This application is for the second competitive renewal (funding for years 09-14) of a grant that has focused on positional cloning of obesity genes using congenic mouse strains. Congenic strains are mouse strains that have a small chromosomal region from a donor strain in the genome of a background strain. Phenotype differences between congenic and background strains are due to donor strain alleles. Thus, congenic strains that differ from background strains for fat mass define small chromosomal regions that must have a gene that influences obesity and that has functionally different alleles in the donor and background strains. In the current grant cycle we used marker directed selection to produce 11 subcongenic strains from the congenic strain B6.C-H1, each with reduced donor chromosomal regions. Four of these subcongenic strains will become the founding strains for this proposal. Three strains exhibit significant obesity effects. The fourth subcongenic strain contains a maternal effects gene that influences the obesity of adult progeny. Maternal effects refer to the observation that maternal nutrition or genotype can program obesity of progeny. The core goal of this proposal is to identify the four Quantitative Trait Genes that are included in these four subcongenic strains. Gene isolation from subcongenics uses the tools of positional cloning - minimizing the number of candidate genes by breeding and then testing these genes for their effects on the phenotype. We propose three specific aims to isolate the obesity genes and the maternal effects gene.
In specific aim 1 we will test several methods to assess maternal effects.
In specific aim 2, we will use breeding and identification of recombinants to narrow the target regions for the four subcongenics.
In specific aim 3 we will test genes in subcongenics with phenotypes by sequencing and expression analysis. We believe that this study offers the opportunity to identify a gene causing maternal effects on obesity, as well as three other obesity genes, by using well characterized congenic mouse strains.
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