Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 143-155). Also available in print.

published_or_final_version / Statistics and Actuarial Science / Doctoral / Doctor of Philosophy

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Genomic imprinting provides an exception to the Mendelian rule of inheritance, as imprinted genes are preferentially expressed in a parent-of-origin specific manner. They play important roles in the development of embryonic and extra-embryonic lineages and postnatally in the maintenance of correct metabolic homeostasis as well as regulation of adult behaviour. The parental conflict theory predicts that maternally expressed genes act as growth suppressors, limiting the usage of maternal resources, and that paternally expressed genes function in an opposite manner to promote growth at the expense of maternal resources. Growth factor bound protein 10 (Grb10) is an imprinted gene encoding an intracellular adaptor protein that can interact with several receptor tyrosine kinases and downstream signalling molecules. Recently, our lab has identified Grb10 as a unique imprinted gene capable of influencing fetal growth, postnatal energy metabolism and adult behaviour depending on functions of each of the parental alleles in distinct tissues. Grb10 predominantly expressed from the maternal allele during embryogenesis affects fetal and placental growth along with postnatal glucose homeostasis, whereas paternal Grb10 expression within the CNS influences social behaviour. Delta-like homologue 1 is (Dlk1) a paternally expressed imprinted gene coding for a protein belonging to the Notch/Delta family that acts as a membrane-associated or a soluble protein known to regulate differentiation of various cell types, notably adipocytes. In vivo Dlk1 has been associated with perinatal survival, regulation of normal growth and development and maintenance of the correct course of adipogenesis. Here a hypothesis is proposed that Grb10, as a predominantly maternally expressed growth inhibitor and Dlk1, a paternally expressed growth promoter, act antagonistically in a common genetic pathway. To test this hypothesis, we have generated Grb10m/+/Dlk1+/p double knockout mice and performed a phenotypic characterisation in comparison with wild type as well as the respective single knockout animals. Results obtained from allometric and metabolic analyses, together with histological studies, reveal strong similarities between the phenotypes of Grb10m/+and Grb10m/+/Dlk1+/p knockout mice. We found that overgrowth of Grb10m/+/Dlk1+/p embryos and placentae resemble the phenotype seen in Grb10m/+ mutants and that tissue overgrowth most likely results from higher proliferation rates of Grb10m/+and Grb10m/+/Dlk1+/p cells. Furthermore, Grb10m/+and Grb10m/+/Dlk1+/p knockout mice each exhibit improved glucose clearance and share an unusual characteristic accumulation of lipid in neonatal liver. These results are consistent with the proposed hypothesis and indicate that the Dlk1 and Grb10 genes might be involved in the same genetic pathway. Moreover, the data suggest Dlk1 is an inhibitor of Grb10 which is in turn acting as a growth suppressor.

A gene is imprinted when its expression is dependent on the sex of the parent from which it was inherited. An increasing number of studies are suggesting that imprinted genes have a major influence on medically, agriculturally and evolutionarily important traits, such as disease severity and livestock production traits. While some genes have a large effect on the traits of an individual, quantitative characters such as height are influenced by many genes and by the environment, including maternal effects. The interaction between these genes and the environment produces variation in the characteristics of individuals. Many quantitative characters are likely to be influenced by a small number of imprinted genes, but at present there is no general theoretical model of the quantitative genetics of imprinting incorporating multiple loci, environmental effects and maternal effects. This research develops models for the quantitative genetics of imprinting incorporating these effects, including deriving expressions for genetic variation and resemblances between relatives. Imprinting introduces both parent-of-origin and generation dependent differences in the derivation of standard quantitative genetic models that are generally equivalent under Mendelian expression. Further, factors such as epistasis, maternal effects and interactions between genotype and environment may mask the effect of imprinting in a quantitative trait. Maternal effects may also mimic a number of signatures in variance and covariance components that are expected in a population with genomic imprinting. This research allows a more comprehensive understanding of the processes influencing an individual�s characteristics.

A gene is imprinted when its expression is dependent on the sex of the parent from which it was inherited. An increasing number of studies are suggesting that imprinted genes have a major influence on medically, agriculturally and evolutionarily important traits, such as disease severity and livestock production traits. While some genes have a large effect on the traits of an individual, quantitative characters such as height are influenced by many genes and by the environment, including maternal effects. The interaction between these genes and the environment produces variation in the characteristics of individuals. Many quantitative characters are likely to be influenced by a small number of imprinted genes, but at present there is no general theoretical model of the quantitative genetics of imprinting incorporating multiple loci, environmental effects and maternal effects. This research develops models for the quantitative genetics of imprinting incorporating these effects, including deriving expressions for genetic variation and resemblances between relatives. Imprinting introduces both parent-of-origin and generation dependent differences in the derivation of standard quantitative genetic models that are generally equivalent under Mendelian expression. Further, factors such as epistasis, maternal effects and interactions between genotype and environment may mask the effect of imprinting in a quantitative trait. Maternal effects may also mimic a number of signatures in variance and covariance components that are expected in a population with genomic imprinting. This research allows a more comprehensive understanding of the processes influencing an individual�s characteristics.

Thesis (Ph.D.) -- Australian National University, 2008.