Maternal and indirect genetic effects on behavioural and developmental traits in mammalian disease models

Abstract

In the study of social behaviour, a fundamental question is to what degree specific genes and environmental influences predispose individuals to develop certain behaviours. The discovery of maternal effects on phenotypic traits has added a significant factor that needs to be accounted for, along with genetic and other environmental factors, when trying to understand the causes of variation in normal and disease phenotypes. This has been addressed in my PhD by studying the human genetic disorder Williams-Beuren syndrome (WBS) that affects both physiological and behavioural traits. WBS results from a chromosomal micro-deletion, on chromosome seven, and is characterised by an interesting cognitive profile; although compromised in visuospatial abilities and fine-motor coordination, WBS individuals have significantly elevated social behaviours. The aim of my PhD was to assess the functions of two genes, Gtf2ird1 and Gtf2ird2, deleted in WBS. Using single-gene knockout mouse models, I explored the unique hyper-social demeanour in WBS along with fine-motor skill efficiency and underlying neurohormone levels. In addition, I analysed indirect genetic effects (IGEs) where genes expressed in a focal individual have phenotypic effects in an interacting individual.In Chapters One and Two of this thesis, a detailed behavioural protocol with a cross-fostered, transgenerational experimental design was implemented to record any variation in maternal behaviours in Gtf2ird1 knockout mice compared to heterozygous and wildtypes. The study found a number of physiological impairments in Gtf2ird1 knockout mice that are analogous of WBS such as metabolic or anxiety-related traits with previously found phenotypes such as severely misaligned jaws and growth retardation. This study also found significant maternal effects on disease phenotypes thus highlighting the importance of studying maternal effects. Chapter Three of the thesis introduces the very first knockout model of Gtf2ird2. This study found upregulated social behaviour in the knockout mice compared to wildtypes. Further analysis of brain tissues of this model found elevated oxytocin mRNA levels in the knockouts and a similarly low levels of oxytocin receptor mRNA. This finding not only provides an initial link between genes deleted in WBS and social neuropeptides, but the lower level of oxytocin receptor mRNA is also indicative of an oxytocin induced desensitisation; a mechanism which has previously been reported in human myometrium cells. Although further studies are required to confirm these findings, this study certainly provides an insight in the role played by Gtf2ird2 in WBS. Finally, Chapter Four, concentrates on taking genotype-phenotype correlation studies further by mapping quantitative trait loci (QTL) using the largest recombinant inbred panel, BXD mice, to find indirect genetic effects on weight traits in inbred, C57BI/6J (B6) mice. The study found three significant QTL and one suggestive QTL affecting weight changes of B6 pups and mothers.

Date of Award	1 Aug 2016
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mayada Tassabehji (Supervisor) & Reinmar Hager (Supervisor)