Genetic structure of Mexico

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Science 13 June 2014:
Vol. 344 no. 6189 pp. 1280-1285

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

Andrés Moreno-Estrada

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.

Link

mtDNA D1 from 12-13 thousand year old Paleoamerican

This is interesting both because it's a >12,000 year old skeleton from the bottom of the sea (!) and because it establishes that an individual with clear Paleoamerican morphology belonged to a common modern Amerindian mtDNA haplogroup. Together with the recent publication of the Anzick genome, it seems that everything points towards continuity of Native Americans since the earliest settlement, rather than a more recent arrival of the ancestors of Native Americans that replaced an earlier "Paleoamerican" gene pool.

Science 16 May 2014: Vol. 344 no. 6185 pp. 750-754 DOI: 10.1126/science.1252619

Late Pleistocene Human Skeleton and mtDNA Link Paleoamericans and Modern Native Americans

James C. Chatters

Because of differences in craniofacial morphology and dentition between the earliest American skeletons and modern Native Americans, separate origins have been postulated for them, despite genetic evidence to the contrary. We describe a near-complete human skeleton with an intact cranium and preserved DNA found with extinct fauna in a submerged cave on Mexico’s Yucatan Peninsula. This skeleton dates to between 13,000 and 12,000 calendar years ago and has Paleoamerican craniofacial characteristics and a Beringian-derived mitochondrial DNA (mtDNA) haplogroup (D1). Thus, the differences between Paleoamericans and Native Americans probably resulted from in situ evolution rather than separate ancestry.

Link

Mexicans got type 2 diabetes risk allele from Neandertals

Nature (2013) doi:10.1038/nature12828

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico

The SIGMA Type 2 Diabetes Consortium

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others1, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings2, 3, 4, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10−13; odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10−4; OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.

Link

Native Native American dogs

Proc. R. Soc. B doi: 10.1098/rspb.2013.1142

Pre-Columbian origins of Native American dog breeds, with only limited replacement by European dogs, confirmed by mtDNA analysis

Barbara van Asch et al.

Dogs were present in pre-Columbian America, presumably brought by early human migrants from Asia. Studies of free-ranging village/street dogs have indicated almost total replacement of these original dogs by European dogs, but the extent to which Arctic, North and South American breeds are descendants of the original population remains to be assessed. Using a comprehensive phylogeographic analysis, we traced the origin of the mitochondrial DNA lineages for Inuit, Eskimo and Greenland dogs, Alaskan Malamute, Chihuahua, xoloitzcuintli and perro sín pelo del Peru, by comparing to extensive samples of East Asian (n = 984) and European dogs (n = 639), and previously published pre-Columbian sequences. Evidence for a pre-Columbian origin was found for all these breeds, except Alaskan Malamute for which results were ambigous. No European influence was indicated for the Arctic breeds Inuit, Eskimo and Greenland dog, and North/South American breeds had at most 30% European female lineages, suggesting marginal replacement by European dogs. Genetic continuity through time was shown by the sharing of a unique haplotype between the Mexican breed Chihuahua and ancient Mexican samples. We also analysed free-ranging dogs, confirming limited pre-Columbian ancestry overall, but also identifying pockets of remaining populations with high proportion of indigenous ancestry, and we provide the first DNA-based evidence that the Carolina dog, a free-ranging population in the USA, may have an ancient Asian origin.

Link

Native American origins from whole-genome and exome data (Gravel et al. 2013)

arXiv:1306.4021 [q-bio.PE]

Reconstructing Native American Migrations from Whole-genome and Whole-exome Data

Simon Gravel et al.

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 48% in MXL, 25% in CLM, and 13% in PUR. Native American ancestry in PUR appears most closely related to Equatorial-Tucanoan-speaking populations, supporting a Southern America ancestry of the Taino 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 three-population demographic model. The ancestral populations to the three groups likely split in close succession: the most likely scenario, based on a peopling of the Americas 16 thousand years ago (kya), supports that the MXL Ancestors split 12.2kya, with a subsequent split of the ancestors to CLM and PUR 11.7kya. The model also features a Mexican population of 62,000, a Colombian population of 8,700, and a Puerto Rican population of 1,900. 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 size and the earlier migration from Europe.

Link

Aztec conquest of Xaltocan led to population replacement

This study represents a good example of how ancient DNA analysis can supplement traditional archaeology. Issues of population replacement/continuity are often encountered in archaeology, especially when there are traditions of conquest/resettlement, or such events might be hypothesized by changes in the material record.

But, such events are often difficult to interpret, because people living through periods of turmoil might have a tendency to exaggerate their importance, while culture is malleable and may shift without large-scale population replacement.

Am J Phys Anthropol DOI: 10.1002/ajpa.22152

The Genetic Impact of Aztec Imperialism: Ancient Mitochondrial DNA Evidence From Xaltocan, Mexico 

Jaime Mata-Mıguez et al.

