Despite a strong genetic contribution to obesity and diabetes, genome wide association studies have identi?ed variants that can only explain less than 10% of the observed heritability. This discrepancy, known as the missing heritability problem, has stimulated research aimed at understanding the bases and possible explanations for this observation. One prominent hypothesis, now supported by substantial amount of experimental evidence, points at epigenetic inheritance. Parental environmental experiences indeed cause phenotypic variation in unexposed offspring through genetic-independent epigenetic mechanisms. Beside environmentally acquired epigenetic inheritance, published ?ndings and our own preliminary data suggest that parental genetics can also control phenotypic variation in the wild-type progeny through epigenetic mechanisms.
Parental control of offspring health: characterisation of novel genetic determinants of (epi)genetic inheritance and phenotypic variation in mammals
A preliminary in silico screening in our lab, using data from the International Mouse Phenotyping Consortium (IMPC), identiﬁed several potential non-canonical epigenetic modiﬁers. Aim of this PhD project is to further characterise one of these candidates, by reproducing the phenotype in a more controlled environment and taking into account maternal and paternal contributions; and by identifying the molecular mechanisms by which parental genetics affects offspring phenotypic trajectories. In particular, the PhD student will generate cohorts of wild-type animals coming from either mutant parents or isogenic control individuals and run an in-depth metabolic phenotyping, which includes monitoring of body weight and composition, glucose tolerance, insulin sensitivity, energy expenditure and response to dietary challenges. For the mechanistic dissection of the parental effects, the PhD candidate will discriminate germ-cell dependent and independent mechanisms by applying state-of-the art bulk and single cell molecular proﬁlings such as RNA-, Chip- and ATAC-Seq.
The overall goal of the project will be to identify and mechanistically characterise novel genetic determinants of (epi)genetic inheritance of metabolic phenotypes in mammals.
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