Biology, The University at Buffalo

March 28, 2019 3:30, CC Room 26 C

The growth hormone receptor (GHR) gene codes for the central receptor protein for the growth hormone pathway. As such, this gene is highly conserved among mammals. Despite this, the third exon of the GHR gene is deleted in approximately 50% of the human genomes. The deleted variant (GHRd3) has been associated with human height, longevity, and metabolic markers. Our lab has previously reported that this deletion is also found in the sequenced Neanderthal and Denisovan genomes. This suggests that GHRd3 has been maintained for at least 400,000 years in the human lineage. Based on population genetic analyses, we found evidence of non-neutral evolution acting on variation in this locus in humans. To investigate the phenotypic impact of GHRd3, we constructed a CRISPR-Cas9 based mouse model carrying the orthologous exon 3 deletion. We showed that there is a differential rate of growth between GHRd3 and wildtype in male mice. Moreover, RNA-sequencing analyses showed that GHRd3 affects the expression of genes which are significantly enriched for metabolic processes. Based on these data, we hypothesize that GHRd3 has been maintained in a frequency-dependent manner in the human lineage as a response to feast-famine cycles.