In AD 1428, the city-states of Tenochtitlan, Texcoco, and Tlacopan formed the Triple Alliance, laying the foundations of the Aztec empire. Although it is well documented that the Aztecs annexed numerous polities in the Basin of Mexico over the following years, the demographic consequences of this expansion remain unclear. At the city-state capital of Xaltocan, 16th century documents suggest that the site's conquest and subsequent incorporation into the Aztec empire led to a replacement of the original Otomí population, whereas archaeological evidence suggests that some of the original population may have remained at the town under Aztec rule. To help address questions about Xaltocan's demographic history during this period, we analyzed ancient DNA from 25 individuals recovered from three houses rebuilt over time and occupied between AD 1240 and 1521. These individuals were divided into two temporal groups that predate and postdate the site's conquest. We determined the mitochondrial DNA haplogroup of each individual and identified haplotypes based on 372 base pair sequences of first hypervariable region. Our results indicate that the residents of these houses before and after the Aztec conquest have distinct haplotypes that are not closely related, and the mitochondrial compositions of the temporal groups are statistically different. Altogether, these results suggest that the matrilines present in the households were replaced following the Aztec conquest. This study therefore indicates that the Aztec expansion may have been associated with significant demographic and genetic changes within Xaltocan.

Link

Instantaneous vs. continuous admixture dynamics (Jin et al. 2012)

A new paper in AJHG discusses the distribution of chromosomal segments of distinct ancestry (CSDAs) under three different models of admixture dynamics (left). In the hybrid isolation (HI) model, admixture is instantaneous and results in a hybrid population that evolves with drift and recombination only. In the gradual admixture (GA) model, the hybrid population continues to receive admixture from the unadmixed parental populations. Finally, in the continuous gene flow model (CGF), one of the populations becomes admixed while the other continues to exist unadmixed and to contribute to the admixed one.

In practical terms, the HI model results in the diminution of CSDA length due to recombination over time, and at "present" there is a paucity of long CSDAs. In the GA model there are more long CSDAs for both populations, while in the CGF model there is an asymmetry in the CSDAs donated by Pop1 and Pop2, with those from the "donor" population being longer (because fresh "long" segments are added in every generation).

The conclusions of the paper regarding some particular admixture cases are also interesting. For African Americans:

Although the actual population admixture of African Americans might be more complex than what our simulation suggested, the CGF1 model setting at 14 generations was found to be reasonably  epresentative, capturing the main pattern of the population admixture dynamics.

The CGF1 model has Africans as recipients and Europeans as donors. This makes sense, since African Americans are descended from slaves who were transported to the New World, with the slave trade ending centuries ago, hence there was mostly no replenishment of the AA population with fresh African-origin individuals. On the other hand, European Americans, both due to social dynamics and their numerical majority continued to exist as a distinct population that contributed to the AA population.

I should mention that according to HAPMIX, the admixture time was 7 generations, with is close to the 6 +/- 1 generations inferred by rolloff analysis by Moorjani et al. So, in this case this admixture time appears to be an "average" of a continuing process of admixture that began 14 generations ago.

Onto Mexicans:

In short, the GA model at 24 generations fit the empirical data best among all these simulated scenarios, as indicated by the distribution of EMDs.

Again, this makes sense, because in Mexico there continued to exist unadmixed populations of Europeans and Amerindians that contributed to the Mestizo population of the country.

On the African admixture in Mozabites:

Comparing the empirical distribution of CSDAs with that simulated, we found that the Mozabite admixture process essentially fit the HI model with 100 generations since admixture. There was an almost complete absence of recent gene flow from European populations to the Mozabite gene pool (Figure 6A). For the Sub-Saharan African ancestral component, there were more long CSDAs at the tail of empirical distribution than those in the HI model, which confirmed that recent gene flow from African populations had contributed to the Mozabite gene pool (Figure 6B). 

Again, this makes sense: Berber groups were not replenished from other Caucasoid sources, so their original admixture with native Africans resulted in a blend that persisted largely unaffected by "Europeans", but did find occasion of admixture with Sub-Saharans. Hence, the asymmetry in the presence of long "European" vs. "Sub-Saharan" segments.

A similar pattern was evident for Bedouin, Palestinians, and Druze:

Analyses of European ancestral component in Bedouin and Palestinian populations also showed that the empirical distributions essentially fit the HI model for both populations (Figures 6C and 6E). Although the empirical CSDA distribution of Sub-Saharan African ancestral component also fit the HI model  best, both distributions showed a long tail at the right compared with those under the HI model, indicating that recent gene flow from Sub-Saharan Africans also contributed to the two admixed populations (Figures 6D and 6F). ... For Druze, their European component of ancestry fit the HI model very well. However, their African ancestral component contained much shorter CSDAs than those of simulated (Figure S14), which might indicate that previous studies had underestimated the admixture time of Druze. In addition, populations receiving recent gene flow from their parental populations showed higher variation of individual ancestral proportions than those who did not (Figure S13).

The Druze have well-known Egyptian connections, and they may have largely avoided Sub-Saharan African admixture during the Islamic period, principally because of its avoidance of proselytism. Hence, their African admixture may stem from Egyptian adherents who were themselves a product of much earlier Caucasoid/Sub-Saharan admixture during the course of pre-Islamic Egypt.


