Organismal
Organismal

Richard Glynne, Ph.D.
Director of Genetics
 

One normally thinks of organisms apart from technology, but in the Mammalian Genetics Department at GNF, we make no such distinctions. We are using our latest technologies to investigate several sources of genetic variation in the mammalian genome and to explore new strategies for treating disease.

In our first approach, we take an unbiased look at biology to identify new targets that affect a particular phenotype. We use a chemical mutagen to increase genetic variation, and then screen through this variation for phenotypes relevant to human health.  For example, one experiment identified several strains resistant to the effects of a high fat, Western style diet, which is a considerable risk factor for heart disease, diabetes, and obesity. The mutations carried in these strains cause loss of function of genes that have never before been implicated in metabolic disease. As such, the genetic lesions suggest ways in which we might be able to develop drugs with new mechanisms.

In another example, we have identified new strains with characteristics that point the way toward new therapeutics aimed at manipulating the immune system and ameliorating unwanted and dangerous immune responses. These strains have defective immune responses, which is the opposite of what is encountered in autoimmune diseases, where an overactive immune system gives rise to disorders like type I diabetes, rheumatoid arthritis, and multiple sclerosis. Overactive immune systems are also to blame for the rejection of transplanted tissue, which is too often the case in organ transplants. Rejection can be a major medical problem, severely curtailing the function of the transplanted organs and limiting the ability of these surgeries to save lives.

We are also looking at genetic variation across a wide range of inbred strains to correlate genomic regions shared between inbred strains with similar characteristics. For example, some inbred strains have higher levels of high density lipoprotein (HDL) or “good cholesterol” than others, and there are strong correlations between regions of the genome in inbred strains that share similar levels of HDL. By systematically collecting information on the characteristics of a panel of inbred strains, we are able to compare this information with our genetic data and identify lists of candidate genes that might control particular traits. These candidate genes can then be tested in more focused assays to provide new insights into the control of different aspects of mammalian biology.

Finally, we are taking full advantage of the cutting-edge technologies at GNF that might collectively be described as a post-genomics toolbox. By bringing these technologies to bear on our areas of interest, we are able to look at the tissues in which a gene is expressed, examine the structure of the encoded protein, and measure the effects of altering expression of the gene in cell-based models of human biology. With all this information about a single gene, we can make good predictions about how manipulating that gene would affect biology. To test, refine, and extend these predictions, we are taking advantage of targeted mutations in the genome. By deleting or overexpressing a gene in all or some tissues, we can gauge the gene’s physiological effect in a mammalian context.