Rebbeck1,5 Abstract Dissecting the Within-Africa Ancestry of Populations of African Descent in the Americas Klara Stefflova1*, Matthew C. Dulik2, Jill S. Barnholtz-Sloan3, Athma A. Pai4, Amy H. Walker1, Timothy R. 1 Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 2 Department of Anthropology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 3 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America, 4 Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America, 5 Abramson Cancer Center, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Background: The ancestry of African-descended Americans is known to be drawn from three distinct populations: African, European, and Native American. While many studies consider this continental admixture, few account for the genetically distinct sources of ancestry within Africa – the continent with the highest genetic variation. Here, we dissect the within- Africa genetic ancestry of various populations of the Americas self-identified as having primarily African ancestry using uniparentally inherited mitochondrial DNA. Methods and Principal Findings: We first confirmed that our results obtained using uniparentally-derived group admixture estimates are correlated with the average autosomal-derived individual admixture estimates (hence are relevant to genomic ancestry) by assessing continental admixture using both types of markers (mtDNA and Y-chromosome vs. ancestry informative markers). We then focused on the within-Africa maternal ancestry, mining our comprehensive database of published mtDNA variation (,5800 individuals from 143 African populations) that helped us thoroughly dissect the African mtDNA pool. Using this well-defined African mtDNA variation, we quantified the relative contributions of maternal genetic ancestry from multiple W/WC/SW/SE (West to South East) African populations to the different pools of today’s African- descended Americans of North and South America and the Caribbean. Conclusions: Our analysis revealed that both continental admixture and within-Africa admixture may be critical to achieving an adequate understanding of the ancestry of African-descended Americans. While continental ancestry reflects gender- specific admixture processes influenced by different socio-historical practices in the Americas, the within-Africa maternal ancestry reflects the diverse colonial histories of the slave trade. We have confirmed that there is a genetic thread connecting Africa and the Americas, where each colonial system supplied their colonies in the Americas with slaves from African colonies they controlled or that were available for them at the time. This historical connection is reflected in different relative contributions from populations of W/WC/SW/SE Africa to geographically distinct Africa-derived popula- tions of the Americas, adding to the complexity of genomic ancestry in groups ostensibly united by the same demo- graphic label. Citation: Stefflova K, Dulik MC, Barnholtz-Sloan JS, Pai AA, Walker AH, et al. (2011) Dissecting the Within-Africa Ancestry of Populations of African Descent in the Americas. PLoS ONE 6(1): e14495. doi:10.1371/journal.pone.0014495 Editor: Michael Knapp, University of Otago, New Zealand Received May 10, 2010; Accepted December 6, 2010; Published January 6, 2011 Copyright: 2011 Stefflova et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by grants to TRR from the Public Health Service (R29-ES08031, R01-CA85074, and P50-CA105641). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: Klara.Stefflova@cancer.org.uk Introduction The ancestry of people in the Americas self-identified as having origin in Africa reflects the relatively recent admixture of three ‘‘continental’’ ancestral populations: African, European, and Native American [1]. This recent admixture has implications for research in population genetics, anthropology, and epidemiology. For example, of anthropological interest is the influence of admixture from displaced Africans on populations in the Americas [2], [3] and gender-specific admixture processes [4–7]. In the field of molecular epidemiology, admixture presents a challenge to association studies that could suffer from bias due to confounding by admixture or population stratification [8–12]. Typically, association studies use autosomal ancestry-informa- tive markers (AIMs) to correct for population stratification, assessing continental admixture by estimating ancestral proportions of an individual’s (West) African, European and sometimes also Native American ancestry [1], [13–18]. These AIMs-based studies are complemented by reports of continental group ancestry across a variety of populations of the Americas using markers in uniparentally inherited mitochondrial DNA (mtDNA, for example [2], [3], [19–26]) and the non-recombining portion of the Y- chromosome (NRY, [27–29]) or a combination of both (for example [6], [30–35]). While these mtDNA and NRY markers are not suitable for assessing the ancestry of an individual, group ancestry based on the combination of mtDNA and NRY often PLoS ONE | www.plosone.org 1 January 2011 | Volume 6 | Issue 1 | e14495