The American Journal of Human Genetics, 25 October 2012 doi:10.1016/j.ajhg.2012.09.008

Exploring Population Admixture Dynamics via Empirical and Simulated Genome-Wide Distribution of Ancestral Chromosomal Segments

Wenfei Jin et al

Abstract

The processes of genetic admixture determine the haplotype structure and linkage disequilibrium patterns of the admixed population, which is important for medical and evolutionary studies. However, most previous studies do not consider the inherent complexity of admixture processes. Here we proposed two approaches to explore population admixture dynamics, and we demonstrated, by analyzing genome-wide empirical and simulated data, that the approach based on the distribution of chromosomal segments of distinct ancestry (CSDAs) was more powerful than that based on the distribution of individual ancestry proportions. Analysis of 1,890 African Americans showed that a continuous gene flow model, in which the African American population continuously received gene flow from European populations over about 14 generations, best explained the admixture dynamics of African Americans among several putative models. Interestingly, we observed that some African Americans had much more European ancestry than the simulated samples, indicating substructures of local ancestries in African Americans that could have been caused by individuals from some particular lineages having repeatedly admixed with people of European ancestry. In contrast, the admixture dynamics of Mexicans could be explained by a gradual admixture model in which the Mexican population continuously received gene flow from both European and Amerindian populations over about 24 generations. Our results also indicated that recent gene flows from Sub-Saharan Africans have contributed to the gene pool of Middle Eastern populations such as Mozabite, Bedouin, and Palestinian. In summary, this study not only provides approaches to explore population admixture dynamics, but also advances our understanding on population history of African Americans, Mexicans, and Middle Eastern populations.

Link

Admixture and population structure of Mexican Mestizos

J Hum Genet. 2012 Jul 26. doi: 10.1038/jhg.2012.67. [Epub ahead of print]

Admixture and population structure in Mexican-Mestizos based on paternal lineages.

Martínez-Cortés G, Salazar-Flores J, Gabriela Fernández-Rodríguez L, Rubi-Castellanos R, Rodríguez-Loya C, Velarde-Félix JS, Franciso Muñoz-Valle J, Parra-Rojas I, Rangel-Villalobos H.

Abstract

In the nonrecombining region of the Y-chromosome, there are single-nucleotide polymorphisms (Y-SNPs) that establish haplogroups with particular geographical origins (European, African, Native American, etc.). The complex process of admixture that gave rise to the majority of the current Mexican population (∼93%), known as Mestizos, can be examined with Y-SNPs to establish their paternal ancestry and population structure. We analyzed 18 Y-SNPs in 659 individuals from 10 Mexican-Mestizo populations from different regions of the country. In the total population sample, paternal ancestry was predominately European (64.9%), followed by Native American (30.8%) and African (4.2%). However, the European ancestry was prevalent in the north and west (66.7-95%) and, conversely, Native American ancestry increased in the center and southeast (37-50%), whereas the African ancestry was low and relatively homogeneous (0-8.8%). Although this paternal landscape concurs with previous studies based on genome-wide SNPs and autosomal short tandem repeats (STRs), this pattern contrasts with the maternal ancestry, mainly of Native American origin, based on maternal lineages haplogroups. In agreement with historical records, these results confirm a strong gender-biased admixture history between European males and Native American females that gave rise to Mexican-Mestizos. Finally, pairwise comparisons and analysis of molecular variance tests demonstrated significant population structure (F(ST)=4.68%; P less than 0.00005), delimiting clusters that were geographically defined as the following: north-west, center-south and southeast.

Link

Y chromosome diversity in Native Mexicans (Sandoval et al. 2012)

From the paper:

The first dimension of the CoA (60.53%) separates Q-M3 from the rest, and the second dimension (39.47%) C-M130 from the rest. In agreement ith the known distribution of haplogroup C, we observed that the two northernmost populations of this panel (Chippewa and Sioux) cluster next to C-M130 and the rest of populations show varying proportions of Q-M242 and Q-M3. It is noteworthy that Native Mexicans are the only regional group with populations represented next to both the Q-M242 cluster and the Q-M3 cluster. In contrast, all Central and South American samples were grouped significantly closer to the Q-M3 haplogroup (Fig. 3).

Am J Phys Anthropol DOI: 10.1002/ajpa.22062

Y-chromosome diversity in Native Mexicans reveals continental transition of genetic structure in the Americas

Karla Sandoval et al.

The genetic characterization of Native Mexicans is important to understand multiethnic based features influencing the medical genetics of present Mexican populations, as well as to the reconstruct the peopling of the Americas. We describe the Y-chromosome genetic diversity of 197 Native Mexicans from 11 populations and 1,044 individuals from 44 Native American populations after combining with publicly available data. We found extensive heterogeneity among Native Mexican populations and ample segregation of Q-M242* (46%) and Q-M3 (54%) haplogroups within Mexico. The northernmost sampled populations falling outside Mesoamerica (Pima and Tarahumara) showed a clear differentiation with respect to the other populations, which is in agreement with previous results from mtDNA lineages. However, our results point toward a complex genetic makeup of Native Mexicans whose maternal and paternal lineages reveal different narratives of their population history, with sex-biased continental contributions and different admixture proportions. At a continental scale, we found that Arctic populations and the northernmost groups from North America cluster together, but we did not find a clear differentiation within Mesoamerica and the rest of the continent, which coupled with the fact that the majority of individuals from Central and South American samples are restricted to the Q-M3 branch, supports the notion that most Native Americans from Mesoamerica southwards are descendants from a single wave of migration. This observation is compatible with the idea that present day Mexico might have constituted an area of transition in the diversification of paternal lineages during the colonization of the Americas.

