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author:("ree, Karen")
1.  Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits 
We have developed an association-based approach using classical inbred strains of mice in which we correct for population structure, which is very extensive in mice, using an efficient mixed-model algorithm. Our approach includes inbred parental strains as well as recombinant inbred strains in order to capture loci with effect sizes typical of complex traits in mice (in the range of 5 % of total trait variance). Over the last few years, we have typed the hybrid mouse diversity panel (HMDP) strains for a variety of clinical traits as well as intermediate phenotypes and have shown that the HMDP has sufficient power to map genes for highly complex traits with resolution that is in most cases less than a megabase. In this essay, we review our experience with the HMDP, describe various ongoing projects, and discuss how the HMDP may fit into the larger picture of common diseases and different approaches.
doi:10.1007/s00335-012-9411-5
PMCID: PMC3586763  PMID: 22892838
2.  The Number of X Chromosomes Causes Sex Differences in Adiposity in Mice 
PLoS Genetics  2012;8(5):e1002709.
Sexual dimorphism in body weight, fat distribution, and metabolic disease has been attributed largely to differential effects of male and female gonadal hormones. Here, we report that the number of X chromosomes within cells also contributes to these sex differences. We employed a unique mouse model, known as the “four core genotypes,” to distinguish between effects of gonadal sex (testes or ovaries) and sex chromosomes (XX or XY). With this model, we produced gonadal male and female mice carrying XX or XY sex chromosome complements. Mice were gonadectomized to remove the acute effects of gonadal hormones and to uncover effects of sex chromosome complement on obesity. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had up to 2-fold increased adiposity and greater food intake during daylight hours, when mice are normally inactive. Mice with two X chromosomes also had accelerated weight gain on a high fat diet and developed fatty liver and elevated lipid and insulin levels. Further genetic studies with mice carrying XO and XXY chromosome complements revealed that the differences between XX and XY mice are attributable to dosage of the X chromosome, rather than effects of the Y chromosome. A subset of genes that escape X chromosome inactivation exhibited higher expression levels in adipose tissue and liver of XX compared to XY mice, and may contribute to the sex differences in obesity. Overall, our study is the first to identify sex chromosome complement, a factor distinguishing all male and female cells, as a cause of sex differences in obesity and metabolism.
Author Summary
Differences exist between men and women in the development of obesity and related metabolic diseases such as type 2 diabetes and cardiovascular disease. Previous studies have focused on the sex-biasing role of hormones produced by male and female gonads, but these cannot account fully for the sex differences in metabolism. We discovered that removal of the gonads uncovers an important genetic determinant of sex differences in obesity—the presence of XX or XY sex chromosomes. We used a novel mouse model to tease apart the effects of male and female gonads from the effects of XX or XY chromosomes. Mice with XX sex chromosomes (relative to XY), regardless of their type of gonad, had increased body fat and ate more food during the sleep period. Mice with two X chromosomes also had accelerated weight gain, fatty liver, and hyperinsulinemia on a high fat diet. The higher expression levels of a subset of genes on the X chromosome that escape inactivation may influence adiposity and metabolic disease. The effect of X chromosome genes is present throughout life, but may become particularly significant with increases in longevity and extension of the period spent with reduced gonadal hormone levels.
doi:10.1371/journal.pgen.1002709
PMCID: PMC3349739  PMID: 22589744

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