Andres Ruiz-Linares

Reconstructing Native American population history.

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call ‘First American’. However, speakers of Eskimo–Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.

Geographic patterns of genome admixture in Latin American Mestizos.

The large and diverse population of Latin America is potentially a powerful resource for elucidating the genetic basis of complex traits through admixture mapping. However, no genome-wide characterization of admixture across Latin America has yet been attempted. Here, we report an analysis of admixture in thirteen Mestizo populations (i.e. in regions of mainly European and Native settlement) from seven countries in Latin America based on data for 678 autosomal and 29 X-chromosome microsatellites. We found extensive variation in Native American and European ancestry (and generally low levels of African ancestry) among populations and individuals, and evidence that admixture across Latin America has often involved predominantly European men and both Native and African women. An admixture analysis allowing for Native American population subdivision revealed a differentiation of the Native American ancestry amongst Mestizos. This observation is consistent with the genetic structure of pre-Columbian populations and with admixture having involved Natives from the area where the Mestizo examined are located. Our findings agree with available information on the demographic history of Latin America and have a number of implications for the design of association studies in population from the region.

Discerning the ancestry of European Americans in genetic association studies

European Americans are often treated as a homogeneous group, but in fact form a structured population due to historical immigration of diverse source populations. Discerning the ancestry of European Americans genotyped in association studies is important in order to prevent false-positive or false-negative associations due to population stratification and to identify genetic variants whose contribution to disease risk differs across European ancestries. Here, we investigate empirical patterns of population structure in European Americans, analyzing 4,198 samples from four genome-wide association studies to show that components roughly corresponding to northwest European, southeast European, and Ashkenazi Jewish ancestry are the main sources of European American population structure. Building on this insight, we constructed a panel of 300 validated markers that are highly informative for distinguishing these ancestries. We demonstrate that this panel of markers can be used to correct for stratification in association studies that do not generate dense genotype data.

A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome

Summary Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological pain states. We describe an autosomal-dominant familial episodic pain syndrome characterized by episodes of debilitating upper body pain, triggered by fasting and physical stress. Linkage and haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12–8q13. Candidate gene sequencing identified a point mutation (N855S) in the S4 transmembrane segment of TRPA1, a key sensor for environmental irritants. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials. Quantitative sensory testing demonstrated normal baseline sensory thresholds but an enhanced secondary hyperalgesia to punctate stimuli on treatment with mustard oil. TRPA1 antagonists inhibit the mutant channel, promising a useful therapy for this disorder. Our findings provide evidence that variation in the TRPA1 gene can alter pain perception in humans. Video Abstract

Strong Amerind/White sex bias and a possible sephardic contribution among the founders of a population in Northwest Colombia

Historical and genetic evidences suggest that the recently founded population of Antioquia (Colombia) is potentially useful for the genetic mapping of complex traits. This population was established in the 16th-17th centuries through the admixture of Amerinds, Europeans, and Africans and grew in relative isolation until the late 19th century. To examine the origin of the founders of Antioquia, we typed 11 markers on the nonrecombining portion of the Y chromosome and four markers on mtDNA in a sample of individuals with confirmed Antioquian ancestry. The polymorphisms on the Y chromosome (five biallelic markers and six microsatellites) allow an approximation to the origin of founder men, and those on mtDNA identify the four major founder Native American lineages. These data indicate that approximately 94% of the Y chromosomes are European, 5% are African, and 1% are Amerind. Y-chromosome data are consistent with an origin of founders predominantly in southern Spain but also suggest that a fraction came from northern Iberia and that some possibly had a Sephardic origin. In stark contrast with the Y-chromosome, approximately 90% of the mtDNA gene pool of Antioquia is Amerind, with the frequency of the four Amerind founder lineages being closest to Native Americans currently living in the area. These results indicate a highly asymmetric pattern of mating in early Antioquia, involving mostly immigrant men and local native women. The discordance of our data with blood-group estimates of admixture suggests that the number of founder men was larger than that of women.

A Genomewide Admixture Map for Latino Populations

Admixture mapping is an economical and powerful approach for localizing disease genes in populations of recently mixed ancestry and has proven successful in African Americans. The method holds equal promise for Latinos, who typically inherit a mix of European, Native American, and African ancestry. However, admixture mapping in Latinos has not been practical because of the lack of a map of ancestry-informative markers validated in Native American and other populations. To address this, we screened multiple databases, containing millions of markers, to identify 4,186 markers that were putatively informative for determining the ancestry of chromosomal segments in Latino populations. We experimentally validated each of these markers in at least 232 new Latino, European, Native American, and African samples, and we selected a subset of 1,649 markers to form an admixture map. An advantage of our strategy is that we focused our map on markers distinguishing Native American from other ancestries and restricted it to markers with very similar frequencies in Europeans and Africans, which decreased the number of markers needed and minimized the possibility of false disease associations. We evaluated the effectiveness of our map for localizing disease genes in four Latino populations from both North and South America.

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.

The genetics of Mexico recapitulates Native American substructure and affects biomedical traits

The population structure of Native Mexicans The genetics of indigenous Mexicans exhibit substantial geographical structure, some as divergent from each other as are existing populations of Europeans and Asians. By performing genome-wide analyses on Native Mexicans from differing populations, Moreno-Estrada et al. successfully recapitulated the pre-Columbian substructure of Mexico. This ancestral structure is evident among cosmopolitan Mexicans and is correlated with subcontinental origins and medically relevant aspects of lung function. These findings exemplify the importance of understanding the genetic contributions of admixed individuals. Science, this issue p. 1280 Indigenous and cosmopolitan Mexican populations are highly structured with genetic variation of medical relevance. Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.

The Simons Genome Diversity Project: 300 genomes from 142 diverse populations

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.

Autosomal, mtDNA, and Y-Chromosome Diversity in Amerinds: Pre- and Post-Columbian Patterns of Gene Flow in South America

To evaluate sex-specific differences in gene flow between Native American populations from South America and between those populations and recent immigrants to the New World, we examined the genetic diversity at uni- and biparental genetic markers of five Native American populations from Colombia and in published surveys from native South Americans. The Colombian populations were typed for five polymorphisms in mtDNA, five restriction sites in the beta-globin gene cluster, the DQA1 gene, and nine autosomal microsatellites. Elsewhere, we published results for seven Y-chromosome microsatellites in the same populations. Autosomal polymorphisms showed a mean G(ST) of 6.8%, in agreement with extensive classical marker studies of South American populations. MtDNA and Y-chromosome markers resulted in G(ST) values of 0.18 and 0.165, respectively. When only Y chromosomes of confirmed Amerind origin were used in the calculations (as defined by the presence of allele T at locus DYS199), G(ST) increased to 0.22. G(ST) values calculated from published data for other South American natives were 0.3 and 0.29 for mtDNA and Amerind Y chromosomes, respectively. The concordance of these estimates does not support an important difference in migration rates between the sexes throughout the history of South Amerinds. Admixture analysis of the Colombian populations suggests an asymmetric pattern of mating involving mostly immigrant men and native women.