Virginia Ramallo

Admixture in Latin America: Geographic Structure, Phenotypic Diversity and Self-Perception of Ancestry Based on 7,342 Individuals

The current genetic makeup of Latin America has been shaped by a history of extensive admixture between Africans, Europeans and Native Americans, a process taking place within the context of extensive geographic and social stratification. We estimated individual ancestry proportions in a sample of 7,342 subjects ascertained in five countries (Brazil, Chile, Colombia, México and Perú). These individuals were also characterized for a range of physical appearance traits and for self-perception of ancestry. The geographic distribution of admixture proportions in this sample reveals extensive population structure, illustrating the continuing impact of demographic history on the genetic diversity of Latin America. Significant ancestry effects were detected for most phenotypes studied. However, ancestry generally explains only a modest proportion of total phenotypic variation. Genetically estimated and self-perceived ancestry correlate significantly, but certain physical attributes have a strong impact on self-perception and bias self-perception of ancestry relative to genetically estimated ancestry.

A genome-wide association scan implicates DCHS2 , RUNX2 , GLI3 , PAX1 and EDAR in human facial variation

We report a genome-wide association scan for facial features in ∼6,000 Latin Americans. We evaluated 14 traits on an ordinal scale and found significant association (P values<5 × 10−8) at single-nucleotide polymorphisms (SNPs) in four genomic regions for three nose-related traits: columella inclination (4q31), nose bridge breadth (6p21) and nose wing breadth (7p13 and 20p11). In a subsample of ∼3,000 individuals we obtained quantitative traits related to 9 of the ordinal phenotypes and, also, a measure of nasion position. Quantitative analyses confirmed the ordinal-based associations, identified SNPs in 2q12 associated to chin protrusion, and replicated the reported association of nasion position with SNPs in PAX3. Strongest association in 2q12, 4q31, 6p21 and 7p13 was observed for SNPs in the EDAR, DCHS2, RUNX2 and GLI3 genes, respectively. Associated SNPs in 20p11 extend to PAX1. Consistent with the effect of EDAR on chin protrusion, we documented alterations of mandible length in mice with modified Edar funtion.

A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features

We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10−8 to 3 × 10−119), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified locus influencing hair shape includes a Q30R substitution in the Protease Serine S1 family member 53 (PRSS53). We demonstrate that this enzyme is highly expressed in the hair follicle, especially the inner root sheath, and that the Q30R substitution affects enzyme processing and secretion. The genome regions associated with hair features are enriched for signals of selection, consistent with proposals regarding the evolution of human hair.

Brief communication: Restricted geographic distribution for Y-Q* paragroup in South America.

We analyzed 21 paragroup Q* Y chromosomes from South American aboriginal and urban populations. Our aims were to evaluate the phylogenetic status, geographic distribution, and genetic diversity in these groups of chromosomes and compare the degree of genetic variation in relation to Q1a3a haplotypes. All Q* chromosomes from our series and five samples from North American Q* presented the derivate state for M346, that is present upstream to M3, and determined Q1a3* paragroup. We found a restrictive geographic distribution and low frequency of Q1a3* in South America. We assumed that this low frequency could be reflecting extreme drift effects. However, several estimates of gene diversity do not support the existence of a severe bottleneck. The mean haplotype diversity expected was similar to that for South American Q1a3* and Q1a3a (0.478 and 0.501, respectively). The analysis of previous reports from other research groups and this study shows the highest frequencies of Q* for the West Corner and the Grand Chaco regions of South America. At present, there is no information on whether the phylogenetic status of Q* paragoup described in previous reports is similar to that of Q1a3* paragroup though our results support this possibility.

Software for Y-haplogroup predictions: a word of caution

The development of online software designed for genetic studies has been exponentially growing, providing numerous benefits to the scientific community. However, they should be used with care, since some require adjustments. The efficiency of two programs for haplogroup prediction was tested with 119 samples of known haplotypes and haplogroups from Argentine populations. Quantitative estimates of the predictive quality of both software systems were computed with the uncertainty coefficient; and sensitivity, specificity, positive, and negative likelihood ratios were also calculated to assert the reliability of both programs, showing high probabilities of assigning an incorrect haplogroup.

A genome-wide association study identifies multiple loci for variation in human ear morphology

Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10−8 to 3 × 10−14). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1.

Distribution of Y-chromosome q lineages in native americans

Objectives: This investigation was performed to identify and evaluate the distribution of all 15 Y‐chromosome lineages belonging to the Q clade in a sample of natives from South America.

