our Research Focus

We are interested in the development and application of both forward and reverse genetic approaches for understanding the etiology of genome variation and it’s role in health and disease.

We are currently focusing our efforts on an exceptional resource of laboratory mouse strains with proven Mendelian disorders with unknown genetic etiology, strains stewarded by the Mouse Mutant Resource at The Jackson Laboratory for over 50 years. Taking advantage of this resource, our laboratory was the first to apply exome sequencing at scale for the discovery of naturally occurring genetic variants (mutations) that cause Mendelian disease in mice. Using this approach, we have identified causative mutations in nearly 100 new mouse models of Mendelian disease. We are now focusing on the significant proportion of mutations that escape detection by exome sequencing to further understand the nature of these mutations and to improve computational approaches mutation discovery. Using reverse genetic approaches, we are also working closely with the human genetics community to create new strains of mice carrying human Mendelian disease mutations.

Heritable genetic variation is the result of genome instability during germ cell development, instability that arises through mutation, chromosome rearrangement or chromosome mis-segregation during mitosis or meiosis. Germ cells employ mechanisms to counteract these destabilizing events and when these mechanisms are disrupted, aneuploidy and infertility are the result. My post-doctoral work on the identification of genes required for normal germ line development and fertility led to the discovery that the germ line is exquisitely sensitive to mutations in components of the mitotic spindle that have the potential to lead to aneuploidy – this sensitivity may also extend to embryonic and adult stem cells. We have gone on to show that the sensitivity of the germ line genome instability differs across inbred strains of mice, offering a unique opportunity to use systems genetics approaches to discover the underlying pathways governing cell division and survival across a variety of cell types.

Resource Development

As part of the Genetic Resource Science group, resource development is a major focus of my laboratory. Our major resource development projects involve both data and biological resources for a variety of programs including the Mutant Mouse Resource and Research Center at JAX, the Special Mouse Strain Resource, the Mouse Mutant Resource and NICHD’s Cytogenetic Models Resource.

Genomic data resources. In addition to providing support to the Mouse Genomes Project, we have generated whole genome and exome variant call data for over 200 strains of mice. We developed a web-based variant database to enable user-defined queries and we are currently working on the development of new approaches for the optimized analysis of exome data, particularly for unsolved exome cases.

Biological resources. Our current biological resource development efforts include the application of CRISPR/cas9 for the creation of novel mouse strains that carry human mutations. Much of this work is in collaboration with NHLBI’s Bench to Bassinet program and the Centers for Mendelian Genomics. In addition, Dr. Reinholdt’s laboratory developed a novel protocol for derivation of embryonic stem cell line from a variety of strains that were previously deemed recalcitrant after years of failed attempts by the scientific community. This approach is now being used to derive embryonic stem cells from a variety of strains including disease models from which in vitro tools are in demand, including mouse models of Alzheimer’s disease, cytogenetic disorders (Turner’s syndrome and Down syndrome), and tool strains for systems genetics.