Link

Mega-study on Mexican admixture

There have been other studies on Mexican admixture patterns before, but this one breaks new ground, by determining the more specific origin of the three major components of the Mexican population. From the paper:

In addition to the HapMap CEU, who are mostly of Northern European ancestry, we used individuals recruited from Dublin, (Ireland), Warsaw (Poland), Rome (Italy) and Porto (Portugal) to provide references for different areas within Europe. The first two PCs provide good separation of these reference populations, and correspond roughly to North-South and West-East gradients (Figure 3A). Both the MEX1EUR and MEX2EUR virtual genomes are most closely related to intact genomes from Porto, which we interpret as a surrogate for populations from the Iberian Peninsula, [3], consistent with the historical record that the first European migrants to Mexico were Spaniards.

The paper is also methodologically interesting:

Continental-level admixture proportions were estimated two ways: (1) a model-based clustering algorithm implemented in frappe [35], and (2) average locus-specific ancestries across all markers. Locus-specific ancestry was estimated with SABER+, an extension of a previously described approach, SABER, that uses a Markov-Hidden Markov Model [12]. SABER+ differs from SABER in implementation of a new algorithm, an Autoregressive Hidden Markov Model (ARHMM), in which haplotype structure within the ancestral populations is adaptively constructed using a binary decision tree based on as many as 15 markers, and which therefore does not require a priori knowledge of genome-wide ancestry proportions (Johnson et al., in preparation). In simulation studies, the ARHMM achieves accuracy comparable to HapMix [36] but is more flexible in modeling the three-way admixture in the Mexican population and does not require information about the recombination rate.

PLoS Genet 7(12): e1002410. doi:10.1371/journal.pgen.1002410

Ancestral Components of Admixed Genomes in a Mexican Cohort

Nicholas A. Johnson et al.

For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study “virtual genomes” of admixed individuals. We apply this approach to a cohort of 492 parent–offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations—Africa, Europe, and America—vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10–15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people.

Link

Genetic variation in Native Americans consistent with archaeology

The great thing about this study is that the authors came up with a way of studying Native Americans via the genomes of Mexicans. This is possible because Mexican genomes contain largely European and Amerindian segments (and much less African), which can be easily identified as such.

The fact that genomic diversity in Native Americans can be recovered from their admixed descendants presents new hope for prehistoric studies, as in many places of the world (e.g., North Africa or Central Asia), admixture events took place that are not as well understood since they did not happen to be well-recorded by historians.

It also showcases the idiocy of statements such as that from the American Indian Program at Cornell...

“In marked contrast to the goals of the Cornell Ancestry Event, which seeks to define ‘diversity’ biologically in terms of universal genetic codes … Indigenous peoples customarily define themselves not biologically, but socio-culturally and politically in terms of varying ideas of nationhood,” the statement says.

... which thus objected to the Genographic Project's sampling of Native Americans.

If researchers can identify Native American DNA in admixed individuals, then there must be something more concrete to being a "Native American" than socio-cultural/political self-definitions.

Moreover, it shows how futile the quest to limit access to Native American DNA for research purposes actually is, because this DNA can be recovered anyway from admixed individuals (such as many Latinos) who don't mind.

Mol Biol Evol (2011) doi: 10.1093/molbev/msr049

Genetic variation in Native Americans, inferred from Latino SNP and resequencing data

Jeffrey D. Wall et al.

Analyses of genetic polymorphism data have the potential to be highly informative about the demographic history of Native American populations, but due to a combination of historical and political factors, there are essentially no autosomal sequence polymorphism data from any Native American group. However, there are many resequencing studies involving Latinos, whose genomes contain segments inherited from their Native American ancestors. In this study, we introduce a new method for estimating local ancestry across the genomes of admixed individuals and show how this method, along with dense genotyping and targeted resequencing, can be used to assay genetic variation in ancestral Native American groups. We analyze roughly 6 Mb of resequencing data from 22 Mexican-Americans to provide the first large-scale view of sequence-level variation in Native Americans. We observe low levels of diversity and high levels of linkage disequilibrium in the Native American-derived sequences, consistent with a recent, severe population bottleneck associated with the initial peopling of the Americas. Using two different computational approaches, one novel, we estimate that this bottleneck occurred roughly 12.5 thousand years ago; when uncertainty in the estimation process is taken into account, our results are consistent with archeological estimates for the colonization of the Americas.

Link

ADMIXTURE in the New World

Here is the result of running ADMIXTURE on ~450K markers on six HapMap-3 populations; left-to-right: African Americans from the Southwest (ASW), Utah Whites (CEU), Beijing Chinese (CHB), Mexicans from Los Angeles (MEX), Toscans (TSI), and Yoruban from Nigeria (YRI).

Here are the admixture proportions (in %):

It is obvious, however, from the ADMIXTURE plot above, and the triangle plots below (for ASW and MEX), that the admixture is not uniformly distributed.

Notice the two African American individuals with substantial Amerindian admixture (14 and 29%), while the rest are a simple 2-way mix of Europeans and Sub-Saharans with minor Amerindian admixture in some of them. The standard deviation of European admixture is 8.3%, lower than in Mexicans.

Mexicans are variable in terms of their European-Amerindian mix, but with less variable tiny Sub-Saharan component (0.6% with a standard deviation of 1.2%). This is probably due to the fact that blacks were absorbed earlier in Mexico, while European-Amerindian social stratification and continued European immigration has fueled the retention of considerable variation. European admixture in Mexicans is 27.7% on average, but with a standard deviation of 24.0% and minimum/maximum value of 0.0 to 90.5% in the sample I am considering.

