We study how genetic variation controls complex traits, susceptibility to disease, and individual molecular biology. Most prevalent human diseases, most agriculturally important traits, and evolutionary fitness are complex traits, which means they are influenced by a combination of multiple genetic and environmental factors. A long-standing goal in the field is to identify quantitative trait loci (QTL) – genetic variants that influence complex traits. Discovering these relationships is challenging because the individual factors each have small effects, and because genetic variants often interact with the environment (GxE) or other genes (epistasis). Figuring out how these variants change the function of cells or molecules has been even more difficult. Understanding these genetic mechanisms will enable the translation of model organism research to humans and uncover new principles of genetics and genome science. We develop and apply systems genetics approaches that enable us to discover QTL and reveal their mechanisms. We are currently working in three areas:
Genetics and genomics of environmental response
We are using Collaborative Cross mice and molecular profiling to explore individual susceptibility to the drug diethylstilbestrol. DES is a synthetic estrogen that caused infertility and vaginal cancer in some adults who were exposed prenatally. Some DES exposed mouse strains also display reproductive defects (male and female) and uterine cancer. Other mouse strains are unaffected, which indicates a strong genetic component to susceptibility. We are exposing a panel of CC mice to DES to identify QTL and GxE associated with clinical traits, gene expression, and epigenetic profile. The challenge is to piece together these data into a cohesive model. This project will shed valuable light on how early environmental exposures can alter our health as adults, and how genetics can make some of us especially susceptible. The global mechanisms of this process are likely to be similar between mice and humans and our approach will be applicable to a range of environmental exposures, especially other estrogenic chemicals that are a public health concern.
Genetics of hybrid male sterility in house mice
Hybrid sterility is of great evolutionary significance because it maintains barriers between species. Solving the genetics of hybrid sterility is a challenge because fertility is influenced by so many factors, and because hybrids exhibit gene-gene interactions that are hard to detect in conventional QTL mapping designs. Our approaches are designed to overcome just these limitations. We are creating a variety of sterile male hybrids by crossing diverse mouse strains representative of different subspecies, and characterize each hybrids for reproductive parameters and molecular profiles. Recently, we observed delayed-onset sterility and epigenetic profiling also has the potential reveal the mechanism of this novel result.
Bioinformatics approaches to systems genetic data
One of the promises of genetic reference populations is that multiple experiments can be combined to better understand how alleles are expressed in different tissues, stages of development, or environmental conditions. We are pulling together various CC data sets and conducting meta-analyses to understand the context-dependence of QTLs, eQTLs, and epigenomic profiles. This work will reveal the specificity of regulatory variation and identify variants that are expressed in many developmental settings (i.e. multiple tissues) control susceptibilities to entire classes of compounds (e.g. estrogenic chemicals). We also think about how to improve our genetic analysis methods and help other labs analyze their mouse genetic data.