The Reinholdt Lab

Dr. Reinholdt’s research focuses on comparative and functional mammalian genomics, reproductive development and stem cell biology.

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

Cellular Systems Genetics

 Genetic variation impacts multiple aspects of stem cell biology including stability of the pluripotent state in vitro, and the response of pluripotent stem cells to directed differentiation and their subsequent cell fate diversification. Phenotypic variation, manifesting as heterogeneity in cell state, represents a significant challenge for realizing the full promise of individualized, cell-based therapies, but it also offers an opportunity for the advancement of systems genetics research, and the development of systems genetic resources that enable cellular screens of gene-environment interactions. Mouse geneticists have long recognized that, among inbred strains, mouse embryonic stem cells (mESCs) exhibit phenotypic heterogeneity similar to what has been reported in human pluripotent cells. Taking advantage of a well-characterized, rationally-designed genetic reference population, we are creating enabling panels of cells to support widespread adoption of systems genetics in vitro. These resources feature the significant advantages of the laboratory mouse for genetic mapping and reverse genetic in vivo validation. In collaboration with other JAX faculty with interests in systems cellular genetics, we are generating deep, single-cell molecular phenotype data conducting associated data analyses and building an integration framework for generating novel hypotheses. By using this framework to assemble and test predictive models of gene by environment interactions, we will accelerate the discovery and functional validation of the genetic variation that drives phenotypic variation in cells with a focus on pluripotent stem cells. This information is central to unlocking the full potential of pluripotent stem cells for personalized medicine.

Genome stability

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.

Forward genetic discovery

A major area of focus in my laboratory takes advantage of 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. We were 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 also interested in the significant proportion of mutations that escape detection by exome sequencing to further understand the nature of these mutations and to improve computational approaches structural mutation discovery from both short read and more recently, long read sequencing data.

Resource Development
As part of the Genetic Resource Science group, a subset of my laboratory is rooted in resource development. These activities involve both data and biological resource development for a variety of programs including the Mutant Mouse Resource and Research Center, the Special Mouse Strain Resource, and the Mouse Mutant 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 400 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. We developed a platform for derivation of embryonic stem cell lines from a variety of strains that were previously deemed recalcitrant after years of failed attempts by the scientific community. Using these approaches we have derived germ line competent embryonic stem cell lines and iPS cell lines from a wide variety of inbred strains, and more recently, from genetic reference populations.

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