Eva Longoria, for example, who recently learned that she is 70% European in "Faces of America" belongs to the top-5% of Mexican American "European-ness", although there is probably considerable variation of Mexican Americans within the country.

ADMIXTURE on HapMap 3 populations

Here is the result of running ADMIXTURE on about ~50K markers from the HapMap 3 populations. I'll annotate the final K=9 run; the rest are given at the end:

I list the distinctive colors for the populations, Left-to-Right. The minor components are easy enough to pick up and as expected:

ASW (A): African ancestry in Southwest USA [Sub-Saharan blue]

CEU (C): Utah residents with Northern and Western European ancestry from the CEPH collection [European yellow]

CHB (H): Han Chinese in Beijing, China [East Asian orange]
CHD (D): Chinese in Metropolitan Denver, Colorado [East Asian orange]

GIH (G): Gujarati Indians in Houston, Texas [South Asian purple]

JPT (J): Japanese in Tokyo, Japan [East Asian light green]

LWK (L): Luhya in Webuye, Kenya [East African bright green]

MEX (M): Mexican ancestry in Los Angeles, California [Amerindian pink]

MKK (K): Maasai in Kinyawa, Kenya [East African light blue]

TSI (T): Tuscan in Italy [European yellow]

YRI (Y): Yoruban in Ibadan, Nigeria (West Africa) [Sub-Saharan blue]

The rest of the runs for K=3 to K=8 are below:

K=3: Notice: Asian red+Caucasoid blue on Gujarati Indians and Mexicans. At this level of resolution, these two populations look similar. Notice presence of blue in East Africans but not Yorubans (green at the end).

K=4: East Africans get their own (yellow) cluster. Notice the diminution of the Sub-Saharan (purple) element, relative to the previous figure. This is due to the fact that the East African element is intermediate between Caucasoids and Sub-Saharans and "eats up" the other two elements, although residual Caucasoid red and Sub-Saharan purple remains. The tripartite origin of Mexicans is especially visible in this plot, with components being in order of European, East Eurasian, Sub-Saharan.
K=5: Gujarati Indians now get their own (purple) cluster. Here the difference between Luhya (mostly Sub-Saharan blue + East African yellow) and Maasai (the reverse) is quite striking. The former are Bantu speakers and thus not indigenous to east Africa.
K=6: Mexicans get their own cluster (blue) reflecting their Amerindian, rather than East Asian ancestry which could not be resolved in the previous figures.
K=7: the Luhya get their own cluster, splitting off from the Maasai. There are now 3 components in Africa centered on Yorubans (light blue), Luhya (very light green) and Maasai (red).
K=8: A low-frequency element appears in Maasai that is hard to interpret; it is preserved in the next and final K=9 run (shown at the beginning of the post), in which the Japanese and Chinese are split off.

Half of hidden heritability found (for height, at least)

This is a quite interesting paper, as it shows, by sampling a large number of individuals), that the heritability of height is not missing after all. The authors looked at a large number of individuals, and this allowed them to discover statitically significant associations between height and more SNPs than before.

This bears great promise as it may hint that genome-wide association studies, that have come under substantial criticism lately, may be failing not because of an inherent flaw, but rather because they are not sampling enough individuals.

The discovered SNPs account for 45% of the heritability of height. Where is the rest? The authors argue for two additional sources:

First, SNPs in current microarray chips sample the genome incompletely. Locations in-between discovered SNPs are in incomplete linkage disequilibrium with the discovered SNPs. So, there is undetected polymorphism, in the gaps between the hundreds of thousands of SNPs in current chips, that may explain a portion of the missing heritability.

Second, SNPs have different minor allele frequencies. For example, in one SNP the minor allele may occur at 10% of individuals, while in others at 30%. This is important, because it is more difficult to arrive at a statistically significant result in the former case.

Consider a SNP with a minor allele frequency of 2%. Then, if you sample 1,000 individuals, only about 20 of them are expected to have the minor allele. You cannot estimate the average height of the minor allele with a sample of 20 people as securely as you can with a sample of 500. Thus, if the SNP influences height in a small way, you will not be able to detect it.

A further complication, which I've written about before, is that some variation in the human genome is family-related, or at least occurs at fewer individuals than the allele frequency cutoff. If 99.9% of people have C at a given location and 0.1% of people have T, this variant is unlikely to be included in a microarray chp, because it is too rare to matter economically: you would only get a handful of individuals -if you're lucky- in a sample of 1,000 for such a variant. However, rarity does not mean that the variant is functionally unimportant, and the rare allele may play a substantial role in the height of the people who possess it.

The publication of this paper is a cause for optimism, as it shows that progress can be made by brute force: fuller genome coverage and more individuals. We'll have to wait and see whether or not the same approach will work for other complex traits, such as IQ or schizophrenia, that have been hitherto difficult to crack.

Obviously, the cost of sampling more individuals will become an issue in future studies, but the cost-per-individual is expected to drop. So, I'm guessing that more discoveries are in store for us in the next few years.

UPDATE (Jun 28):

Not the main point of the paper, but also included in the supplementary material (pdf) are some nice PCA results.

In the European-only PCA we see the familiar north-south gradient (anchored by Tuscans TSI and Netherlands NET on either side), and the orthogonal deviation of the Finns. Swedes (SWE) occupy a northern European end of the spectrum like the Dutch, but are spread towards Finns, reflecting low-level Finnish admixture in that population. Conversely, Finns are variable along the same axis, reflecting variable levels of admixture. Australians (AUS) and UK, on the other hand, are on the northern European edge of the main European gradient, with a number of individuals spread toward the Tuscan side.

