Evaluation of Group Genetic Ancestry of Populations from Philadelphia and Dakar in the Context of Sex-Biased Admixture in the Americas

Background

Population history can be reflected in group genetic ancestry, where genomic variation captured by the mitochondrial DNA (mtDNA) and non-recombining portion of the Y chromosome (NRY) can separate female- and male-specific admixture processes. Genetic ancestry may influence genetic association studies due to differences in individual admixture within recently admixed populations like African Americans.

Principal Findings

We evaluated the genetic ancestry of Senegalese as well as European Americans and African Americans from Philadelphia. Senegalese mtDNA consisted of ∼12% U haplotypes (U6 and U5b1b haplotypes, common in North Africa) while the NRY haplotypes belonged solely to haplogroup E. In Philadelphia, we observed varying degrees of admixture. While African Americans have 9–10% mtDNAs and ∼31% NRYs of European origin, these results are not mirrored in the mtDNA/NRY pools of European Americans: they have less than 7% mtDNAs and less than 2% NRYs from non-European sources. Additionally, there is <2% Native American contribution to Philadelphian African American ancestry and the admixture from combined mtDNA/NRY estimates is consistent with the admixture derived from autosomal genetic data. To further dissect these estimates, we have analyzed our samples in the context of different demographic groups in the Americas.

Conclusions

We found that sex-biased admixture in African-derived populations is present throughout the Americas, with continual influence of European males, while Native American females contribute mainly to populations of the Caribbean and South America. The high non-European female contribution to the pool of European-derived populations is consistently characteristic of Iberian colonization. These data suggest that genomic data correlate well with historical records of colonization in the Americas.     

Dissecting the within-Africa ancestry of populations of African descent in the Americas

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 populations of the Americas, adding to the complexity of genomic ancestry in groups ostensibly united by the same demographic label.     

Genetic ancestry,admixture and health determinants in Latin America

Background

Modern Latin American populations were formed via genetic admixture among ancestral source populations from Africa, the Americas and Europe. We are interested in studying how combinations of genetic ancestry in admixed Latin American populations may impact genomic determinants of health and disease. For this study, we characterized the impact of ancestry and admixture on genetic variants that underlie health- and disease-related phenotypes in population genomic samples from Colombia, Mexico, Peru, and Puerto Rico.

Results

We analyzed a total of 347 admixed Latin American genomes along with 1102 putative ancestral source genomes from Africans, Europeans, and Native Americans. We characterized the genetic ancestry, relatedness, and admixture patterns for each of the admixed Latin American genomes, finding a spectrum of ancestry proportions within and between populations. We then identified single nucleotide polymorphisms (SNPs) with anomalous ancestry-enrichment patterns, i.e. SNPs that exist in any given Latin American population at a higher frequency than expected based on the population’s genetic ancestry profile. For this set of ancestry-enriched SNPs, we inspected their phenotypic impact on disease, metabolism, and the immune system. All four of the Latin American populations show ancestry-enrichment for a number of shared pathways, yielding evidence of similar selection pressures on these populations during their evolution. For example, all four populations show ancestry-enriched SNPs in multiple genes from immune system pathways, such as the cytokine receptor interaction, T cell receptor signaling, and antigen presentation pathways. We also found SNPs with excess African or European ancestry that are associated with ancestry-specific gene expression patterns and play crucial roles in the immune system and infectious disease responses. Genes from both the innate and adaptive immune system were found to be regulated by ancestry-enriched SNPs with population-specific regulatory effects.

Conclusions

Ancestry-enriched SNPs in Latin American populations have a substantial effect on health- and disease-related phenotypes. The concordant impact observed for same phenotypes across populations points to a process of adaptive introgression, whereby ancestry-enriched SNPs with specific functional utility appear to have been retained in modern populations by virtue of their effects on health and fitness.

     

X‐chromosome lineages and the settlement of the Americas

Most genetic studies on the origins of Native Americans have examined data from mtDNA and Y‐chromosome DNA. To complement these studies and to broaden our understanding of the origin of Native American populations, we present an analysis of 1,873 X‐chromosomes representing Native American (n = 438) and other continental populations (n = 1,435). We genotyped 36 polymorphic sites, forming an informative haplotype within an 8‐kb DNA segment spanning exon 44 of the dystrophin gene. The data reveal continuity from a common Eurasian ancestry between Europeans, Siberians, and Native Americans. However, the loss of two haplotypes frequent in Eurasia (18.8 and 7%) and the rise in frequency of a third haplotype rare elsewhere, indicate a major population bottleneck in the peopling of the Americas. Although genetic drift appears to have played a greater role in the genetic differentiation of Native Americans than in the latitudinally distributed Eurasians, we also observe a signal of a differentiated ancestry of southern and northern populations that cannot be simply explained by the serial southward dilution of genetic diversity. It is possible that the distribution of X‐chromosome lineages reflects the genetic structure of the population of Beringia, itself issued from founder effects and a source of subsequent southern colonization(s). Am J Phys Anthropol, 2009. © 2009 Wiley‐Liss, Inc.     

