Month: February 2013

Identifying Genes Involved in Blood Cell Traits

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blood-hmdp-figure2

In this study, blood cell traits were collected from each strain in the HMDP panel which consists of 100 mouse strains. Using EMMA(10.1534/genetics.107.080101), we identified associations with these traits. The main advantage of the HMDP compared to the traditional genetic cross approach is the increase in resolution of the association.

We identified a particularly striking association with mean corpuscular volume (MCV).  The figure from the paper shows both the manhattan plot for the HMDP as well as the linkage plot from a genetic cross examining the same trait for chromosome 7.  This example clearly shows the advantge of the HMDP compared to the cross in terms of resolution of the association.  The peak is less than 1 Mb from Hbb-b1 which has been previously suggested to affect this trait.

Some reviews covering the HMDP and mouse genetics more broadly are available here.

Full Citation:
Davis, Richard C, Atila van Nas, Brian Bennett, Luz Orozco, Calvin Pan, Christoph D Rau, Eleazar Eskin, and Aldons J Lusis. 2013. Genome-wide association mapping of blood cell traits in mice. Mamm Genomedoi:10.1007/s00335-013-9448-0

Abstract:
Genetic variations in blood cell parameters can impact clinical traits. We report here the mapping of blood cell traits in a panel of 100 inbred strains of mice of the Hybrid Mouse Diversity Panel (HMDP) using genome-wide association (GWA). We replicated a locus previously identified in using linkage analysis in several genetic crosses for mean corpuscular volume (MCV) and a number of other red blood cell traits on distal chromosome 7. Our peak for SNP association to MCV occurred in a linkage disequilibrium (LD) block spanning from 109.38 to 111.75 Mb that includes Hbb-b1, the likely causal gene. Altogether, we identified five loci controlling red blood cell traits (on chromosomes 1, 7, 11, 12, and 16), and four of these correspond to loci for red blood cell traits reported in a recent human GWA study. For white blood cells, including granulocytes, monocytes, and lymphocytes, a total of six significant loci were identified on chromosomes 1, 6, 8, 11, 12, and 15. An average of ten candidate genes were found at each locus and those were prioritized by examining functional variants in the HMDP such as missense and expression variants. These results provide intermediate phenotypes and candidate loci for genetic studies of atherosclerosis and cancer as well as inflammatory and immune disorders in mice

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Genes, Diet, and Body Weight (in Mice)

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What affects body weight? Is it genetic factors or is it diet or is it both?

Our group collaborated with Jake Lusis’ group on a mouse study led by Brian Parks that aimed to address this question and the results were published in Cell Metabolism (10.1016/j.cmet.2012.12.007). From our group, Emrah Kostem contributed to the study. The study received a lot of press coverage including Science News, Huffington Post, and Time.com.

It turns out that not only do both genes and diet contribute to body weight, a significant factor is the interaction between genes and diet. Some strains of mice gained a significant amount of weight on a high fat diet, whiles others did not. These types of interactions, or “gene-by-environment” interactions are if great interest to our group and we are working on several projects on this topic.

What is also exciting about this study is that it is the first published report of our second round of studies using the Hybrid Mouse Diversity Panel (HMDP) (10.1007/s00335-012-9411-5). The first round of studies reported associations for lipids(10.1101/gr.099234.109), bone traits (10.1371/journal.pgen.1002038), and fear conditioning (10.1186/1752-0509-5-43). This next round focuses on gene-by-environment interactions. The HMDP is now no longer just a UCLA project. Now several groups at other institutions including USC, UC Berkeley and University of Washington are also involved in HMDP studies.

 

Full Citation:

Parks, B.W., Nam, E., Org, E., Kostem, E., Norheim, F., Hui, S.T., Pan, C., Civelek, M., Rau, C.D., Bennett, B.J., Mehrabian, M., Ursell, L.K., He, A., Castellani, L.W., Zinker, B., Kirby, M., Drake, T.A., Drevon, C.A., Knight, R., Gargalovic, P., Kirchgessner, T., Eskin, E. & Lusis, A.J., 2013, Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice, Cell Metab, 17(1), pp. 141-52.

Abstract:

Obesity is a highly heritable disease driven by complex interactions between genetic and environmental factors. Human genome-wide association studies (GWAS) have identified a number of loci contributing to obesity; however, a major limitation of these studies is the inability to assess environmental interactions common to obesity. Using a systems genetics approach, we measured obesity traits, global gene expression, and gut microbiota composition in response to a high-fat/high-sucrose (HF/HS) diet of more than 100 inbred strains of mice. Here we show that HF/HS feeding promotes robust, strain-specific changes in obesity that are not accounted for by food intake and provide evidence for a genetically determined set point for obesity. GWAS analysis identified 11 genome-wide significant loci associated with obesity traits, several of which overlap with loci identified in human studies. We also show strong relationships between genotype and gut microbiota plasticity during HF/HS feeding and identify gut microbial phylotypes associated with obesity.

Bibliography