Elucidating the genotype-to-phenotype map is a primary goal of human genomics research. However, a fundamental gap in knowledge exists regarding African genomic and phenotypic variation, resulting in a lag in biomedical research in these populations. African populations harbor immense amounts of genetic diversity and exhibit substantial amounts of phenotypic variation, including body size, lipid and carbohydrate metabolism that are associated with risk for diabetes and cardiovascular disease, partly due to adaptation to diverse environments. Here, we propose to perform field studies to collect novel biological samples as well as detailed phenotypic data on anthropometric and metabolic traits from short statured Pygmy hunter-gatherers in Cameroon and neighboring tall-statured Bantu-speaking farmers. We will apply an integrative evolutionary genomics approach incorporating genomic, metabolic, and gene expression data to better understand the genetic basis of complex adaptive traits, including body size and metabolism, in these under-represented ethnically diverse Africans. Specifically, we will identify novel genetic variants using high coverage whole genome sequencing. We will also use genome-wide SNP arrays to identify targets of natural selection in these populations and to look for genetic associations with anthropometric, hormonal, and cardio-metabolic traits in Pygmy hunter-gatherers and Bantu farmers. We will use functional genomics approaches to identify new candidate loci and to study the impact of candidate variable sites on gene expression in vitro using high-throughput reporter assays in appropriate cell lines. These data will enable us to test the hypothesis that short stature in Pygmies may be a byproduct of selection for traits influenced by genes with pleiotropic effects on metabolism, reproduction, and immunity. The biological samples and data collected will be an important resource for the biomedical research community. In addition, our data will generate a deeper understanding of African genomic diversity, population structure, and patterns of linkage disequilibrium which are critical for the successful application and interpretation of genome wide association studies in African-descent populations. Furthermore, this study will have important implications for understanding the genetic basis of complex traits in Africans, etiology of short stature as well as other traits and diseases influenced by the GH/IGF1 pathway, such as metabolic syndrome, diabetes, cardiovascular disease, longevity, and cancer. Lastly, our study will shed light on human evolutionary history and evolutionary forces shaping patterns of genomic variation in ethnically diverse humans.

Public Health Relevance

We propose to perform field studies to collect novel biological samples as well as detailed phenotypic data on anthropometric and metabolic traits in Central African Pygmy hunter- gatherers and neighboring Bantu farmers. We will identify novel genetic variants using high coverage whole genome sequencing. We will use genome-wide SNP arrays to identify targets of natural selection in these populations and to look for genetic associations with anthropometric, hormonal, and cardio-metabolic traits. We will use functional genomics approaches to identify new candidate loci associated with these traits and will study the impact of candidate regulatory variants on gene expression in cell lines. This study will have important implications for understanding the genetic basis of complex traits of biomedical relevance in populations of recent African descent.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM113657-04
Application #
9413349
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Janes, Daniel E
Project Start
2015-02-15
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Genetics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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