Brief communication: Evolution of a specific O allele (O1vG542A) supports unique ancestry of Native Americans

In this study, we explore the geographic and temporal distribution of a unique variant of the O blood group allele called O1v^G542A, which has been shown to be shared among Native Americans but is rare in other populations. O1v^G542A was previously reported in Native American populations in Mesoamerica and South America, and has been proposed as an ancestry informative marker. We investigated whether this allele is also found in the Tlingit and Haida, two contemporary indigenous populations from Alaska, and a pre‐Columbian population from California. If O1v^G542A is present in Na‐Dene speakers (i.e., Tlingits), it would indicate that Na‐Dene speaking groups share close ancestry with other Native American groups and support a Beringian origin of the allele, consistent with the Beringian Incubation Model. If O1v^G542A is found in pre‐Columbian populations, it would further support a Beringian origin of the allele, rather than a more recent introduction of the allele into the Americas via gene flow from one or more populations which have admixed with Native Americans over the past five centuries. We identified this allele in one Na‐Dene population at a frequency of 0.11, and one ancient California population at a frequency of 0.20. Our results support a Beringian origin of O1v^G542A, which is distributed today among all Native American groups that have been genotyped in appreciable numbers at this locus. This result is consistent with the hypothesis that Na‐Dene and other Native American populations primarily derive their ancestry from a single source population. Am J Phys Anthropol 151:649–657, 2013. © 2013 Wiley Periodicals, Inc.     

Genomic Ancestry,Self-Rated Health and Its Association with Mortality in an Admixed Population: 10 Year Follow-Up of the Bambui-Epigen (Brazil) Cohort Study of Ageing

Background

Self-rated health (SRH) has strong predictive value for mortality in different contexts and cultures, but there is inconsistent evidence on ethnoracial disparities in SRH in Latin America, possibly due to the complexity surrounding ethnoracial self-classification.

Materials/Methods

We used 370,539 Single Nucleotide Polymorphisms (SNPs) to examine the association between individual genomic proportions of African, European and Native American ancestry, and ethnoracial self-classification, with baseline and 10-year SRH trajectories in 1,311 community dwelling older Brazilians. We also examined whether genomic ancestry and ethnoracial self-classification affect the predictive value of SRH for subsequent mortality.

Results

European ancestry predominated among participants, followed by African and Native American (median = 84.0%, 9.6% and 5.3%, respectively); the prevalence of Non-White (Mixed and Black) was 39.8%. Persons at higher levels of African and Native American genomic ancestry, and those self-identified as Non-White, were more likely to report poor health than other groups, even after controlling for socioeconomic conditions and an array of self-reported and objective physical health measures. Increased risks for mortality associated with worse SRH trajectories were strong and remarkably similar (hazard ratio ~3) across all genomic ancestry and ethno-racial groups.

Conclusions

Our results demonstrated for the first time that higher levels of African and Native American genomic ancestry—and the inverse for European ancestry—were strongly correlated with worse SRH in a Latin American admixed population. Both genomic ancestry and ethnoracial self-classification did not modify the strong association between baseline SRH or SRH trajectory, and subsequent mortality.     

Ancestry-related assortative mating in Latino populations

Background

While spouse correlations have been documented for numerous traits, no prior studies have assessed assortative mating for genetic ancestry in admixed populations.

Results

Using 104 ancestry informative markers, we examined spouse correlations in genetic ancestry for Mexican spouse pairs recruited from Mexico City and the San Francisco Bay Area, and Puerto Rican spouse pairs recruited from Puerto Rico and New York City. In the Mexican pairs, we found strong spouse correlations for European and Native American ancestry, but no correlation in African ancestry. In the Puerto Rican pairs, we found significant spouse correlations for African ancestry and European ancestry but not Native American ancestry. Correlations were not attributable to variation in socioeconomic status or geographic heterogeneity. Past evidence of spouse correlation was also seen in the strong evidence of linkage disequilibrium between unlinked markers, which was accounted for in regression analysis by ancestral allele frequency difference at the pair of markers (European versus Native American for Mexicans, European versus African for Puerto Ricans). We also observed an excess of homozygosity at individual markers within the spouses, but this provided weaker evidence, as expected, of spouse correlation. Ancestry variance is predicted to decline in each generation, but less so under assortative mating. We used the current observed variances of ancestry to infer even stronger patterns of spouse ancestry correlation in previous generations.

Conclusions

Assortative mating related to genetic ancestry persists in Latino populations to the current day, and has impacted on the genomic structure in these populations.     

Reconstructing Native American Migrations from Whole-Genome and Whole-Exome Data

There is great scientific and popular interest in understanding the genetic history of populations in the Americas. We wish to understand when different regions of the continent were inhabited, where settlers came from, and how current inhabitants relate genetically to earlier populations. Recent studies unraveled parts of the genetic history of the continent using genotyping arrays and uniparental markers. The 1000 Genomes Project provides a unique opportunity for improving our understanding of population genetic history by providing over a hundred sequenced low coverage genomes and exomes from Colombian (CLM), Mexican-American (MXL), and Puerto Rican (PUR) populations. Here, we explore the genomic contributions of African, European, and especially Native American ancestry to these populations. Estimated Native American ancestry is in MXL, in CLM, and in PUR. Native American ancestry in PUR is most closely related to populations surrounding the Orinoco River basin, confirming the Southern America ancestry of the Taíno people of the Caribbean. We present new methods to estimate the allele frequencies in the Native American fraction of the populations, and model their distribution using a demographic model for three ancestral Native American populations. These ancestral populations likely split in close succession: the most likely scenario, based on a peopling of the Americas thousand years ago (kya), supports that the MXL Ancestors split kya, with a subsequent split of the ancestors to CLM and PUR kya. The model also features effective populations of in Mexico, in Colombia, and in Puerto Rico. Modeling Identity-by-descent (IBD) and ancestry tract length, we show that post-contact populations also differ markedly in their effective sizes and migration patterns, with Puerto Rico showing the smallest effective size and the earlier migration from Europe. Finally, we compare IBD and ancestry assignments to find evidence for relatedness among European founders to the three populations.     

