Class 1 and 11 gene products of the major histocompatibility complex (MHC) present foreign antigens to T-lymphocytes and are thus essential components of the immune response. These genes are also the most polymorphic loci known for vertebrates. It has generally been assumed that the maintenance of this unprecedented genetic diversity is due to the selective forces created by the diverse group of pathogens and parasites that are endemic to each species. However, the failure of one of the most critical predictions, that susceptibility to specific infectious diseases should correlate with certain MHC alleles, has created confusion. A wide variety of data indicate that these polymorphisms are maintained in natural populations by some form of strong balancing selection. Although many selective mechanisms have been postulated to contribute to the maintenance of these polymorphisms, little progress has been made towards identifying which mechanisms actually operate on MHC genes in natural populations. We propose to measure directly the selective mechanisms that maintain MHC diversity by analyzing fitness components in a captive wild mouse population. This population level approach allows the testing of hypotheses that could never be tested in the laboratory (e.g. frequency dependent hypotheses) and will directly answer the fundamental question of how MHC polymorphisms affect the fitness of individuals. The following fitness components will be examined. The influence of MHC genotypes on differential mortality and reproductive success will be measured. These data will allow testing of numerous disease based hypotheses such as heterozygote advantage and frequency dependent selection. Mating preferences within the enclosure will be determined through observations and paternity exclusion techniques (e.g. genetic fingerprinting). Mating preferences will also be tested in the laboratory, which will allow control of confounding variables inherent in natural social systems. Transmission distortion favoring MHC heterozygotes will be tested by checking informative laboratory matings for deviations from Mendelian expectations at birth. Population genetics models indicate that the maintenance of MHC polymorphisms requires relatively extreme levels of selection, operating either on survival or reproductive traits. Our ignorance concerning the mode of this selection is a major gap in our understanding of how pathogens and the vertebrate immune system interact.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039578-07
Application #
2179932
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1989-01-01
Project End
1996-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Ruff, James S; Saffarini, Raed B; Ramoz, Leda L et al. (2017) Mouse fitness measures reveal incomplete functional redundancy of Hox paralogous group 1 proteins. PLoS One 12:e0174975
Ruff, James S; Hugentobler, Sara A; Suchy, Amanda K et al. (2015) Compared to sucrose, previous consumption of fructose and glucose monosaccharides reduces survival and fitness of female mice. J Nutr 145:434-41
Ruff, James S; Saffarini, Raed B; Ramoz, Leda L et al. (2015) Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice. Genetics 201:727-36
Nelson, Adam C; Cauceglia, Joseph W; Merkley, Seth D et al. (2013) Reintroducing domesticated wild mice to sociality induces adaptive transgenerational effects on MUP expression. Proc Natl Acad Sci U S A 110:19848-53
Ruff, James S; Suchy, Amanda K; Hugentobler, Sara A et al. (2013) Human-relevant levels of added sugar consumption increase female mortality and lower male fitness in mice. Nat Commun 4:2245
Nelson, Adam C; Colson, Kevin E; Harmon, Steve et al. (2013) Rapid adaptation to mammalian sociality via sexually selected traits. BMC Evol Biol 13:81
Cunningham, Christopher B; Ruff, James S; Chase, Kevin et al. (2013) Competitive ability in male house mice (Mus musculus): genetic influences. Behav Genet 43:151-60
Kubinak, J L; Ruff, J S; Cornwall, D H et al. (2013) Experimental viral evolution reveals major histocompatibility complex polymorphisms as the primary host factors controlling pathogen adaptation and virulence. Genes Immun 14:365-72