EDAR gene common in East Asians

EDAR gene common in East Asians Apr 22, 2024 19:52:59 GMT

Quote

Post by Admin on Apr 22, 2024 19:52:59 GMT

The first animal model of recent human evolution reveals that a single mutation produced several traits common in East Asian peoples, from thicker hair to denser sweat glands, an international team of researchers report.

The team, led by researchers from Harvard Medical School, Harvard University, the Broad Institute of MIT and Harvard, Massachusetts General Hospital, Fudan University and University College London, also modelled the spread of the gene mutation across Asia and North America, concluding that it most likely arose about 30,000 years ago in what is today central China.

The findings are reported in the cover story of the 14 February issue of Cell.

"There are three parts to this study," said Professor Mark Thomas, UCL Research Department of Genetics, Evolution and Environment, and an author on the paper.

"The first links the version of the EDAR gene common in East Asians to a set of traits including thicker hair and a higher density of sweat glands; the second uses computer simulation to identify where and when the mutation is likely to have arisen, and what its selective advantage was likely to be; and the third showed that when the East Asian version of the gene is inserted into a mouse, that mouse exhibited many of the same traits as those it is linked with in humans."

The mutation was found in a gene for ectodysplasin receptor, or EDAR, part of a signalling pathway known to play a key role in the development of hair, sweat glands and other skin features. While human populations in Africa and Europe had one, ancestral, version of the gene, most East Asians had a derived variant, EDARV370A, which studies had linked to thicker scalp hair and an altered tooth shape in humans.

There are three parts to this study. The first links the version of the EDAR gene common in East Asians to a set of traits including thicker hair and a higher density of sweat glands; the second uses computer simulation to identify where and when the mutation is likely to have arisen, and what its selective advantage was likely to be; and the third showed that when the East Asian version of the gene is inserted into a mouse, that mouse exhibited many of the same traits as those it is linked with in humans.

Dr Pascale Gerbault, a PhD student in Professor Thomas's group, and co-author of the paper said: "What seems unlikely is that the same traits were advantageous throughout the whole of the last 30,000 years; prior to 10,000 years ago the climate was cold and highly variable, but for the last 10,000 years it has been much warmer and relatively stable."

She added: "So perhaps one trait was favoured when it was colder and another when it became warmer. Maybe one of the less visible traits was selected early on, leading to a rise in the frequency of a more visible trait like thicker hair, which was later selected as a cultural preference."

www.ncbi.nlm.nih.gov/pmc/articles/PMC8496850/

EDAR gene common in East Asians Apr 28, 2024 17:57:03 GMT

Quote

Post by Admin on Apr 28, 2024 17:57:03 GMT

Cell. 2013 Feb 14; 152(4): 691–702.
doi: 10.1016/j.cell.2013.01.016
PMCID: PMC3575602
NIHMSID: NIHMS435603
PMID: 23415220

Modeling recent human evolution in mice by expression of a selected EDAR variant

An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in Central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knock-in mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify novel biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.

www.ncbi.nlm.nih.gov/pmc/articles/PMC3575602/

Introduction
Humans are unique among primates in having colonized nearly every corner of the world; consequently, niche-specific selective pressures likely helped shape the phenotypic variation currently evident in Homo sapiens. Identifying the genetic variants that underlie regional adaptations is thus central to understanding present-day human diversity, yet only a few adaptive traits have been elucidated. These include mutations in the Hemoglobin-B and Duffy antigen genes, driving resistance to P. falciparum and P. vivax malaria, respectively (Kwiatkowski, 2005); mutations in lactase allowing some adult humans to digest milk following the domestication of milk-producing livestock (Enattah et al., 2002); and mutations in SLC24A5 and other genes driving variation in skin pigmentation (Lamason et al., 2005).

Although breakthroughs in genomic technology have facilitated the identification of hundreds of candidate genetic variants with evidence of recent positive natural selection, validation and characterization of putative genetic adaptations requires functional evidence linking genotypes to phenotypes that could affect an organism’s fitness (Akey, 2009). This is made difficult by experimental challenges in isolating the phenotypic effects of candidate loci and by methodological limitations on the phenotypes that can be readily assessed in humans. Accordingly, the best-characterized human adaptive alleles are typically those whose phenotypic outcomes are easily measured and strongly related to known genetic variation, such as lactase persistence or skin pigmentation. Many genes, however, have unknown or pleiotropic effects, making their adaptive advantage difficult to uncover (Sivakumaran et al., 2011). A promising alternative to tackle these difficulties is to study the effects of candidate adaptive alleles in animal models. Although such models, particularly using mice, have been used extensively to study human disease alleles, they have not been used to model the subtle phenotypic changes expected to result from human adaptive variation.

A compelling candidate human adaptive allele to emerge from genome-wide scans is a derived coding variant of the Ectodysplasin A (EDA) receptor (EDAR), EDARV370A (370A) (Sabeti et al., 2007; Grossman et al., 2010). Computational fine-mapping of the selection signal and the restricted occurrence of 370A in East Asian and Native American populations have led to suggestions that 370A was selected in Asia (Bryk et al., 2008). In support of this hypothesis, 370A was shown to associate with increased scalp hair thickness and incisor tooth shoveling in multiple East Asian populations (Fujimoto et al., 2008a, 2008b; Kimura et al., 2009; Park et al., 2012). However, because association studies quantify correlation rather than causation, it remains to be ascertained whether 370A is the genetic change driving the observed phenotypes.

The biochemical properties of 370A support the possibility that the variant directly causes the associated phenotypes. Structural models predict that V370A lies in the EDAR Death Domain (DD) required for interaction with the downstream signal transducer EDARADD(Sabeti et al., 2007). Moreover, overexpression of 370A has been reported to up-regulate downstream NFκB signaling in vitro relative to 370V (Bryk et al., 2008; Mou et al., 2008). This finding suggested that a pre-existing mouse model, in which the ancestral 370V allele is overexpressed, might provide insight into 370A’s phenotypic consequences (Headon and Overbeek, 1999; Mou et al., 2008). Indeed, transgenic mice expressing multiple copies of 370V have thicker hair shafts as seen in humans with the 370A allele (Fujimoto et al., 2008a, 2008b; Mou et al., 2008). In addition, these animals exhibit increased mammary gland branching, enlarged mammary glands and hyperplastic sebaceous and Meibomian glands that secrete hydrophobic films as a barrier to water loss in the skin and eyes, respectively (Chang et al., 2009). These latter phenotypes led to the proposal that the 370A variant may have been selected in response to cold and arid environmental conditions (Chang et al., 2009).

Evaluating which forces may have contributed to the spread of 370A requires knowledge of both the environmental context in which this variant was selected and its phenotypic effects. We therefore employed a multi-disciplinary approach to test the role of 370A in recent human evolution. This included modeling to reconstruct the evolutionary history of 370A, and a knock-in mouse model to examine its direct phenotypic consequences. Analysis of the mouse knock-in revealed phenotypes not previously reported in human genetic studies, which we further characterized in a Han Chinese cohort. This work highlights the utility of modeling non-pathological human genetic variation in mice, providing a framework for assessing other candidate adaptive human alleles.