Blood group O alleles in Native Americans: Implications in the peopling of the Americas

All major ABO blood alleles are found in most populations worldwide, whereas the majority of Native Americans are nearly exclusively in the O group. O allele molecular characterization could aid in elucidating the possible causes of group O predominance in Native American populations. In this work, we studied exon 6 and 7 sequence diversity in 180 O blood group individuals from four different Mesoamerican populations. Additionally, a comparative analysis of genetic diversity and population structure including South American populations was performed. Results revealed no significant differences among Mesoamerican and South American groups, but showed significant differences within population groups attributable to previously detected differences in genetic drift and founder effects throughout the American continent. Interestingly, in all American populations, the same set of haplotypes O¹, O^1v, and O^1v(G542A) was present, suggesting the following: (1) that they constitute the main genetic pool of the founding population of the Americas and (2) that they derive from the same ancestral source, partially supporting the single founding population hypothesis. In addition, the consistent and restricted presence of the G542A mutation in Native Americans compared to worldwide populations allows it to be employed as an Ancestry informative marker (AIM). Present knowledge of the peopling of the Americas allows the prediction of the way in which the G542A mutation could have emerged in Beringia, probably during the differentiation process of Asian lineages that gave rise to the founding population of the continent. Am J Phys Anthropol, 2010. © 2009 Wiley‐Liss, Inc.     

Y-chromosome evidence for differing ancient demographic histories in the Americas

To scrutinize the male ancestry of extant Native American populations, we examined eight biallelic and six microsatellite polymorphisms from the nonrecombining portion of the Y chromosome, in 438 individuals from 24 Native American populations (1 Na Dené and 23 South Amerinds) and in 404 Mongolians. One of the biallelic markers typed is a recently identified mutation (M242) characterizing a novel founder Native American haplogroup. The distribution, relatedness, and diversity of Y lineages in Native Americans indicate a differentiated male ancestry for populations from North and South America, strongly supporting a diverse demographic history for populations from these areas. These data are consistent with the occurrence of two major male migrations from southern/central Siberia to the Americas (with the second migration being restricted to North America) and a shared ancestry in central Asia for some of the initial migrants to Europe and the Americas. The microsatellite diversity and distribution of a Y lineage specific to South America (Q-M19) indicates that certain Amerind populations have been isolated since the initial colonization of the region, suggesting an early onset for tribalization of Native Americans. Age estimates based on Y-chromosome microsatellite diversity place the initial settlement of the American continent at approximately 14,000 years ago, in relative agreement with the age of well-established archaeological evidence.     

Y chromosome polymorphisms in Native American and Siberian populations: identification of Native American Y chromosome haplotypes

We have initiated a study of ancient male migrations from Siberia to the Americas using Y chromosome polymorphisms. The first polymorphism examined, a C→T transition at nucleotide position 181 of the DYS199 locus, was previously reported only in Native American populations. To investigate the origin of this DYS199 polymorphism, we screened Y chromosomes from a number of Siberian, Asian, and Native American populations for this and other markers. This survey detected the T allele in all five Native American populations studied at an average frequency of 61%, and in two of nine native Siberian populations, the Siberian Eskimo (21%) and the Chukchi (17%). This finding suggested that the DYS199 T allele may have originated in Beringia and was then spread throughout the New World by the founding populations of the major subgroups of modern Native Americans. We further characterized Native American Y chromosome variation by analyzing two additional Y chromosome polymorphisms, the DYS287 Y Alu polymorphic (YAP) element insertion and a YAP-associated A→G transition at DYS271, both commonly found in Africans. We found neither African allele associated with the DYS199 T allele in any of the Native American or native Siberian populations. However, we did find DYS287 YAP+ individuals who harbored the DYS199 C allele in one Native American population, the Mixe, and in one Asian group, the Tibetans. A correlation of these Y chromosome alleles in Native Americans with those of the DYS1 locus, as detected by the p49a/p49f (p49a,f) probes on TaqI-digested genomic DNA, revealed a complete association of DYS1 alleles (p49a,f haplotypes) 13, 18, 66, 67 and 69 with the DYS199 T allele, while DYS1 alleles 8 and 63 were associated with both the DYS199 C and T allele. Received: 18 November 1996 / Accepted: 19 May 1997     

An ancient DNA test of a founder effect in Native American ABO blood group frequencies

Anthropologists have assumed that reduced genetic diversity in extant Native Americans is due to a founder effect that occurred during the initial peopling of the Americas. However, low diversity could also be the result of subsequent historical events, such as the population decline following European contact. In this study, we show that autosomal DNA from ancient Native American skeletal remains can be used to investigate the low level of ABO blood group diversity in the Americas. Extant Native Americans exhibit a high frequency of blood type O, which may reflect a founder effect, genetic drift associated with the historical population decline, or natural selection in response to the smallpox epidemics that occurred following European contact. To help distinguish between these possibilities, we determined the ABO genotypes of 15 precontact individuals from eastern North America. The precontact ABO frequencies were not significantly different from those observed in extant Native Americans from the same region, but they did differ significantly from the ABO frequencies in extant Siberian populations. Studies of other precontact populations are needed to better test the three hypotheses for low ABO blood group diversity in the Americas, but our findings are most consistent with the hypothesis of a founder effect during the initial settlement of this continent.     

