WAYNE POTTS

4. Organismal Performance Assays (OPAs) provide sensitive assessment of health degradation from genetic and other treatments. To determine the fitness consequences of inbreeding, we conducted one generation of full-sib inbreeding on wild-caught mice and then competed these mice against outbred control mice in our seminatural populations. Assessment of inbreeding had been done several times before in Mus and all of these studies had found about a 10% decline in reproductive output as measured by litter size. The surviving offspring from the full-sib matings lived as long and reproduced as well in cages as the outbred controls so it was concluded that this 10% decline in reproductive success represented the major negative consequence of a full-sib inbreeding. We observed the same 10% reduction in litter size from full-sib matings, but then we competed these offspring against outbred offspring in semi-natural enclosures. We detected an additional 500% effect; outbred males had 5 times more offspring than inbred males. We have demonstrated that this system is sensitive due to the never-ending competition over resources. Individuals that are slightly less healthy lose these competitions and their survival and reproductive success is diminished. We now call this methodology Organismal Performance Assays (OPAs) and have applied it to a variety of genetic manipulations and toxicity assessment of nutritional substances and pharmaceuticals. We have patented this approach for “toxicity” assessment (US Patent 8,304,208; 2012) and believe it has great potential for protecting public health by identifying unknown toxicants. We were the first to show adverse health consequences to both dietary sugar at human relevant levels and to two pharmaceuticals that ultimately caused health problems after public release. We have recently demonstrated health problems from the replacement of one Hox gene with a Hox paralog; the original study reported that these mice were phenotypically normal. We envision OPAs as a major new tool to detect toxicities of a variety of treatments relevant to public health. We have patented OPAs for this type of use and have been pursuing these avenues with the University of Utah Technology Commercialization group.

a.     2000 Meagher S., D.J. Penn, and W.K. Potts, Male-male competition magnifies inbreeding depression in wild house mice. Proc. Nat. Acad. Sci. 97:3324-3329. PMCID: PMC16238

b.     2015 Gaukler, S.M., J.S. Ruff, T. Galland, K.A. Kandaris, T.K. Underwood, N.M. Liu, E.L. Young, L.C. Morrison, G.S. Yost, W.K. Potts. Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay.  Neurotoxicology and teratology. 47:46-53. PMCID: PMC4416947

c.     2013 Ruff, J.S., Suchy, A.K., Hugentobler, S.A., Sosa, M.M., Schwartz, B.L., Morrison, L.C., Gieng, S.H., Shigenaga, M.K. & Potts, W.K. Human-relevant levels of added sugar consumption increase female mortality and lower male fitness in mice. Nat Commun. 4:2245. PMCID: PMC3775329

d.     2015 Ruff, J.S., Saffarini, R.B., Ramoz, L.L., Morrison, L.C., Baker, S., Laverty, S.M., Tvrdik, P. & Potts, W.K. Fitness assays reveal incomplete functional redundancy of the HoxA1 and HoxB1 paralogs of mice. Genet. 201: 727-736. PMCID: PMC4596679

5. Epigenetic transgenerational inheritance of high cost social pheromones. Parents exposed to our semi-natural populations produce sons that realize 40% higher reproductive success than sons from parents breeding in conventional housing; this is despite the fact that neither type of offspring had experienced semi-natural conditions prior to founding and competing under semi-natural conditions. We have shown that offspring with semi-natural ancestry produce higher levels of MUPs (major urinary proteins), which are excreted in mg/ml quantities of urine. These high cost MUPs act as social signals in territory formation and mate attraction. We demonstrated that this MUP upregulation is associated with demethylation of a MUP promoter region. We also demonstrated that expression levels of a particular MUP predict winners of social dominance (as does body mass and locomotor economy).

a.     2013 Nelson, A.C., K.E. Colson, S. Harmon, W.K. Potts. The role of sexual selection during rapid adaptation to a socially competitive environment. BMC Evolutionary Biology. 13:81-95. doi: 10.1186/1471-2148-13-81.

b.     2013 Nelson, A.C., J. W. Cauceglia, S.D. Merkley, N.A. Youngson, A.J. Oler, R.J. Nelson, B.R. Cairns, E. Whitelaw, W.K. Potts. Reintroducing domesticated wild mice to sociality induces adaptive transgenerational effects on MUP expression. Proceedings of the National Academy of Sciences USA. 110:19848–19853. PMCID: PMC3856842

c.     2015 Nelson, A.C, C. Cunningham, J.S. Ruff, W.K. Potts. Protein pheromone expression levels predict and respond to the formation of social dominance networks. Journal of Evolutionary Biology. 28: 1213–1224. PMCID: PMC4478133

d.     2017 Ruff, J.S., Cornwall, D.H, Morrison, L.C., Cauceglia, J.W., Nelson, A.C., Gaukler, S.M, Meagher, S.M., Carroll, L.S., and Potts, W.K. Sexual selection constrains the body mass of male but not female mice Ecol Evol. 7: 1271-1275. PMCID: PMC5306010 (Cover photo article, Feb. issue)

6. Transmission of malaria from asymptomatic individuals in mice and men

Malaria kills 600,000 individuals per year, most of which are children under five years of age. Malarial disease is caused by transmission of Plasmodium parasites and transmitted to humans through the bite of infected Anopheles mosquitoes. Transmission by asymptomatic carriers plays a major role in the dynamics of many pathogens ranging from SARS-CoV-2 to malaria. The majority of the population in many malaria endemic areas (>60%) are asymptomatic (without overt symptoms), even in high transmission areas. Progress has been hindered by the lack of an animal model. We have recently developed the first animal model that allows us to experimentally test a myriad of hypothesis associated with asymptomatic malaria. In collaboration with Tracey Lamb (Department of Pathology), we currently have two major federal grant proposals under review aimed at tackling these problems.