Abstract
Mouse genetics is a powerful approach for discovering genes and other genome features influencing human pain sensitivity. Genetic mapping studies have historically been limited by low mapping resolution of conventional mouse crosses, resulting in pain-related quantitative trait loci (QTL) spanning several megabases and containing hundreds of candidate genes. The recently developed Diversity Outbred (DO) population is derived from the same eight inbred founder strains as the Collaborative Cross, including three wild-derived strains. DO mice offer increased genetic heterozygosity and allelic diversity compared to crosses involving standard mouse strains. The high rate of recombinatorial precision afforded by DO mice makes them an ideal resource for high-resolution genetic mapping, allowing the circumvention of costly fine-mapping studies. We utilized a cohort of ~300 DO mice to map a 3.8 Mbp QTL on chromosome 8 associated with acute thermal pain sensitivity, which we have tentatively named Tpnr6. We used haplotype block partitioning to narrow Tpnr6 to a width of ~230 Kbp, reducing the number of putative candidate genes from 44 to 3. The plausibility of each candidate gene’s role in pain response was assessed using an integrative bioinformatics approach, combining data related to protein domain, biological annotation, gene expression pattern, and protein functional interaction. Our results reveal a novel, putative role for the protein-coding gene, Hydin, in thermal pain response, possibly through the gene’s role in ciliary motility in the choroid plexus–cerebrospinal fluid system of the brain. Real-time quantitative-PCR analysis showed no expression differences in Hydin transcript levels between pain-sensitive and pain-resistant mice, suggesting that Hydin may influence hot-plate behavior through other biological mechanisms.
Highlights
Human pain sensitivity varies widely between individuals, and the significant influence of genetic factors on pain sensitivity is widely appreciated (Mogil et al 1999a)
We have presented here the first application of Diversity Outbred (DO) mice to pain genetics research
The ability to map a 3.8 Mbp quantitative trait loci (QTL) is a marked improvement over conventional two-strain mapping cross studies, which typically result in pain-related confidence intervals of *30 Mbp
Summary
Human pain sensitivity varies widely between individuals, and the significant influence of genetic factors on pain sensitivity is widely appreciated (Mogil et al 1999a). A genetic understanding of variability in pain sensitivity is essential to developing improved prevention and treatment methods for both acute and chronic pain. The application of complex trait analysis to human pain genetics research has facilitated the discovery of genes that underlie variability in pain sensitivity and analgesic response (Chou et al 2006; Compton et al 2003; Diatchenko et al 2005, 2006; Fillingim et al 2005; Indo et al 1996; Janicki et al 2006; Klepstad et al 2004; Nackley et al 2006; Poulsen et al 1996; Rakvag et al 2005; ReyesGibby et al 2007; Sindrup et al 1990; Tsao et al 2011; Zubieta et al 2003).
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