Oral metagenomes from Native American Ancestors reveal distinct microbial lineages in the pre-contact era

Objectives

Limited studies have focused on how European contact and colonialism impacted Native American oral microbiomes, specifically, the diversity of commensal or opportunistically pathogenic oral microbes, which may be associated with oral diseases. Here, we studied the oral microbiomes of pre-contact Wichita Ancestors, in partnership with the Descendant community, The Wichita and Affiliated Tribes, Oklahoma, USA.

Materials and Methods

Skeletal remains of 28 Wichita Ancestors from 20 archeological sites (dating approximately to 1250–1450 CE) were paleopathologically assessed for presence of dental calculus and oral disease. DNA was extracted from calculus, and partial uracil deglycosylase-treated double-stranded DNA libraries were shotgun-sequenced using Illumina technology. DNA preservation was assessed, the microbial community was taxonomically profiled, and phylogenomic analyzes were conducted.

Results

Paleopathological analysis revealed signs of oral diseases such as caries and periodontitis. Calculus samples from 26 Ancestors yielded oral microbiomes with minimal extraneous contamination. Anaerolineaceae bacterium oral taxon 439 was found to be the most abundant bacterial species. Several Ancestors showed high abundance of bacteria typically associated with periodontitis such as Tannerella forsythia and Treponema denticola. Phylogenomic analyzes of Anaerolineaceae bacterium oral taxon 439 and T. forsythia revealed biogeographic structuring; strains present in the Wichita Ancestors clustered with strains from other pre-contact Native Americans and were distinct from European and/or post-contact American strains.

Discussion

We present the largest oral metagenome dataset from a pre-contact Native American population and demonstrate the presence of distinct lineages of oral microbes specific to the pre-contact Americas.     

Predictions of native American population structure using linguistic covariates in a hidden regression framework

Background

The mainland of the Americas is home to a remarkable diversity of languages, and the relationships between genes and languages have attracted considerable attention in the past. Here we investigate to which extent geography and languages can predict the genetic structure of Native American populations.

Methodology/Principal Findings

Our approach is based on a Bayesian latent cluster regression model in which cluster membership is explained by geographic and linguistic covariates. After correcting for geographic effects, we find that the inclusion of linguistic information improves the prediction of individual membership to genetic clusters. We further compare the predictive power of Greenberg''s and The Ethnologue classifications of Amerindian languages. We report that The Ethnologue classification provides a better genetic proxy than Greenberg''s classification at the stock and at the group levels. Although high predictive values can be achieved from The Ethnologue classification, we nevertheless emphasize that Choco, Chibchan and Tupi linguistic families do not exhibit a univocal correspondence with genetic clusters.

Conclusions/Significance

The Bayesian latent class regression model described here is efficient at predicting population genetic structure using geographic and linguistic information in Native American populations.     

Reconstructing the Population Genetic History of the Caribbean

The Caribbean basin is home to some of the most complex interactions in recent history among previously diverged human populations. Here, we investigate the population genetic history of this region by characterizing patterns of genome-wide variation among 330 individuals from three of the Greater Antilles (Cuba, Puerto Rico, Hispaniola), two mainland (Honduras, Colombia), and three Native South American (Yukpa, Bari, and Warao) populations. We combine these data with a unique database of genomic variation in over 3,000 individuals from diverse European, African, and Native American populations. We use local ancestry inference and tract length distributions to test different demographic scenarios for the pre- and post-colonial history of the region. We develop a novel ancestry-specific PCA (ASPCA) method to reconstruct the sub-continental origin of Native American, European, and African haplotypes from admixed genomes. We find that the most likely source of the indigenous ancestry in Caribbean islanders is a Native South American component shared among inland Amazonian tribes, Central America, and the Yucatan peninsula, suggesting extensive gene flow across the Caribbean in pre-Columbian times. We find evidence of two pulses of African migration. The first pulse—which today is reflected by shorter, older ancestry tracts—consists of a genetic component more similar to coastal West African regions involved in early stages of the trans-Atlantic slave trade. The second pulse—reflected by longer, younger tracts—is more similar to present-day West-Central African populations, supporting historical records of later transatlantic deportation. Surprisingly, we also identify a Latino-specific European component that has significantly diverged from its parental Iberian source populations, presumably as a result of small European founder population size. We demonstrate that the ancestral components in admixed genomes can be traced back to distinct sub-continental source populations with far greater resolution than previously thought, even when limited pre-Columbian Caribbean haplotypes have survived.     

