Mark Shriver - US grants

This research will focus on identifying gene specific evidence for genetic adaptation to high altitude hypoxia using independent, highland populations from distinct geographic regions. This includes the populations of the Andes (Quechua and Aymara) and the populations of the Tibetan Plateau (Qiang, Khama, Baima, Tibetans). Three major questions will be addressed: 1) Is there gene-specific evidence for natural selection among populations of the Tibetan Plateau? 2) Is there gene-specific evidence for natural selection among populations of the Andean Altiplano? 3) Do the Tibetan and Andean populations exhibit similarities and/or differences in genes or functionally different changes in the same genes involved in high altitude adaptation? In order to answer these questions, a variety of molecular and functional assays will be performed on the study populations. These include screening candidate genes for evidence of natural selection using single nucleotide polymorphism data (SNP) followed by detecting departures from neutrality using sequencing-based methods and finally functional assays to determine the physiological differences between particular genotypes.

Within the last two decades, the field of biological anthropology has embraced molecular genetic techniques to more precisely understand human biological variation and natural selection's role in shaping this variation. Despite the obvious benefits of using these methods, only a small number of studies looking for signatures of natural selection in the human genome have been conducted. This project, which looks at the role of natural selection in shaping the genomes of high altitude human populations, surpasses previous attempts to study this evolutionary process. Rather than focusing on one human population that has adapted to life at altitude, this research examines two separate high-land groups and compares them to lowland groups. Focusing on two of the major human populations that have adapted to life at high altitude will increase the likelihood of successfully identifying candidate genes and also provide a means to compare and contrast the ways in which these populations have adapted. In addition to genetic tests for natural selection, we will also be able to test for the effects of these candidate genes on particular altitude phenotypes, combining the power of physiological inquiry with quantitative and evolutionary genetics. This research will aid in identifying genotype-phenotype correlations as well as elucidate variables involved in natural selection.

Today, areas of high altitude, such as the Colorado highlands, are experiencing heavy population growth. It is currently estimated that 140 million people live at high altitude, defined as >2500 m above sea level. This migration of low altitude natives to high altitude environs has led to a rise in high altitude associated health risks, such as complications with pregnancy. The proposed study provides a framework to test for the effects of variation found at the candidate genes on specific altitude phenotypes. By understanding the genetic bases for the physiological adaptations of high-altitude natives, we will be better suited to treat conditions associated with differences in ambient oxygen tension, such as preeclampsia (pregnancy-induced hypertension).

Human facial features are clearly under strong genetic control. Identical twins often have nearly indistinguishable facial features, and related individuals show notable familial resemblances. Persons affected with particular Mendelian conditions have consistently distinctive facial features. Human facial features also exhibit extensive normal variation throughout the world. Anthropologists have long been able to use morphometric measures to quantify this variation, finding many similarities within and differences among populations from around the world.

While much is known about morphological variation in facial features among populations, the underlying genes that are responsible for these traits have yet to be identified. Abundant evidence suggests that some alleles have strong phenotypic effects on facial morphology, but very little is currently known about these genes. The aim of this project is to investigate the relationships among morphological variation of the face, genetic ancestry and candidate genes in a sample of admixed individuals. Through a process known as admixture mapping, it is possible to identify genes for traits which vary between the parental populations that contributed to the admixed population. To accomplish this, facial variation will be quantified from three-dimensional images using several morphometric methods and genetic variation will be measured via a panel of ancestry-informative markers. A list of candidate genes will be identified from the literature and tested for signatures of non-neutral evolution. Single-nucleotide polymorphisms in these candidate genes will be tested for effects on facial variation while controlling for genetic stratification resulting from admixture. The results of these analyses will be the identification of some of the first genes involved in normal variation in facial morphology.

Given the evolutionary and anthropological significance of the human face, understanding normal variation in human facial features is an important direction for future genetic exploration. Finding genes involved in facial variation can and should provide new insights into our understanding of modern human variation and presents a new avenue for investigating the evolution of human facial variation.

This study seeks to identify genes causing darkening of skin pigmentation in Indigenous Americans following expansion into the New World. As populations migrated from northern into southern latitudes, darker skin was more adaptive as protection against damage from ultra-violet radiation. The search for these genes will be conducted in individuals of admixed European and Indigenous American ancestry from New Mexico, Colorado, Mexico and Colombia where ultra-violet radiation is at high levels. 82 genes associated with variation in skin pigmentation were investigated for evidence of natural selection. In the 12 genes showing the strongest evidence of selection, 48 single nucleotide polymorphisms (SNPs) representing the overall variation in the selection nominated candidate genes will be genotyped in individuals of admixed ancestry. These SNPs show substantial allele frequency differences between the parental populations so the genes responsible for variation in skin pigmentation can be identified by an excess of Indigenous American alleles at that gene in individuals with darker skin. This admixture linkage analysis is especially powerful for studying traits like skin pigmentation which vary substantially between the parental populations because this methodology requires fewer total markers than a standard association study.
There is substantial intellectual merit in this study because skin pigmentation is an ideal model for the evolution of complex traits in the fluctuating environments encountered by Indigenous Americans dispersing into the New World. However, previous researchers have largely ignored these populations. An increased understanding of the evolution of skin pigmentation also has broader impacts including understanding the selective pressures causing continuous skin color variation which is often mistakenly thought of as a 'racial' trait. Additionally, forensic researchers are interested in the ability to predict skin color from an unknown DNA sample. Finally, this grant will contribute to the training of a female graduate student, an under-represented group in this field.

Human scalp hair varies considerably in form and color, within and among human populations. This study will analyze recently collected hair samples representing a wide range of human populations, enabling an unprecedented microscopic investigation of variability in human scalp hair features and laying the groundwork for future research that links hair form and color with their underlying genetics. The project will advance science and benefit society by providing additional measures of hair variation that can be used in forensic contexts to address questions of ancestry and personal identification, and by providing new information on how the forces of evolution have influenced hair morphology in our species.

The investigators will apply recent technological advances in optical microscopy, transmission electron microscopy (TEM), and three dimensional scanning electron microscopy (3D SEM) to define and measure the dimensions of external hair forms and internal structures. Specific attention will be focused on identification of patterns of variation in curl patterns, cross sectional dimensions, cuticle thickness, and orientation of cortical structures within and along the length of the hair shaft. The nature and significance of the observed patterns of variation will be rigorously tested using appropriate statistical methods. Because the hair samples are associated with genotyped DNA samples, future studies correlating single nucleotide polymorphisms (SNPs) and morphological variation will be possible. These investigations are expected to shed light on the range of diversity in human hair forms, illuminate instances of convergent evolution in hair form, and suggest specific avenues for further exploration of the relative roles of natural selection, gene flow, and genetic drift in the evolution of human scalp hair form. By understanding the morphological hair features in detail the investigators will be able to plan efficient and focused phenotyping programs for both gene discovery and forensic efforts.

This project is jointly supported by the National Institute of Justice and the Biological Anthropology Program at NSF.