Organisms with extreme phenotypes provide a special window into the evolutionary process. Compared to their mainland relatives, populations on islands often exhibit exceptional body sizes. Among mammals, insular populations of small-bodied species tend to evolve larger sizes, whereas bigger species tend to get smaller, a phenomenon known as the ?island rule?. This pattern raises the intriguing possibility of a common evolutionary mechanism, but its genetic basis remains mostly uncharacterized. With multiple independent examples of substantial size increase on islands, historical records of colonization, and an expansive genetic toolkit, house mice offer a promising model system for understanding the genetics of the island rule. The largest wild house mice in the world reside on Gough Island, a remote island in the middle of the South Atlantic Ocean. In just a few hundred generations, mice on Gough Island evolved to be twice the size their mainland relatives. During the first funding period of our R01 (?The Genetics and Evolution of Extreme Body Size in Mice from Gough Island?), we identified quantitative trait loci (QTL) ? including anatomically global size regulators ? responsible for this remarkable case of rapid evolution. The proposed research, a renewal of that project, will build strategically on our progress in two directions. First, we will functionally characterize and fine- map QTL for body size in Gough Island mice ? two necessary steps toward identifying the causative genes and mutations. We will use congenic strains to evaluate QTL effects on intermediate phenotypes that play key roles in growth and we will use sub-congenic strains to refine QTL intervals to contain manageable numbers of candidate genes. Second, we will map QTL for extreme body size evolution in a second island population from Papa Westray. By comparing QTL in mice from Papa Westray and Gough Island, we will determine whether independent instances of the island rule share genetic properties. The powerful combination of functionally characterizing individual QTL with comparative mapping of the overall genetic architecture will generate key insights into complex trait evolution and phenotypic convergence in nature. This project will reveal the genetic determinants of a common evolutionary phenomenon. In humans, body size variation is connected to risk for a plethora of common disorders, including cancer, cardiovascular disease, obesity, and diabetes. The proposed research will benefit genetic studies of human disease by developing and characterizing mouse models of naturally occurring size variation. 1

Public Health Relevance

In humans, body size variation is connected to risk for a plethora of common disorders, including cancer, cardiovascular disease, obesity, and diabetes. The proposed research will benefit genetic studies of human disease by developing and characterizing mouse models of naturally occurring size variation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM100426-07
Application #
9647462
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Janes, Daniel E
Project Start
2012-09-10
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Genetics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Dapper, Amy L; Payseur, Bret A (2018) Effects of Demographic History on the Detection of Recombination Hotspots from Linkage Disequilibrium. Mol Biol Evol 35:335-353
Parmenter, Michelle D; Nelson, Jacob P; Weigel, Sara E et al. (2018) Masticatory Apparatus Performance and Functional Morphology in the Extremely Large Mice from Gough Island. Anat Rec (Hoboken) :
Wang, Richard J; Gray, Melissa M; Parmenter, Michelle D et al. (2017) Recombination rate variation in mice from an isolated island. Mol Ecol 26:457-470
Wang, Richard J; Payseur, Bret A (2017) Genetics of Genome-Wide Recombination Rate Evolution in Mice from an Isolated Island. Genetics 206:1841-1852
Gasch, Audrey P; Payseur, Bret A; Pool, John E (2016) The Power of Natural Variation for Model Organism Biology. Trends Genet 32:147-154
Payseur, Bret A; Rieseberg, Loren H (2016) A genomic perspective on hybridization and speciation. Mol Ecol 25:2337-60
Parmenter, Michelle D; Gray, Melissa M; Hogan, Caley A et al. (2016) Genetics of Skeletal Evolution in Unusually Large Mice from Gough Island. Genetics 204:1559-1572
Haasl, Ryan J; Payseur, Bret A (2016) Fifteen years of genomewide scans for selection: trends, lessons and unaddressed genetic sources of complication. Mol Ecol 25:5-23
Payseur, Bret A (2016) Genetic Links between Recombination and Speciation. PLoS Genet 12:e1006066
Gray, Melissa M; Parmenter, Michelle D; Hogan, Caley A et al. (2015) Genetics of Rapid and Extreme Size Evolution in Island Mice. Genetics 201:213-28

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