Socioeconomic and nutritional factors account for the association of gastric cancer with amerindian ancestry in a latin american admixed population

Gastric cancer is one of the most lethal types of cancer and its incidence varies worldwide, with the Andean region of South America showing high incidence rates. We evaluated the genetic structure of the population from Lima (Peru) and performed a case-control genetic association study to test the contribution of African, European, or Native American ancestry to risk for gastric cancer, controlling for the effect of non-genetic factors. A wide set of socioeconomic, dietary, and clinic information was collected for each participant in the study and ancestry was estimated based on 103 ancestry informative markers. Although the urban population from Lima is usually considered as mestizo (i.e., admixed from Africans, Europeans, and Native Americans), we observed a high fraction of Native American ancestry (78.4% for the cases and 74.6% for the controls) and a very low African ancestry (<5%). We determined that higher Native American individual ancestry is associated with gastric cancer, but socioeconomic factors associated both with gastric cancer and Native American ethnicity account for this association. Therefore, the high incidence of gastric cancer in Peru does not seem to be related to susceptibility alleles common in this population. Instead, our result suggests a predominant role for ethnic-associated socioeconomic factors and disparities in access to health services. Since Native Americans are a neglected group in genomic studies, we suggest that the population from Lima and other large cities from Western South America with high Native American ancestry background may be convenient targets for epidemiological studies focused on this ethnic group.     

Updated three-stage model for the peopling of the Americas

Background

We re-assess support for our three stage model for the peopling of the Americas in light of a recent report that identified nine non-Native American mitochondrial genome sequences that should not have been included in our initial analysis. Removal of these sequences results in the elimination of an early (i.e. ∼40,000 years ago) expansion signal we had proposed for the proto-Amerind population.

Methodology/Findings

Bayesian skyline plot analysis of a new dataset of Native American mitochondrial coding genomes confirms the absence of an early expansion signal for the proto-Amerind population and allows us to reduce the variation around our estimate of the New World founder population size. In addition, genetic variants that define New World founder haplogroups are used to estimate the amount of time required between divergence of proto-Amerinds from the Asian gene pool and expansion into the New World.

Conclusions/Significance

The period of population isolation required for the generation of New World mitochondrial founder haplogroup-defining genetic variants makes the existence of three stages of colonization a logical conclusion. Thus, our three stage model remains an important and useful working hypothesis for researchers interested in the peopling of the Americas and the processes of colonization.     

The impact of Converso Jews on the genomes of modern Latin Americans

Modern day Latin America resulted from the encounter of Europeans with the indigenous peoples of the Americas in 1492, followed by waves of migration from Europe and Africa. As a result, the genomic structure of present day Latin Americans was determined both by the genetic structure of the founding populations and the numbers of migrants from these different populations. Here, we analyzed DNA collected from two well-established communities in Colorado (33 unrelated individuals) and Ecuador (20 unrelated individuals) with a measurable prevalence of the BRCA1 c.185delAG and the GHR c.E180 mutations, respectively, using Affymetrix Genome-wide Human SNP 6.0 arrays to identify their ancestry. These mutations are thought to have been brought to these communities by Sephardic Jewish progenitors. Principal component analysis and clustering methods were employed to determine the genome-wide patterns of continental ancestry within both populations using single nucleotide polymorphisms, complemented by determination of Y-chromosomal and mitochondrial DNA haplotypes. When examining the presumed European component of these two communities, we demonstrate enrichment for Sephardic Jewish ancestry not only for these mutations, but also for other segments as well. Although comparison of both groups to a reference Hispanic/Latino population of Mexicans demonstrated proximity and similarity to other modern day communities derived from a European and Native American two-way admixture, identity-by-descent and Y-chromosome mapping demonstrated signatures of Sephardim in both communities. These findings are consistent with historical accounts of Jewish migration from the realms that comprise modern Spain and Portugal during the Age of Discovery. More importantly, they provide a rationale for the occurrence of mutations typically associated with the Jewish Diaspora in Latin American communities.     

Characterizing the admixed African ancestry of African Americans

Background

Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.

Results

From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.

Conclusions

These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.     