The PCA with all populations is also quite interesting. East Eurasians (Chinese and Japanese) form a tight pole at the bottom right. Gujarati Indians (GIH) form a different pole, spread towards Europeans, reflecting variable levels of West Eurasian admixture in that population, probably corresponding to the ANI element recently discovered in Indian populations. Mexicans (MEX) are spread towards East Asians, reflecting their Amerindian admixture, but notice how they are not positioned exactly on the European-East Asian axis, probably reflecting the third, minority, Sub-Saharan element in their ancestry, as well as the fact that Amerindians are not perfectly represented by East Asians. Finns are tilted towards East Asians, as expected, reflecting the fact that their genetic specificity vis a vis Northern Europeans is due to low-level East Eurasian ancestry.

An interesting aspect of the first two PCs is the fact that the Maasai (MKK) and Luhya (LUW) from Kenya are not separated from Caucasoids, and neither are Yoruba from Nigeria (YRI). This is a good reminder of the fact that identity in the first two principal components may mask difference revealed in higher order components. This difference (at least for Maasai) is seen in the next two PCs.

Nature Genetics doi:10.1038/ng.608

Common SNPs explain a large proportion of the heritability for human height

Jian Yang et al.

Abstract

SNPs discovered by genome-wide association studies (GWASs) account for only a small fraction of the genetic variation of complex traits in human populations. Where is the remaining heritability? We estimated the proportion of variance for human height explained by 294,831 SNPs genotyped on 3,925 unrelated individuals using a linear model analysis, and validated the estimation method with simulations based on the observed genotype data. We show that 45% of variance can be explained by considering all SNPs simultaneously. Thus, most of the heritability is not missing but has not previously been detected because the individual effects are too small to pass stringent significance tests. We provide evidence that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to date.

Link

Ancestry-related assortative mating in latino populations (Risch et al. 2009)

When different races admix, then in the first few generations there is a spectrum of ancestry proportions, ranging from pure individuals of the constituent races to admixed individuals with varying proportions of ancestry.

If there is random mating, then over several generations all individuals tend to have similar ancestry proportions, determined by the number of founders from the two constituent races. Mix 30,000 Europeans with 70,000 Africans, randomly mate them for 10-20 generations, and pretty soon almost everyone will have 30:70 European/African ancestral proportions with a little variation.

However, if there is assortative mating, then this process takes much longer to complete, as matings of individuals with very different ancestry proportions are rare, and the spectrum of varying individual ancestry is maintained. In the above-mentioned example, if there is perfect assortative mating, then after 10-20 generations you will still have 30% of the population having 100% European genes, and 70% of them having 100% African ones.

Previously, I had argued that the fact that Latin Americans, unlike Central Asian Turkic populations (such as the Uyghurs), have such a wide spectrum of ancestry proportions is due to the more recent admixture in the Americas than in Central Asia (less time for homogenization to take place), and the continued importation of Europeans.

Assortative mating is a third factor that may be behind this phenomenon. A stronger parallel may be found in South Asia, where the two constituents have been co-existing for a much longer time, but under a rigid, formalized regime of assortative mating (the caste system), homogenization has not taken place.

Genome Biology doi:10.1186/gb-2009-10-11-r132

Ancestry-related assortative mating in latino populations

Neil Risch et al.

Abstract

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.

Link

Admixture in northeastern Mexico

J Hum Genet. 2009 Aug 14. doi:10.1038/jhg.2009.65.

Ancestry informative markers and admixture proportions in northeastern Mexico

Martinez-Fierro ML, Beuten J, Leach RJ, Parra EJ, Cruz-Lopez M, Rangel-Villalobos H, Riego-Ruiz LR, Ortiz-Lopez R, Martinez-Rodriguez HG, Rojas-Martinez A.

To investigate the ancestral admixture in the Mestizo population in northeastern Mexico, we genotyped 74 ancestral informative markers (AIMs) and 15 Y-single-nucleotide polymorphisms (Y-SNPs) in 100 individuals. The Native American contribution is 56% (range: 27.4-81.2%), the European contribution is 38% (range: 16.7-70.5%) and the West African contribution is 6%. The results show a higher European contribution than was reported in other similar studies in the country, albeit with a predominant Native American ancestry. No remarkable differences in the ancestry proportions were observed using subgroups of 74, 54, 34 and 24 AIMs. The paternal lineage calculated by genotyping of 15 Y-SNPs, shows a major component of European and Eurasian ancestry markers ( approximately 78%), compared with Amerindian ( approximately 12%) and African markers (10%). This information will set a reference for future determinations of admixture proportions in the Mestizo population from Mexico and for population-based association studies of complex diseases.

Link

Ancestry informative marker set for determining continental origin (Nassir et al. 2009)

UPDATE: This PCA plot from the paper is very instructive:




In PC1 vs PC2 (top left), the five major races (Caucasoids, East Asian Mongoloids, Amerindians, Australoids, Negroids) are clearly separable, but their relationships are not very clear. Australoids are somewhere between Caucasoids and East Asians. If we were to go by this figure alone, we might even infer that they are some type of mix of the two. But, look at PC3 vs PC4 (top right). Here it is the case that Australoids are not intermediate between Caucasoids and Mongoloids, but occupy their own space, and we can conclude that they are not in fact such a mix.

