Using reverse genetics to illuminate human metabolic and endocrine phenotypes

Deep characterisation of the functional impact of damaging human mutations, through studies in cells, animal models and humans, can provide novel insights into the control of human metabolic and endocrine phenotypes. Increasing availability of data from whole-exome and -genome sequencing, particularly in populations from which participants can be recalled by genotype for detailed phenotypic study, provides an unprecedented opportunity to accelerate the rate at which such discoveries are made through “reverse human genetics”. Using sequencing data from UK populations, each with specific features that facilitate our aims, we will identify damaging or protective variants in genes implicated in the control of key metabolic and endocrine pathways but whose role in the control of human physiology is poorly understood. Having established the impact of mutations on protein function, we will proceed to in-depth physiological phenotyping of individuals recalled by genotype and, where necessary and potentially illuminating, create and characterise cellular and/or murine models. We provide initial examples encompassing genes highly relevant to metabolic phenotypes that encode for regulators of adipocyte metabolism, nuclear receptors, and GPCRs and their ligands. In these, we have already identified UK-based people who carry heterozygous or homozygous loss-of-function mutations and who are recallable for detailed further study.