Research

Our research program consists of several complimentary and integrated parts including bench science, bioinformatics, and fieldwork. Bench science and bioinformatics are performed in the Bigham Lab of Anthropological Genomics. We take a mixed approach that uses genotyping, high-throughput DNA sequencing, and analysis of publicly available data to characterize gene diversity in global populations. We actively engage in fieldwork through projects in Latin America including the countries of Peru, Brazil, and most recently Mexico. Below I detail the three main projects that are current in my lab. Through these areas of study, we hope to contribute to our understanding of genotype-phenotype relationships and shed light onto the patterns of complex phenotypes and disease prevalence.

Genetic Adaptation to High Altitude

The capacity of long-term high-altitude populations (e.g. Andeans and Tibetans) to live in a chronic hypoxia state provides an unprecedented opportunity to investigate the underlying mechanisms governing their physiological adaptations. Such knowledge is likely to profoundly impact our understanding of the genetic control of phenotypic traits as well as provide the basis for therapies for chronic ischemic diseases such as ischemic heart disease, cerebrovascular disease, and chronic obstructive pulmonary disease.  We focus on Andean patterns of adaptation as well as cross-population comparisons to understand the prevalence of convergent or parallel evolution among Andeans and Tibetans. We are currently investigating the role of oxygen sensing genes in controlling high-altitude adaptive phenotypes among Peruvian Quechua. During the summers of 2012 and 2013, my team traveled to Cerro de Pasco, Peru to conduct fieldwork involving participant recruitment and phenotype collection at high altitude. We are now investigating genotype correlations with Andean high-altitude adaptive phenotypes. This summer, we will augment the existing dataset with data contributed by long-term low-altitude residents of Mexico that will be recruited as part of the Mexican Biological Variation Project Field School to be run in southern Mexico. We have also initialized functional genetics studies aimed at understanding the biological consequences of particular genetic changes. In collaboration with Dr. Frank Lee, a hematologist at the University of Pennsylvania, our lab is working to decipher the functional effects of changes to a particular gene (EGLN1) involved in oxygen sensing and metabolism among Tibetan and Andean highlanders.  Most recently, we have started to explore the potential for epigenetic modifications contributing to altitude adaptive phenotypes.

Host Susceptibility and Resistance to Dengue Fever

Dengue is a mosquito-borne RNA virus that is widespread in subtropic and tropic environments, with an estimated 50–100 million infections each year, reaching epidemic proportions in Asia and Latin America. This study implements an evolutionary perspective to prioritize host genetic risk factors within native Latin American populations. To do this, we have identified signatures of natural selection in genes related to immune function. Then, as part of a newly initiated collaborative project on dengue virus resistance and susceptibility in Brazil, we will take a two-pronged approach to understanding the role of host genetic factors in determining the innate and adaptive immune responses to viral infection. A case-control association study of host resistance/susceptibility loci will identify genetic factors associated with disease outcome. We will interrogate regions of the genome identified from the aforementioned selection screen as well as those within known dengue and immune response pathways. We will then use expression profiling of particular target genes and proteins to identify host genetic factors affecting particular molecular phenotypes. The results of this study will 1) contribute to our understanding of how infectious disease shaped modern human genetic diversity, 2) aide in future association studies looking at infectious disease susceptibility in Latin American populations, 3) develop a more detailed model of the immunological responses to dengue infection, and 4) help identify the key defining points determining disease outcome. Overall, the lessons learned from understanding the host genetic factors involved in dengue severity and pathogenesis will offer translational potential towards treatment of infection and could prove useful in the treatment of related flaviviruses.

 

Genetic Resistance to HIV-1

The notion that host gene products interact with HIV-1 during infection is a fundamental component of our molecular understanding of this virus’s disease pathogenesis. Examples of natural resistance to HIV-1 infection are well documented in persons who remain uninfected despite high exposure levels to the virus. Some of the host genetic variants that confer this natural resistance to infection have been defined such as a 32 base-pair deletion in the cellular CCR5 chemokine receptor gene (CCR5delta32) that serves as a co-receptor for HIV-1 cell entry. However, this variant is absent or extremely rare in Africans. Furthermore, our knowledge of genetic risk factors for HIV-1 outcomes in African populations is limited despite the fact that 65% percent of the global disease burden is concentrated here. These observations highlight the need for independent discovery and confirmation of host genetic variants influencing HIV-1 acquisition and pathogenesis in global populations. In collaboration with researchers in the School of Public Health at the University of Washington, this work has focused on identifying candidate gene associations with HIV-1 seroconversion and disease progression in both adult and pediatric Sub-Saharan African cohorts. Using a targeted gene approach, we identified variants in host genes whose protein products interact with HIV-1 during the virus replication cycle and were associated with disease outcomes. Our results are an important first step towards extending genotype-phenotype association studies of HIV-1 phenotypes to African populations and show that host genetic variants modify acquisition risk and disease progression.