How Genes Have Illuminated the History of Early Americans and Latino Americans

The American continent currently accounts for ∼15% of the world population. Although first settled thousands of years ago and fitting its label as “the New World,” the European colonial expansion initiated in the late 15th century resulted in people from virtually every corner of the globe subsequently settling in the Americas. The arrival of large numbers of immigrants led to a dramatic decline of the Native American population and extensive population mixing. A salient feature of the current human population of the Americas is, thus, its great diversity. The genetic variation of the Native peoples that recent immigrants encountered had been shaped by demographic events acting since the initial peopling of the continent. Similarly, but on a compressed timescale, the colonial history of the Americas has had a major impact on the genetic makeup of the current population of the continent. A range of genetic analyses has been used to study both the ancient settlement of the continent and more recent history of population mixing. Here, I show how these two strands of research overlap and make use of results from other scientific disciplines to produce a fuller picture of the settlement of the continent at different time periods. The biological diversity of the Americas also provides prominent examples of the complex interaction between biological and social factors in constructing human identities and of the difficulties in defining human populations.A multiplicity of research approaches have been used to explore the original settlement of the American continent, often focusing on three prominent questions: (1) the route of entry of the initial settlers, (2) their time of arrival, and (3) the pattern of subsequent migration. These questions have been approached with variable degrees of success using various types of genetic markers examined in “Native” populations, defined on anthropological grounds (particularly language). Early studies used information from blood groups and proteins (Cavalli-Sforza et al. 1994) and were followed by DNA analyses mainly of mitochondrial DNA (mtDNA) (Forster et al. 1996; Tamm et al. 2007; Fagundes et al. 2008; Kitchen et al. 2008) and the Y chromosome (Lell et al. 1997; Bianchi et al. 1998; Karafet et al. 1999; Bortolini et al. 2003). The more recent studies have examined the human genome at increasing levels of resolution, from analyses with restricted sets of markers (Wang et al. 2007; Ray et al. 2010) to ongoing studies based on full genome sequences. Although a range of scenarios for the initial peopling of the Americas have been envisaged, genetic evidence points to the continent being settled by people migrating into the northwestern tip of the continent from Asia. This migration would have been facilitated by the existence, at that time, of a land bridge connecting Siberia to Alaska, which later was submerged beneath the Bering Strait by the rising sea level at the end of the last glaciation, around 15,000 years ago (Fiedel 2000). Genetic support for an American settlement from Eastern Siberia includes the finding that Native Americans are genetically most similar to North Asians (Cavalli-Sforza et al. 1994; Wang et al. 2007) and the existence of a gradient of declining genetic diversity from northwest North America southward (Wang et al. 2007; Reich et al. 2012). This gradient extends beyond that seen in the “Old World” for populations at increasing distance from Africa, possibly resulting from a sequence of population contractions that occurred as small groups of humans moved from settled areas into uninhabited territories (Ramachandran et al. 2005; Handley et al. 2007; Wang et al. 2007). The American continent, being the last major landmass to have been settled by humans, shows a low genetic diversity as compared with all other continents (Wang et al. 2007).Estimating the date of the initial settlement of the Americas has proven a difficult and contentious issue. Geological information provides a key reference point in that because of extensive ice sheets covering North America at the peak of the last glaciation (around 20,000 years ago), the continent would have been impenetrable then (Fig. 1). Therefore, this leaves two broad opportunities for settlement: before or after this last glacial maximum (LGM). Calculating the time of initial settlement of the continent from genetic information requires a number of assumptions of which the exact validity is difficult to assess, including variation in factors such as population demography, mutation rates, and the influence of selection. Perhaps, not surprisingly, the range of genetic estimates for the time of human settlement of America is quite wide, extending to both sides of the glacial maximum. It is, however, encouraging that most of the recent estimates, based on increasingly larger amounts of data and more sophisticated statistical methods, point to a settlement not long after the LGM. These estimates show greater consistency with the archaeological evidence, which, although itself not devoid of controversy, points to a human presence in the Americas by ∼14,000 years ago.Open in a separate windowFigure 1.First peopling of the American continent. Settlement is thought to have occurred from Eastern Siberia through several waves of migration (arrows) across a land bridge connecting Siberia to Alaska, existing at the time. Crossing was impossible during the last glacial maximum (LGM) (∼20,000 years ago) because of glaciers covering a large part of North America. Most genetic studies of contemporary Native Americans point to a settlement of the continents soon after the LGM, subsequent to the retreat of the ice sheets. Although classical studies associated initial settlement with the Clovis archaeological complex of North America (∼13,000 years ago), older sites have been identified, including Monte Verde in South America (dated at ∼15,000 years ago). The Native American populations placed on this map are those included in the phylogenetic tree shown in Figure 3. Analysis of genetic data from these populations is consistent with the important role of the coast during the initial settlement of the continent (Reich et al. 2012).The pattern of migration into the continent has also been the subject of considerable disagreement. An influential model put forward in the mid-1980s posited that the settlement of the continent occurred in three sequential migratory waves from Asia, corresponding to the three major linguistic stocks in which the linguist Joseph Greenberg classified Native American languages (Greenberg et al. 1986; Greenberg 1987; Ruhlen 1991). The first migration would have given rise to a very large Amerind linguistic family comprising populations living all over the continent, whereas two subsequent migrations, restricted to North America and the Arctic, would be associated with populations speaking languages of the Na-Dene and Eskimo-Aleut linguistic families, respectively. Although early blood group and protein data were interpreted in support of the Greenberg model (Cavalli-Sforza et al. 1994), subsequent mtDNA and Y-chromosome analyses have been mostly interpreted as indicative of a single migration wave into the continent (Bonatto and Salzano 1997; Tamm et al. 2007; Fagundes et al. 2008; Kitchen et al. 2008). The recent genome-wide