R35GM139412

Evolution of Phenotypic Extremes and Mechanisms Governing Inheritance - Project Summary

We propose a research program in evolutionary genetics and genomics that emphasizes two distinct themes.

The first theme focuses on the Island Rule - the widespread phenomenon of populations evolving unusual body sizes after colonizing islands. Advances in our laboratory have established mice from Gough Island, the largest wild house mice in the world, as a tractable system for understanding genetic mechanisms responsible for the evolution of extreme body size. Through comprehensive characterization of novel congenic strains, we will identify genes and mutations involved in this instance of the Island Rule. To elucidate causes and consequences of gigantism, we will extend this unique system to genetically dissect another trait associated with evolution on islands: exploratory behavior. This research direction will reveal genetic principles of complex trait evolution in novel environments.

The second theme centers on recombination, a process that diversifies offspring genomes and ensures proper chromosomal segregation during meiosis in many species. Using single-cell methods that enable us to quantify recombination in individuals, we have discovered that house mice evolved substantial differences in genomic crossover number over short timescales, with females and males showing discordant trajectories. Motivated by this advance, we will reconstruct the evolutionary dynamics of the recombination landscape in house mice across genomic scales (from hotspots to whole genomes) and temporal scales (from thousands to millions of years). To identify cellular processes involved in the evolution of recombination, we will integrate high-resolution, sex-specific positioning of crossovers with cellular profiling of key meiotic phenotypes. This research direction will unveil mechanisms that drive the evolution of a primary determinant of genetic variation.

These distinct themes of research showcase a program that exploits the power of genetics and genomics in house mice to address fundamental evolutionary questions with breadth and depth. Beyond their evolutionary significance, the traits of interest are connected to common human diseases. Defects in recombination are the leading genetic cause of birth defects, body size is related to the metabolic syndrome, and exploratory activity is associated with neurological disorders. Our research offers potential to illuminate these conditions by deciphering natural variation in the premier genetic model organism for human disease.

University Of Wisconsin System

THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES (NIGMS) SUPPORTS BASIC RESEARCH THAT INCREASES OUR UNDERSTANDING OF BIOLOGICAL PROCESSES AND LAYS THE FOUNDATION FOR ADVANCES IN DISEASE DIAGNOSIS, TREATMENT, AND PREVENTION. NIGMS ALSO SUPPORTS RESEARCH IN SPECIFIC CLINICAL AREAS THAT AFFECT MULTIPLE ORGAN SYSTEMS: ANESTHESIOLOGY AND PERI-OPERATIVE PAIN, CLINICAL PHARMACOLOGY ?COMMON TO MULTIPLE DRUGS AND TREATMENTS, AND INJURY, CRITICAL ILLNESS, SEPSIS, AND WOUND HEALING.? NIGMS-FUNDED SCIENTISTS INVESTIGATE HOW LIVING SYSTEMS WORK AT A RANGE OF LEVELSFROM MOLECULES AND CELLS TO TISSUES AND ORGANSIN RESEARCH ORGANISMS, HUMANS, AND POPULATIONS. ADDITIONALLY, TO ENSURE THE VITALITY AND CONTINUED PRODUCTIVITY OF THE RESEARCH ENTERPRISE, NIGMS PROVIDES LEADERSHIP IN SUPPORTING THE TRAINING OF THE NEXT GENERATION OF SCIENTISTS, ENHANCING THE DIVERSITY OF THE SCIENTIFIC WORKFORCE, AND DEVELOPING RESEARCH CAPACITY THROUGHOUT THE COUNTRY.

93.859 - Biomedical Research and Research Training

National Institute of General Medical Sciences (NIGMS) [HHS - NIH]

Madison, Wisconsin 53715 United States

Single Zip Code

Maximizing Investigators' Research Award (R35 - Clinical Trial Optional) (PAR-19-367)

Amendment Since initial award the total obligations have increased 400% from $970,385 to $4,854,981.