Compare with Mexicans (bottom left), who occupy the same space as East Asians in PC1 vs PC2. Does that mean that they are East Asians? An alternative explanation is that they are a mix of Caucasoids and Amerindians, since they occupy an intermediate position between the two groups, which happens to coincide with the position of East Asians. But, if we look at PC3 vs P4 (bottom right), it is clear that Mexicans are indeed better explained as a Caucasoid-Amerindian mix, as they occupy an intermediate position between Caucasoids and Columbians/Quechuans (who are on the left), and not at all that of East Asians (who are on the right).

Next, consider African Americans. In PC1 vs PC2 they occupy an intermediate position between Negroids and Caucasoids (bottom left), as expected by their known ancestry. But, what if we didn't know about their history, and we wanted to infer their origin based on their genomes, as we did with Australoids? Unlike Australoids, in PC3 vs PC4, African Americans do not form a cluster of their own, but overlap with both Caucasoids and Negroids who occupy the same space in these two dimensions. Thus, we are more certain that they are indeed a Caucasoid-Negroid mixed population.

Next, consider Mozabites and South Asians, both of which deviate from Caucasoids, in a Negroid, and Mongoloid direction respectively (top left). North African Mozabites may indeed by Negroid-influenced, as is evident in the STRUCTURE analysis of this paper. South Asian Indians, however, who show "admixture" with the East Asian cluster at K=5 in the STRUCTURE analysis, are revealed to form a cluster of their own at higher K (pink), suggesting that they are not, in fact a Caucasoid-Mongoloid mixed population.

The important lesson from all of this, is to use as much information as possible when trying to examine population relationships from graphical plots, because things may not always be "what they seem", and a number of alternative explanations may result in identical two-dimensional plots.

BMC Genetics 2009, 10:39doi:10.1186/1471-2156-10-39

An ancestry informative marker set for determining continental origin: validation and extension using human genome diversity panels

Rami Nassir et al.

Abstract (provisional)

Background

Case-control genetic studies of complex human diseases can be confounded by population stratification. This issue can be addressed using panels of ancestry informative markers (AIMs) that can provide substantial population substructure information. Previously, we described a panel of 128 SNP AIMs that were designed as a tool for ascertaining the origins of subjects from Europe, Sub-Saharan Africa, Americas, and East Asia.

Results

In this study, genotypes from Human Genome Diversity Panel populations were used to further evaluate a 93 SNP AIM panel, a subset of the 128 AIMS set, for distinguishing continental origins. Using both model-based and relatively model-independent methods, we here confirm the ability of this AIM set to distinguish diverse population groups that were not previously evaluated. This study included multiple population groups from Oceana, South Asia, East Asia, Sub-Saharan Africa, North and South America, and Europe. In addition, the 93 AIM set provides population substructure information that can, for example, distinguish Arab and Ashkenazi from Northern European population groups and Pygmy from other Sub-Saharan African population groups.

Conclusion

These data provide additional support for using the 93 AIM set to efficiently identify continental subject groups for genetic studies, to identify study population outliers, and to control for admixture in association studies.

Link

mtDNA of Native Mexicans

Human Genetics doi:10.1007/s00439-009-0693-y

Linguistic and maternal genetic diversity are not correlated in Native Mexicans

Karla Sandoval et al.

Abstract

Mesoamerica, defined as the broad linguistic and cultural area from middle southern Mexico to Costa Rica, might have played a pivotal role during the colonization of the American continent. The Mesoamerican isthmus has constituted an important geographic barrier that has severely restricted gene flow between North and South America in pre-historical times. Although the Native American component has been already described in admixed Mexican populations, few studies have been carried out in native Mexican populations. In this study, we present mitochondrial DNA (mtDNA) sequence data for the first hypervariable region (HVR-I) in 477 unrelated individuals belonging to 11 different native populations from Mexico. Almost all of the Native Mexican mtDNAs could be classified into the four pan-Amerindian haplogroups (A2, B2, C1, and D1); only two of them could be allocated to the rare Native American lineage D4h3. Their haplogroup phylogenies are clearly star-like, as expected from relatively young populations that have experienced diverse episodes of genetic drift (e.g., extensive isolation, genetic drift, and founder effects) and posterior population expansions. In agreement with this observation, Native Mexican populations show a high degree of heterogeneity in their patterns of haplogroup frequencies. Haplogroup X2a was absent in our samples, supporting previous observations where this clade was only detected in the American northernmost areas. The search for identical sequences in the American continent shows that, although Native Mexican populations seem to show a closer relationship to North American populations, they cannot be related to a single geographical region within the continent. Finally, we did not find significant population structure in the maternal lineages when considering the four main and distinct linguistic groups represented in our Mexican samples (Oto-Manguean, Uto-Aztecan, Tarascan, and Mayan), suggesting that genetic divergence predates linguistic diversification in Mexico.