High twinning rate in Cândido Godói: a new role for p53 in human fertility

BACKGROUND Cândido Godói (CG) is a small town in South Brazil, which has the highest prevalence of twin births in Brazil. Recently, a number of studies have shown that p53 plays an important role in reproduction through blastocyst implantation and intra utero embryo survival. Thus, gene polymorphisms in the p53 pathway were investigated in this population. METHODS Single nucleotide polymorphisms from five genes in the p53 pathway were investigated, as well as background characteristics of 42 mothers of twins (cases) and 101 mothers of singletons (controls), all residents from CG. RESULTS Mothers of twins have higher number of pregnancies and higher frequencies of P72 allele at TP53 and T allele at MDM4 genes compared with controls. Logistic regression shows that both TP53 and number of pregnancies maintained their association with twinning (P =0.004 and P =0.002, respectively), with TP53 having a higher odds ratio than number of pregnancies (2.73 versus 1.70, respectively). No interactive effect between TP53 and MDM4 (P =0.966) is observed. As expected, mothers of twins have three times more cases of cancer in their first-degree relatives than control mothers (P =0.011). CONCLUSIONS Our results suggest that the P72 allele of TP53 is a strong risk factor for twinning in CG, while the number of pregnancies and the T allele at MDM4 may represent weaker risk factors. These two alleles are associated with infertility, but the anti-apoptotic effect of low levels of p53 in general, and of the P72 allele in particular, may play a role after implantation, enhancing the chance for a double pregnancy to succeed to term.

Facial asymmetry and genetic ancestry in Latin American admixed populations

Fluctuating and directional asymmetry are aspects of morphological variation widely used to infer environmental and genetic factors affecting facial phenotypes. However, the genetic basis and environmental determinants of both asymmetry types is far from being completely known. The analysis of facial asymmetries in admixed individuals can be of help to characterize the impact of a genomes heterozygosity on the developmental basis of both fluctuating and directional asymmetries. Here we characterize the association between genetic ancestry and individual asymmetry on a sample of Latin-American admixed populations. To do so, three-dimensional (3D) facial shape attributes were explored on a sample of 4,104 volunteers aged between 18 and 85 years. Individual ancestry and heterozygosity was estimated using more than 730,000 genome-wide markers. Multivariate techniques applied to geometric morphometric data were used to evaluate the magnitude and significance of directional and fluctuating asymmetry (FA), as well as correlations and multiple regressions aimed to estimate the relationship between facial FA scores and heterozygosity and a set of covariates. Results indicate that directional and FA are both significant, the former being the strongest expression of asymmetry in this sample. In addition, our analyses suggest that there are some specific patterns of facial asymmetries characterizing the different ancestry groups. Finally, we find that more heterozygous individuals exhibit lower levels of asymmetry. Our results highlight the importance of including ancestry-admixture estimators, especially when the analyses are aimed to compare levels of asymmetries on groups differing on socioeconomic levels, as a proxy to estimate developmental noise.

Nasal airflow simulations suggest convergent adaptation in Neanderthals and modern humans

Significance Due to its role in humidifying and warming the air before it reaches the lungs, adaptations in the internal nasal anatomy are suspected to have been essential for modern humans and Neanderthals during the settlement of Eurasian harsh landscapes. Unfortunately, the lack of soft-tissue evidence in the fossil record precludes any study of Neanderthal respiratory performance. Here, we use warping techniques to reconstruct a generic Neanderthal nose, computational fluid dynamics simulations to compare the respiratory performance on both species, and evolutionary analyses to detect signals of selection. We report striking differences on fluid residence times under cold/dry climatic conditions. Different from previously suggested, our results indicate that both species would have achieved an advantageous species-specific respiratory performance in cold climates. Both modern humans (MHs) and Neanderthals successfully settled across western Eurasian cold-climate landscapes. Among the many adaptations considered as essential to survival in such landscapes, changes in the nasal morphology and/or function aimed to humidify and warm the air before it reaches the lungs are of key importance. Unfortunately, the lack of soft-tissue evidence in the fossil record turns difficult any comparative study of respiratory performance. Here, we reconstruct the internal nasal cavity of a Neanderthal plus two representatives of climatically divergent MH populations (southwestern Europeans and northeastern Asians). The reconstruction includes mucosa distribution enabling a realistic simulation of the breathing cycle in different climatic conditions via computational fluid dynamics. Striking across-specimens differences in fluid residence times affecting humidification and warming performance at the anterior tract were found under cold/dry climate simulations. Specifically, the Asian model achieves a rapid air conditioning, followed by the Neanderthals, whereas the European model attains a proper conditioning only around the medium-posterior tract. In addition, quantitative-genetic evolutionary analyses of nasal morphology provided signals of stabilizing selection for MH populations, with the removal of Arctic populations turning covariation patterns compatible with evolution by genetic drift. Both results indicate that, departing from important craniofacial differences existing among Neanderthals and MHs, an advantageous species-specific respiratory performance in cold climates may have occurred in both species. Fluid dynamics and evolutionary biology independently provided evidence of nasal evolution, suggesting that adaptive explanations regarding complex functional phenotypes require interdisciplinary approaches aimed to quantify both performance and evolutionary signals on covariation patterns.