Ancestral functions of genes regulated by imprinting in mammals

Around 100 mammalian genes are subject to regulation by genomic imprinting such that only one of the two parental
alleles is expressed. This form of epigenetic regulation is unique to mammals and the evolution of imprinting has been
hotly debated since its discovery around 30 years ago. The most widely accepted evolutionary theory for imprinting
predicts a critical role for imprinted genes in regulating growth during development.
However, while it is clear some imprinted genes are important regulators of growth, there are many with other functions.
Much of what we know about imprinted genes comes from mouse genetic studies and relatively little is known about the
functions of the analogous genes in animal species in which imprinting does not exist. For each gene with imprinted
expression in mammals this project will identify orthologues in non-mammalian vertebrate and invertebrate species. By
comparing gene function in different species, the aim is to test the hypothesis that imprinting first evolved to act on genes
with established roles in growth regulation. Alternative hypotheses will be considered.
The PhD project will combine two main approaches to be carried out in parallel: First, through careful evaluation of the
literature and genome databases, evidence of gene function in both mammalian and non-mammalian species will be
gathered and evaluated. It is anticipated that functional information from studies of non-mammalian models will be scarce
relative to a wealth of information for mammalian genes, particularly from mouse genetic studies. This exercise will go
some way to addressing the hypothesis, and will identify a short-list of imprinted gene orthologues for functional testing
in zebrafish. The second approach will involve genetic testing of gene function in zebrafish and will begin with zebrafish
orthologues of Grb10, which is expressed from the maternally-inherited allele in mouse and is an important regulator of
fetal growth. Mutant grb10 zebrafish strains are available and will be used to identify whether growth regulation, or other
functions known from mouse genetic studies, are conserved in fish. This will involve studying morphology, histology and
physiology of developing zebrafish. Additionally, the molecular phenotype will be addressed using antibody staining and
mRNA in situ hybridisation to assess expression of marker genes and through the generation of an RNA-seq data set.