Body size is a fundamental aspect of biology and health. However, despite many recent gains in understand- ing its genetic variation underpinnings, the proximate cellular causes of variation in intra- and inter-population body size are largely unknown. At one extreme, small body size, or the ?pygmy? phenotype, is a characteris- tic of rainforest hunter-gatherers (RHGs) worldwide, and this genetically-mediated trait is likely an adaptation to the harsh ecological conditions of tropical rainforests for human inhabitants. Comparisons between RHG and non-RHG populations thus present a natural human model for studying the genetic, functional, and evolutionary bases of growth and body size. I propose to investigate the genome-wide regulatory response to Insulin-like Growth Factor 1 (IGF1) and a Fibroblast Growth Factor (FGF-9) in experiments with chondrocytes derived from induced pluripotent stem cells (iPSCs) for population samples of the Batwa RHGs of Uganda (N=20) and their agriculturalist neighbors the Bakiga (N=20). I will estimate genome-wide gene expression responses to IGF1 and FGF-9 via RNAseq and identify differentially expressed (DE) genes by treatment (baseline vs. challenge), population, and population x treatment interaction?i.e. genes with Batwa-speci?c response to IGF1 or FGF-9. I will also simultaneously characterize the IGF1 and FGF-9 responses in chimpanzee and baboon iPSC-derived chondrocytes, thus allowing the partitioning of variation in growth factor response into human lineage-speci?c, human population-speci?c, and shared components. The sets of Batwa- and Bakiga-speci?c DE response genes will be intersected with results from population genomic analyses of SNP genotype data from the same popula- tions to test whether DE genes are signi?cantly enriched within genome regions containing signatures of positive selection. Comparisons to other datasets will facilitate the identi?cation of loci with potential phenotypic and clin- ical signi?cance. This comparative functional genomics investigation of a powerful, relevant in vitro system from a natural human model will advance our understanding of critical human growth and development pathways. The proposed study will be the ?rst genome-wide functional genomic investigation in a relevant cell type of the growth factor response in a human population characterized by the pygmy phenotype. As one of the ?rst iPSC studies of Africans and the ?rst of RHGs, the project integrates human cellular models with population genomic methods to afford an expanded view of human genomic and functional diversity. Unlike previous studies, the proposed project will have the scope, relevant cell type, and power necessary to explore the growth factor pathway disruptions that play a role in the pygmy phenotype in RHGs. The project and training proposed as part of my NRSA fellowship will advance my career goal of integrating population genomic and functional genomic approaches to understand biomedically relevant adaptations and will be ideal for my transition to an independent researcher exploring the biomedical relevance of past evolutionary adaptations.
Our investigation of the cellular underpinnings of height variation using a natural human model for small body size and short stature will generate fundamental knowledge about growth pathways in populations often overlooked in clinical research. The chondrocyte response to growth factors is under-characterized, but the use of recently developed iPSC technology makes it possible to experimentally manipulate human cells underlying stature using a powerful in vitro system and identify differential response to the growth factors between populations. Through comparisons between a rainforest hunter-gatherer (RHG) population with genetically-mediated short stature (the pygmy phenotype) and a neighboring human population with typical stature with two non-human primate species, we will identify both divergent and constrained portions of the growth factor regulatory response, with the former important in understanding RHG small body size evolution and the latter of interest to help identify genes for which regulatory disruptions would likely lead to a disease phenotype in all humans.
|Bergey, Christina M; Lopez, Marie; Harrison, Genelle F et al. (2018) Polygenic adaptation and convergent evolution on growth and cardiac genetic pathways in African and Asian rainforest hunter-gatherers. Proc Natl Acad Sci U S A 115:E11256-E11263|