Integrative Genomic Analyses of Human Evolution and Complex Traits in Africa

Africa is the site of origin of modern humans, contains the greatest levels of human genomic variation, and is the source of the worldwide range expansion of modern humans in the past 100,000 years. However, a fundamental gap in knowledge exists regarding African genomic and phenotypic variation, resulting in a lag in biomedical research with relevance to populations of all ancestries. We will apply an integrative evolutionary genomics approach incorporating genomic, metabolomic, proteomic, microbiome, epigenomic, and transcriptomic data in combination with detailed phenotypic data to reconstruct population history and better understand how genetic and environmental variation impacts complex anthropometric, cardio-metabolic, and immune related traits. We will determine the effectiveness of polygenic risk score estimates for these traits developed in non-Africans when applied to Africans and vice-verse and we will study the role of gene X environment interactions on traits. We will use functional genomics approaches to identify causal regulatory loci and to study their impact on gene expression in vitro using high-throughput luciferase reporter assays in appropriate cell lines. We will also use Crispr-Cas9 technology to validate and characterize the functional impact of potential casual variants in both human cells and in vivo in model systems. Lastly, we will characterize gut microbiome diversity and examine correlations with diet, genetic and environmental variation. This study will generate a deeper understanding of human genomic variation, population structure, and patterns of linkage disequilibrium that are critical for the successful application and interpretation of genome wide association studies in multi-ancestry populations. Furthermore, this study will have important implications for understanding the genetic basis of intermediate phenotypes such as gene expression, the metabolome, and proteome. In addition, the data collected will be an important resource for the biomedical research community. Project Number: 1R35GM161902-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Sarah Tishkoff | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $688,506 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MGG-D (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11260842