Link

Admixture in Mexican Mestizos

Gene Expression points me towards a new open access paper in PNAS about genetic diversity in Mexican Mestizos:

We analyzed data from 300 nonrelated self-identified Mestizo individuals from 6 states located in geographically distant regions in Mexico: Sonora (SON) and Zacatecas (ZAC) in the north, Guanajuato (GUA) in the center, Guerrero (GUE) in the center– Pacific, Veracruz (VER) in the center–Gulf, and Yucatan (YUC) in the southeast. Considering that Zapotecos have been shown as a good ancestral population for predicting Amerindian (AMI) ancestry in Mexican Mestizos (16), we included 30 Zapotecos (ZAP) from the southwestern state of Oaxaca (Fig. 1). For comparative purposes, we included similar data sets from HapMap populations: northern Europeans (CEU), Africans (YRI), and East Asians (EA), including Chinese (CHB) and Japanese (JPT).

As expected, Mestizo admixture is mainly between Caucasoids and Amerindians, with a very little Sub-Saharan African thrown in at the individual level. Moreover, as with many populations, such as the Uyghur, where admixture took place several generations ago, individual admixture levels are fairly uniform, with very few individuals deviating strongly towards either the Caucasoid or Amerindian end of the spectrum.

The variation in individual admixture appears only somewhat stronger than in the Uyghur, which may be explained either by the smaller number of markers used here, making the assessment of admixture "noisier", or alternatively might be the result of the fact that admixture in Mexican Mestizos happened more recently, and immigration into the Americas from Europe continued hence, hence the homogenization of the population is still ongoing.

Table S1 from the Supplementary material (pdf) shows the exact admixture proportions in the studied Mestizo populations and the HapMap populations.

Related:

• Genomic ancestry of Mexicans
• Mexican American admixture mapping

PNAS doi:10.1073/pnas.0903045106

Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico

Irma Silva-Zolezzi et al.

Abstract

Mexico is developing the basis for genomic medicine to improve healthcare of its population. The extensive study of genetic diversity and linkage disequilibrium structure of different populations has made it possible to develop tagging and imputation strategies to comprehensively analyze common genetic variation in association studies of complex diseases. We assessed the benefit of a Mexican haplotype map to improve identification of genes related to common diseases in the Mexican population. We evaluated genetic diversity, linkage disequilibrium patterns, and extent of haplotype sharing using genomewide data from Mexican Mestizos from regions with different histories of admixture and particular population dynamics. Ancestry was evaluated by including 1 Mexican Amerindian group and data from the HapMap. Our results provide evidence of genetic differences between Mexican subpopulations that should be considered in the design and analysis of association studies of complex diseases. In addition, these results support the notion that a haplotype map of the Mexican Mestizo population can reduce the number of tag SNPs required to characterize common genetic variation in this population. This is one of the first genomewide genotyping efforts of a recently admixed population in Latin America.

Link

Admixture, ethnicity, and pigmentation of Hispanics and Native Americans

A very interesting new study co-authored by fellow blogger Yann Klimentidis, which tries to untangle many correlated but not equivalent concepts: genetic admixture from continental groups (in this case primarily Caucasoids and American Mongoloids), skin color, self-reported ethnicity, and self-assessed levels of admixture.

It was found that Native Americans tend to overestimate their genetic Native American-ness, while Hispanics tend to underestimate it. I don't find this surprising since Hispanics are descended from Spanish-influenced groups with Spanish as their language, and Catholicism as their religion, who viewed themselves in counterdistinction to the non-Spanish-influenced populations on the one hand, and English-speaking Americans to their north on the other. Thus, they may emphasize their "Spanish-ness" since it distinguishes them from both groups. Native Americans, on their other hand, view themselves in counterdistinction to Anglo-Americans, and identify with their native traditions, and hence tend to emphasize their "nativenesss".

Another interesting finding is that ethnicity among Hispanics (i.e. labels such as "half-white, half-Hispanic", "Spanish", "Mexican American" or "Mexican") is correlated with Native American genetic admixture in the expected order. 

Skin color was also associated with genetic admixture, although the correlation wasn't as strong, and skin color was a relatively weak predictor of ancestral proportions. That does not argue so much against physical anthropological determination of race, but rather against the use of a single trait. Mark Shriver's group had looked at the correlation between skin pigmentation and ancestry in a previous study.

American Journal of Physical Anthropology doi: 10.1002/ajpa.20945

Genetic admixture, self-reported ethnicity, self-estimated admixture, and skin pigmentation among Hispanics and Native Americans

Yann C. Klimentidis et al.

Abstract

The relationship between ethnicity and biology is of interest to anthropologists, biomedical scientists, and historians in understanding how human groups are constructed. Ethnic self-identification in recently admixed groups such as Hispanics, African Americans, and Native Americans (NA) is likely to be complex due to the heterogeneity in individual admixture proportions and social environments within these groups. This study examines the relationships between self-identified ethnicity, self-estimated admixture proportions, skin pigmentation, and genetic marker estimated admixture proportions. These measures were assessed using questionnaires, skin color measurements, and genotyping of a panel of 76 ancestry informative markers, among 170 Hispanics and NAs from New Mexico, a state known for its complex history of interactions between people of NA and European (EU) ancestry. Results reveal that NAs underestimate their degree of EU admixture, and that Hispanics underestimate their degree of NA admixture. Within Hispanics, genetic-marker estimated admixture is better predicted by forehead skin pigmentation than by self-estimated admixture. We also find that Hispanic individuals self-identified as half-White, half Hispanic and Spanish have lower levels of NA admixture than those self-identified as Mexican and Mexican American. Such results highlight the interplay between culture and biology in how individuals identify and view themselves, and have implications for how ethnicity and disease risk are assessed in a medical setting.

Link