
	1999 Summer Scholars Program

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Fine Mapping Adult Body Weight in Mice: QTL Analysis

By Brandon Roberts
Mentor: Dr. James Cheverud
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO

During the past six weeks, I have had the pleasure of working with Dr. James Cheverud and his staff at the Washington University School of Medicine. Dr. Cheverud's research is designed to obtain the entire genetic architecture of obesity-causing traits in the mouse genome. Obesity is a widespread condition that serves as a risk factor in other physiological problems such as diabetes, hypertension, heart disease, breathing problems, and some forms of cancer. Obesity is also a condition that is controlled by multiple genes. Our research on obesity will serve as a paradigm for the study of other physiological problems that are controlled by multiple genes.

Our lab seeks to locate QTLs throughout the mouse genome and to fine-map the regions where QTLs are expected to exist. "QTL" is an acronym for Quantitative Trait Loci and represents a segment on a chromosome that may contain multiple genes with each gene having a relatively small effect on a physical characteristic. In the preliminary stages of Dr. Cheverud's research, the genotypes of the second generation of mice (F2), which were created from an inbred large strain and an inbred small strain, were obtained using a multitude of microsatellite markers. By determining a linkage between the genotypes and phenotypes at different markers, this initial study revealed the existence of 18 QTLs affecting adult body size. This study gives us a general idea of where the QTLs are located. In order to fine-map a QTL, we use an Advanced Intercross Line (AIL). The AIL is a form of breeding where we mate non-siblings in order to expand the mouse genome markers, which makes it possible to establish more microsatellite markers and correlate a greater number of genotypes with phenotypes. The AIL allows us to more accurately define the region of the QTL compared to the F2 genetic map.

I have been working to fine-map chromosomes 8, 18, and 12 in the F10. The DNA is extracted from liver tissue of the mouse, which is removed during necropsies. The DNA is added to a cocktail that contains a given primer. The primers are designed to flank a small portion of a chromosome and during the Polymerase Chain Reaction (PCR), the DNA that composes that portion of the chromosome is amplified. Next, the DNA is run through agarose gels, stained, photographed, and scored. The QTL region may contain a number of genes and these genes will be located using a genetic database on the World Wide Web.

As more QTLs are fine-mapped, a more complete picture of the genetic architecture will be discovered. This will result in a better understanding of obesity and will allow the necessary steps to be taken to treat the problem in humans.

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