MIDDLEBURY, Vt. – Joshua Yuan, a Middlebury College senior from Portland, Oregon, is the lead author on a new paper that is shedding light on the genetic mapping of complex traits in mammals. The paper was published in the April 2018 edition of the journal Mammalian Genome, and the coauthors include two Middlebury faculty members and seven alumni who were research assistants in the lab.
Under the direction of principal investigator Clarissa Parker, an assistant professor of psychology and neuroscience, Yuan and the collaborators measured the testes weight of 502 “diversity outbred” (DO) mice over a two-year period, while an independent lab genotyped a tissue sample from the tail of each of the animals.
The investigators then performed a genome-wide association analysis between the testes weight and DNA of the mice, which resulted in the identification of specific genomic regions associated with testes weight.
The techniques used in Professor Parker’s lab are helping scientists better understand how to identify genes that are implicated in complex traits, said Yuan. Complex traits are those traits that are influenced by more than one gene across any chromosome. The research also has important implications for livestock fertility and, notably, for human fertility as well.
“One of the great things about the diversity outbred mice”—mice that have been bred from wild strains, as opposed to mice that have been inbred in labs for generations—“is that DO mice are more genetically diverse than traditional inbred strains and, due to their unique breeding design, they are more representative of the diversity seen in human populations,” explains Parker.
“So, for any genes that we identify as being related to out trait of interest [i.e., testes weight], there’s most likely going to be a gene in humans that has the exact same function and will be related to that trait.”
Yuan, who is double majoring in computer science and molecular biology and biochemistry, played a key role in the computational phase of the project, said Parker. Using publicly available databases developed by other researchers, he used search algorithms to determine which genes can have a direct effect on testes weight.
Explaining it further, Parker said, “Let’s assume we have identified a genetic region of a chromosome that has 50 genes in it. We still don’t know which of those 50 genes are really driving the trait in question. Now all the cells in the human body have the same genes, but those genes don’t all have the same function or activity, and the activity of the gene is what determines whether you have a skin cell, or a hair cell, or a brain cell.
“Genes work by turning on or off, and we are going to be most interested in the genes that are active in the testes because if they are not expressed [or turned on], then they are probably not going to contribute to testes weight. One of the databases Josh used showed which of these genes are expressed in the testes, and we are grateful to the other scientists who did the work and made their data available.”
The approach used by the Middlebury researchers can be applied to any complex trait in mammals. “So any trait you are interested in, whether it’s body weight in mice or a neuropsychiatric disorder like depression in humans—our approach can be applied to all of these,” Parker added. “Our results demonstrate the utility of using DO mice in any high-resolution genetic mapping of complex traits.”
Yuan, the Middlebury undergraduate at the forefront of the research paper published by Mammalian Genome, is graduating summa cum laude in May 2018. During his years at Middlebury, the Portland, Ore., resident was a research assistant and a volunteer emergency medical technician on campus.
Yuan capped off his senior year by presenting the paper at a poster session at the recent Population, Evolutionary and Quantitative Genetics Conference at the University of Wisconsin–Madison. Hoping to attend medical school beginning in the fall of 2019, Yuan will spend the next year gaining clinical experience by working as a medical scribe in a physician’s office.
The alumni collaborators on the research project, all of whom are listed as coauthors on the groundbreaking paper, are Steven Kasparek ’16, Andrew Kreuzman ’16, Benjamin Mansky ’15, Kayvon Sharif ’16, Dominik Taterra ’17, Walter Taylor ’15, and Mary Thomas ’17.
Also coauthoring were: Jeremy Ward, the Albert D. Mead Professor of Biology at Middlebury; Daniel Gatti, Vivek Philip, and Elissa Chesler – three scientists from the Jackson Laboratory for biomedical research; and Andrew Holmes of the National Institutes of Health’s Laboratory of Behavioral and Genomic Neuroscience.
Parker earned a BA in psychology at Colorado College and PhD in psychology at the Center for Neuroscience at the University of Colorado. She was a postdoctoral research fellow in behavioral genetics for four years at the University of Chicago prior to joining the Middlebury faculty in 2013. Her research uses mouse models to develop concepts, test neurobiological hypotheses, and identify genes that underlie traits with relevance to human psychiatric disorders.