture patterns provide genetic evidence for early back-to-Africa migrations, the possible existence of extant HG populations in western Africa—compatible with archaeological evidence15, and patterns of gene flow consistent with the Bantu expansion, including genetic assimilation of populations resident across the region.
This admixture also has important implications for the assessment of differentiation and positive selection in Africa. Accounting for these elements, we have identified loci under positive selection that are linked with hypertension, malaria, and other pathogens. This provides a proof-of-concept for the ability of geographically widespread genetic data within Africa to identify loci under selection related to diverse environments.
Our evidence for the broad transferability of genetic association signals and their statistical refinement has important implications for medical genetic research in Africa. Importantly, we highlight that such studies are feasible and can be enabled through the development of more efficient genotype arrays and diverse WGS reference panels for accurate imputation of common variation. In this context, we describe a framework for a new pan-African genotype array that could directly facilitate large-scale genomic studies in Africa.
A critical next step is the large-scale deep sequencing of multiple and diverse populations across Africa, which should be integrated with ancient DNA data. This would enable us to identify and understand signals of ancient admixture, patterns of historical population movements, and to provide a comprehensive resource for medical genomic studies in Africa.
Source:http://www.nature.com/nature/journal/v517/n7534/full/nature13997.html
Published online 03 December 2014.
Abstract
Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.
http://www.nature.com/nature/journal/v517/n7534/images/nature13997-f1.jpg
----------------------------------------
Formal tests for admixture (the three population test or f3 statistic)11, confirmed widespread Eurasian and HG admixture in SSA (Supplementary Tables 2 and 3). Quantification of admixture (Supplementary Table 4, Supplementary Methods and Supplementary Notes 3 and 4) indicated substantial Eurasian ancestry in many African populations (ranging from 0% to 50%), with the greatest proportion in East Africa (Fig. 2 and Supplementary Table 4). Similarly, HG admixture ranged from 0% to 23%, being greatest among Zulu and Sotho (Fig. 2 and Supplementary Table 5).
We found evidence for historically complex and regionally distinct admixture with multiple HG and Eurasian populations across SSA (Fig. 2 and Supplementary Note 5). Specifically, ancient Eurasian admixture was observed in central West African populations (Yoruba; ~7,500–10,500 years ago), old admixture among Ethiopian populations (~2,400–3,200 years ago) consistent with previous reports10, 12, and more recent complex admixture in some East African populations (~150–1,500 years ago) (Fig. 2, Extended Data Fig. 7 and Supplementary Note 5). Our finding of ancient Eurasian admixture corroborates findings of non-zero Neanderthal ancestry in Yoruba, which is likely to have been introduced through Eurasian admixture and back migration, possibly facilitated by greening of the Sahara desert during this period13, 14.
http://www.nature.com/nature/journal/v517/n7534/images/nature13997-f2.jpg
--------------------------------------------------------------------------------------
We also find evidence for complex and regionally distinct HG admixture across SSA (Fig. 2, Extended Data Figs 7 and Supplementary Note 5), with ancient gene flow (~9,000 years ago) among Igbo and more recent admixture in East and South Africa (multiple events ranging from 100 years ago to 3,000 years ago), broadly consistent with historical movements reflecting the Bantu expansion. An exploration of the likeliest sources of admixture in our data suggested that HG admixture in Igbo was most closely represented by modern day Khoe-San populations rather than by rainforest HG populations (Supplementary Note 5). Given limited archaeological and linguistic evidence for the presence of Khoe-San populations in West Africa, this extant HG admixture might represent ancient populations, consistent with the presence of mass HG graves from the early Holocene period comprising skeletons with distinct morphological features15, and with evidence of HG rock art dating to this period in the western Sahara16, 17. In East Africa, our analyses suggested that Mbuti rainforest HG populations most closely represented ancient HG mixing populations (Supplementary Note 5), with admixture dating to ~3,000 years ago, suggesting that HG ancestry here is likely to be older than previously reported18. The primary source of HG admixture in Zulu and Sotho populations was from Khoe-San populations (Fig. 2 and Supplementary Note 5), consistent with linguistic assimilation of click consonants among these populations.
The marked haplotype diversity within Africa has important implications for the design of large-scale medical genomics studies across the region, as well as studies of population history and evolution. In this context, the AGVP is a resource that will facilitate a broad range of genomic studies in Africa and globally.
Although Africa is the most genetically diverse region in the world, we provide evidence for relatively modest differentiation among populations representing the major sub-populations in SSA, consistent with recent population movement and expansion across the region beginning around 5,000 years ago—the Bantu expansion8. Although the history of the Bantu expansion is probably complex, assessments of population admixture can provide new insights. We note historically complex and regionally distinct admixture with multiple HG and Eurasian populations across SSA, including ancient HG and Eurasian ancestry in West and East Africa and more recent complex HG admixture in South Africa. As well as explaining genetic differentiation among modern populations in SSA, these admixture patterns provide genetic evidence for early back-to-Africa migrations, the possible existence of extant HG populations in western Africa—compatible with archaeological evidence15, and patterns of gene flow consistent with the Bantu expansion, including genetic assimilation of populations resident across the region.
This admixture also has important implications for the assessment of differentiation and positive selection in Africa. Accounting for these elements, we have identified loci under positive selection that are linked with hypertension, malaria, and other pathogens. This provides a proof-of-concept for the ability of geographically widespread genetic data within Africa to identify loci under selection related to diverse environments.
Our evidence for the broad transferability of genetic association signals and their statistical refinement has important implications for medical genetic research in Africa. Importantly, we highlight that such studies are feasible and can be enabled through the development of more efficient genotype arrays and diverse WGS reference panels for accurate imputation of common variation. In this context, we describe a framework for a new pan-African genotype array that could directly facilitate large-scale genomic studies in Africa.
A critical next step is the large-scale deep sequencing of multiple and diverse populations across Africa, which should be integrated with ancient DNA data. This would enable us to identify and understand signals of ancient admixture, patterns of historical population movements, and to provide a comprehensive resource for medical genomic studies in Africa.
Source:http://www.nature.com/nature/journal/v517/n7534/full/nature13997.html