surveys of diversity with increasing resolution have, however, provided a different view. These are inconsistent with the single migration model and are more in line with the occurrence of multiple migrations (Fig. 1). Particularly strong support for several ancient migrations comes from a study based on a large survey of populations and using data for hundreds of thousands of genetic markers. With this type of data, it is possible to estimate the ancestry of every segment of DNA along the genome and state whether such a segment is of African, European, or Native American origin. Analyses can then focus only on the Native American segments of the genome (Fig. 2). This means that Native American individuals, and populations, that previously had to be excluded from study because of admixture with non-Natives can now be included, facilitating a more extensive population survey and reducing bias. These recent data have provided strong evidence that the Eskimo-Aleut, Na-Dene, and Amerind linguistic groups show evidence of differential gene flow from Asia, inconsistent with stemming from a discrete single colonization event with no subsequent migration (Fig. 1). Noticeably, although North American populations show evidence of multiple episodes of gene exchange with Asia, Native populations from Mexico to the Southern tip of South America appear to stem from one colonization wave with no subsequent Asian gene flow. This observation agrees with the highly controversial proposal of grouping widely separated Native American languages into a single “Amerindian” linguistic family (Greenberg 1987; Ruhlen 1991). These data also confirm the correlation of population diversity with distance from the Bering Strait, in agreement with settlement in a north-to-south direction. Interestingly, this correlation increases when considering the coasts as facilitators of population movement, suggesting an important role of the coast during the initial population dispersals on the continent. A phylogenetic tree relating the Native American populations examined in that survey is also consistent with the north-to-south settlement of the continent, as it shows a sequence of major population splits separating groups of populations mostly along a north-to-south axis (Figs. 1 and ​and3).3). Consistent with some degree of parallel evolution for languages and genes (Cavalli-Sforza et al. 1994), resulting from population separation followed by relative isolation, the major clusters of populations in this genetic tree show a broad correspondence with the linguistic affiliation of the populations (Fig. 3).Open in a separate windowFigure 2.Inference of local ancestry along the two copies of chromosome 1 in an admixed Native American individual. The height of the thick line indicates local ancestry as the number of chromosome copies at that position that are estimated to be Native American (0, 1, or 2). Numbers on the x-axis refer to the position along chromosome 1 (in kilobases) of the genetic markers allowing inference of local ancestry. (Modified from data in Reich et al. 2012.)Open in a separate windowFigure 3.Phylogenetic tree relating representative African, European, Oceanian, East Asian, and Native American populations based on high-density genetic marker data. For this analysis, Native American data used was restricted to genome segments of confirmed Native ancestry (determined as in Fig. 2). The tree branches are color-coded to represent the linguistic affiliation of the populations, as shown in the inset. Numbers in parentheses refer to sample size in each population. The length of the branches on this tree is proportional to a measure of genetic differentiation (F_ST). (From Reich et al. 2012; reprinted, with permission, from the author.)The recent study by Reich et al. (2012) illustrates the potential of high-density genotyping for extending studies focused on the original settlement of the Americas to Native individuals with evidence of admixture with recent immigrants. This admixture is extensive across the continent and involves not only Natives but also the general population, particularly in the countries of what is now referred to as Latin America. Historically, a major driver behind population mixing in this region was the fact that immigrants from Spain and Portugal, particularly in the early phases of the colonial expansion, were mostly men (Boyd-Bowman 1973). It is well documented that many Conquistadors had children with Native women, the most famous example possibly being that of the Conquistador of Mexico, Hernán Cortez, and the Nahua woman known as “Malinche” (Fig. 4). This “sex-biased” pattern of mating between immigrant men and Native women had been alluded to by historians (Morner 1967), but it was only with mtDNA and Y-chromosome studies that the full genetic impact of this feature became apparent. Because mtDNA and the Y chromosome are only transmitted by mothers and fathers, respectively, they allow the inference of the maternal (mtDNA) and paternal (Y-chromosome) ancestry of individuals. One of the first such studies was performed in Antioquia (Colombia), a population traditionally considered as mainly of Spanish descent. Consistent with this view, it was found that >90% of men in Antioquia had Y-chromosome lineages of European origin (Carvajal-Carmona et al. 2000). Surprisingly, when examining their mtDNA, a sharply different picture was observed. In 90% of individuals, maternal ancestry was Native American (Carvajal-Carmona et al. 2000). Similar observations have now been made in many Latin American countries (Alves-Silva et al. 2000; Green et al. 2000; Carvalho-Silva et al. 2001; Marrero et al. 2007), although with a considerable variation in ancestry proportions between them (Fig. 5). These studies, in addition, show a higher African ancestry with mtDNA than the Y chromosome, indicating that, historically, admixture with Africans has also mostly involved African women.Open in a separate windowFigure 4.The Native American woman known as “Malinche” or Malintzin (her Nahuatl name) was the interpreter and mistress of the Spanish Conquistador, Hernán Cortés. In 1523, she gave him a son, Martín, who is one of the first recorded individuals of mixed Native–European ancestry born in the Americas. Such offspring between immigrant men and Native women were a common occurrence in early colonial Latin America. The drawing shown is from the late 16th century “Codex Tlaxcala” and represents a meeting between the Mexican ruler, Moctezuma, and Hernán Cortés, with Malintzin (on the right) translating.Open in a separate windowFigure 5.Proportion of Native American, European, and African ancestry in 13 Latin American populations estimated using mtDNA and Y-chromosome markers. Samples from urban centers in five countries were examined (Mexico—Mexico City; Guatemala—Oriente; Costa Rica—Central Valley of Costa Rica [CVCR]; Colombia—Peque, Medellín, and Cundinamarca; Chile—Paposo and Quetalmahue; Argentina—Salta, Tucuman, and Tacamarca; and Brazil—Rio Grande do Sul [RGS]). Ancestry proportion (fraction of the pie chart) is color-coded: African (green), European (blue), and Native American (red). (Data for 20 individuals per population are from Wang et al. 2007, Yang et al. 2010, and NN Yang et al. unpubl.)The large variation in ancestry seen across Latin America relates to differences in pre-Columbian Native population density