Funded Projects

Recent studies have revealed that genomic structural variants (SVs) are common in human populations and that they are major determinants of disease susceptibility. However, the evolutionary forces that shape structural variation remain incompletely understood. Gokcumen laboratory has a long-term goal to elucidate the evolutionary, biomedical and functional impact of human genomic structural variation. The objective for this proposal is to determine why a key example of a functional structural variation, the common deletion of the third exon of the growth hormone receptor (GHR) gene remains in human populations. The central hypothesis, based on preliminary analysis, is that GHRd3 has been adaptively maintained in human populations because even though it affects susceptibility to metabolic and developmental disorders, it also gives a fitness advantage in times of low food supply. The proposed work will integrate evolutionary genetics, cell biology, and mouse genetics to complete its objective and test the above-mentioned central hypothesis under three specific aims: (i) Elucidate the evolutionary history of GHRd3 and its links to human phenotype; (ii) Determine if GHRd3 affect transcriptome variation in multiple tissues; (iii) Determine the organismal-level effect of GHRd3 in a mouse model. We have now established a strong team of researchers at UB to tackle these questions. The results of our proposal will shed light on the functional mechanism and phenotypic impact of GHRd3, resulting in a better understanding of the genetic basis of a variety of developmental and metabolic disorders and providing the ability to fine-tune growth hormone treatments for patients carrying the deletion. On a broader scale, this study will provide a model for studying the evolutionary and functional impact of hundreds of complex structural variations that have been maintained in the human genome.