Full Scientific Report for Beth Dumont
My research leverages the power of the house mouse model system to address open questions in evolutionary genomics. Currently, my group’s efforts are concentrated into three main research foci:
Understanding the causes and consequences of variation in the mechanisms that govern DNA inheritance. Intergenerational DNA transmission is shaped by the fundamental processes of chromosome segregation, recombination, and de novo mutation. The simplified and known genetic background of captive mouse populations such as the Collaborative Cross, BXD recombinant inbred strain panel, the Diversity Outbred population, and collections of diverse inbred strains render them uniquely powerful resources for studying the mechanisms of short-term genome evolution and genomic inheritance. To this end, my current research program leverages genomic resources from purpose-bred, pedigreed, and mouse diversity panels to quantify variation in recombination, mutation, and chromosome assortment; elucidate the impact of this variation on reproductive fitness; map genetic modifiers of mutation and recombination rates; and identify environmental factors that influence their action. Toward this latter goal, we are current testing how artificial reproductive technologies impact genome stability and mutation rates.
Evolutionary genomics of functional chromatin domains: Centromeres and pseudoautosomal regions (PARs) are highly specialized chromatin domains that are indispensable for proper chromosome segregation. Centromeres provide chromosomal points of attachment to the cellular segregation machinery, linking chromosomes to the proteins that pull them to the cell poles during both somatic and germline cell divisions. The PAR is a region of conserved sequence identity between the X and Y chromosomes over which the meiotic program of pairing, synapsis, and recombination unfolds to ensure correct sex chromosome segregation. Mutations that disrupt centromere integrity or reduce homology between X- and Y-linked PARs can lead to chromosome segregation errors and constitute important genetic mechanisms for cancer, cellular senescence, and infertility. Despite their fundamental significance for chromosome transmission and genome stability, little is known about the levels and patterns of genetic diversity across centromeres and the PAR, or the biological impacts of this variation. The highly repetitive sequence content of these regions poses a major barrier to their molecular analysis, and the PAR and centromeres remain unassembled or incompletely assembled on many of highest quality reference genomes, including mouse. My group is leveraging state-of-the-art sequencing technologies and bioinformatic methods to catalog variation across the PAR and centromeres. In parallel, we are pursuing experimental tests of the functional consequences of genetic variation across these loci.
Wild mouse population genomics and resources for biomedical research: The classical laboratory inbred mouse strains derive from a small, ancestral population of wild mice that were selectively bred for traits of interest by mouse fanciers in the late 19th and early 20th centuries. As a consequence of their unique historical origins, the genetic diversity captured in laboratory mice represents an extremely limited sample of the diversity found in wild mouse populations. Our prior work has demonstrated that wild mouse populations harbor numerous predicted functional and disease-associated alleles, the majority of which are not present in classical inbred mouse strains and have therefore never been experimentally tested in the laboratory. Thus, we contend that wild mice present an untapped opportunity for developing new mouse models of human disease and advancing new biomedical discoveries. With the broad goal of elevating the profile of wild mice in biomedical research, my group is pursuing population genomic investigations in wild mice to understand the natural evolutionary forces that shape variation in wild mouse populations. We are also actively involved in the development of new strain and genomic resources derived from wild-caught animals.
My research aims to understand the causes and consequences of variation in the mechanisms that govern DNA inheritance: chromosome segregation, recombination, and de novo mutation. My PhD work combined phylogenetic, cytogenetic, and quantitative methods to address the genetic and evolutionary causes of species differences in recombination rate. My work relied on wild-derived inbred mice as a model system, and I gained relevant practical experience with wild mouse husbandry, colony maintenance, and mouse reproductive phenotyping. As a postdoctoral trainee at the University of Washington, I used computational approaches to mine large-scale genomic datasets to identify and catalog signatures of one specific subclass of recombination - gene conversion – within structurally complex and repetitive genomic regions. Building on these training experiences, I then pursued an independent postdoctoral position with the Initiative in Biological Complexity (IBC) at North Carolina State University. My independent work was supported by a K99/R00 award from NIGMS to study the evolution and meiotic function of the most recombinogenic region of the mammalian genome: the pseudoautosomal region (PAR), a highly repetitive and structurally complex locus. Research in my independent group is continuing to address the genetic basis of recombination rate variation and properties of PAR evolution using both wet-bench and computational approaches. Additionally, since starting my own group at The Jackson Laboratory in late 2016, I have initiated new research program areas in (1) wild mouse population genomics, (2) centromere evolution and its implications for meiotic drive, and (3) mutation rate variation.
My current research program relies heavily on publicly available genomic resources for mouse diversity populations such as the Collaborative Cross, BXD recombinant inbred panel, the Diversity Outbred population, and collections of diverse inbred strains. Many recent and active projects in my group capitalize on the basic insight that patterns of genetic transmission in these populations reflect the action of recombination, mutation, and chromosome assortment. The simplified and known genetic background of these populations renders them uniquely powerful resources for studying the mechanisms of genome evolution, an application outside their conventional use in gene mapping studies. In parallel to investigations of mice in the lab, my team has also been analyzing population genomic datasets for wild mice with the overarching goal of understanding how the interplay of selection, demography, and mutation have shaped contemporary patterns of wild mouse diversity across the globe. Collectively, my past and current research experiences have afforded me deep familiarity with the structure of genomic variation across mouse diversity panels (e.g., PMIDs: 34740238, 28159751, 30753674, 19535547) and wild populations (e.g., PMID 34794440), as well as extensive, hands-on expertise with the analysis of diverse genomic datatypes, the statistical analysis of quantitative trait data, and methods for quantitative trait mapping (e.g., PMIDs: 34740238, 21695226, 19535547, 20978138). These training experiences and research expertise combine to make me uniquely suited to oversee the construction of new mouse populations founded from wild mice and to lead genomic and phenotypic data collection and analysis efforts in such populations.