and the pattern of recent immigration into specific regions of the continent. For instance, most studies performed so far have mainly focused on areas with little documented African immigration and consistently show a relatively low African genetic ancestry. In these population samples, the variation in individual European and Native American ancestry is very large, to the extent that it overlaps with that seen in Native population samples (Fig. 6). The variation in individual ancestry seen in these samples thus effaces their designation as “Native” or “non-Native.” This observation punctuates the interest of incorporating admixed Latin American populations, traditionally considered non-Native, into studies on the initial settlement of the continent. Similar to what has been performed in the recent survey by Reich et al. (2012), the inference of ancestry of each genome segment in Latin Americans could be used to focus solely on Native American segments of the genome. This is an avenue of research that is just beginning to be explored and shows great potential for the future. It promises to be of particular importance for the analysis of regions where anthropologically recognizable Native populations and individuals are virtually nonexistent, as they have been absorbed into the current mixed population. This is the case for the many areas that were relatively sparsely populated in pre-Columbian times and, subsequently, received a large flow of immigrants, such as from the Caribbean and many parts of North and South America. Consequently, estimation of individual ancestry along the genome will facilitate denser demographic history analyses across the Americas, as well as a reexamination of the original settlement of the continent based on a more comprehensive population sampling.Open in a separate windowFigure 6.Distribution of individual Native ancestry estimated in samples from Native Americans (shown in blue) and two Latin American urban centers (850 residents of Medellín, Colombia shown in red, and 220 residents of Mexico City, Mexico shown in green). For each of the three population samples, the x-axis indicates the proportion of Native ancestry (in 0.1 unit intervals) and the y-axis indicates the proportion of individuals with that ancestry estimate. The Native American group includes 225 individuals from North, Central, and South America. Ancestry proportions were estimated using autosomal genetic markers. (Data from Florez et al. 2009, Campbell et al. 2011, and Reich et al. 2012.)Other than being informative for addressing questions of population history, the study of Latin American populations promises to facilitate the genetic characterization of biological attributes differentiated among the populations that participated in admixture on the continent. For instance, a range of facial features differ between Native Americans and Europeans, and the genetic study of admixed Latin Americans promises to help in the identification of genes explaining variation in facial appearance. Such research is of interest for understanding disorders of craniofacial development and could also have forensic applications. Another example is type 2 diabetes (T2D), a disease that has a very high frequency in Native Americans and for which a higher risk is associated with increased Native American ancestry. This observation led to the proposal of the “thrifty genotype” hypothesis, which posits that the increased risk of T2D in Native Americans results from genetic adaption to a low-calorie/high-exercise way of life that became detrimental with the recent change to a high-calorie/low-exercise lifestyle (Pollard 2008). The study of large, carefully characterized samples from Latin American populations offers a unique opportunity for conducting a detailed assessment of this hypothesis. The identification of genes explaining the variable frequency of diseases between populations (such as T2D) will be an important step forward in the development of novel, more effective (even individualized) disease-management strategies that account for human population diversity.The overlap of individual genetic ancestry estimates, seen in Latin and Native American populations (Fig. 5), raises the question of the relationship of these estimates to the perception that individuals have of their own ancestry. A recent analysis of a large sample of individuals from five Latin American countries found a highly significant correlation between self-perception and genetically estimated ancestry (Fig. 7). However, this study also found evidence that self-perception is biased. A particularly clear bias involves pigmentation: individuals with greater pigmentation tend to overestimate their Native and African ancestry, whereas individuals with lighter pigmentation tend to overestimate their European ancestry (AR Ruiz-Linares, in press). Statistically significant differences were also observed between countries, pointing to the influence of social factors in self-perception. Consistent with this observation, social scientists have argued that, in Latin America, self-identification as Native or non-Native is often strongly influenced by social cues (Wade 2010).Open in a separate windowFigure 7.Box plots displaying the relationship of individual genetic ancestry estimates to self-perceived ancestry in 7342 Latin Americans (from Mexico, Colombia, Peru, Chile, and Brazil). Self-perception was categorized into 20% bands for African, European, and Native American ancestry. There is a highly significant correlation between the genetic estimate and self-perception for each continental ancestry component. However, there is a trend at higher Native American and African ancestry for self-perception to exceed the genetic estimates. Correspondingly, at lower European ancestry, there is a trend for the genetic estimates to exceed self-perception. Further analyses show that pigmentation impacts on these differences. Individuals with lower skin pigmentation tend to overestimate their European ancestry, whereas individuals with higher pigmentation overestimate their Native American and African ancestries. Orange lines indicate the median and the blue boxes are delimited by the 25th and 75th percentiles. (From AR Ruiz-Linares et al., in press; with permission from the author.)The insights into the initial settlement of the continent provided by the genetic study of Native Americans illustrate the fact that a population sampling that maximizes diversity based on anthropological grounds (such as language) can facilitate investigations concerned with the first settlement of the continent. However, the analysis of intercontinental admixture both in Native and non-Native Latin American populations show some of the complexities of defining human groups, with population labels suggesting a potentially misleading genetic singularity. The biological reality is that of a gradient in the genetic makeup of these populations (and individuals) involving various degrees of mixture between the initial settlers of the continent and more recent immigrants. The genetic diversity of Latin Americans is, thus, a prominent example of the fuzzy meaning of the labels used to refer to human populations. Although these labels can assist in study design and facilitate certain historical inferences, ethnicity, race, and other such terms are social constructs devoid of a clear-cut biological meaning.