Sex‐specific variability and a ‘cage effect’ independently mask a neuropathic pain quantitative trait locus detected in a whole genome scan

Abstract

Sex and environment may dramatically affect genetic studies, and thus should be carefully considered. Beginning with two inbred mouse strains with contrasting phenotype in the neuroma model of neuropathic pain (autotomy), we established a backcross population on which we conducted a genome-wide scan. The backcross population was partially maintained in small social groups and partially in isolation. The genome scan detected one previously reported quantitative trait locus (QTL) on chromosome 15 (pain1), but no additional QTLs were found. Interestingly, group caging introduced phenotypic noise large enough to completely mask the genetic effect of the chromosome 15 QTL. The reason appears to be that group-caging animals from the low-autotomy strain together with animals from the high-autotomy strain dramatically increases autotomy in the otherwise low-autotomy mice (males or females). The converse, suppression of pain behaviour in the high-autotomy strain when caged with the low-autotomy strain was also observed, but only in females. Even in isolated mice, the genetic effect of the chromosome 15 QTL was significant only in females. To determine why, we evaluated autotomy levels of females in 12 different inbred stains of mice and compared them to previously reported levels for males. Strikingly larger environmental variation was observed in males than in females for this pain phenotype. The high baseline variance in males can explain the difficulty in detecting the genetic effect, which was readily seen in females. Our study emphasizes the importance of sex and environment in the genetic analysis of pain.

Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon

“…A more sophisticated perspective is that sex and genetic background (and their interaction) are both simply components of inter-individual variability that need to be explained. As might be expected given this interaction, genes (quantitative trait loci) with sex-dependent effects on pain trait variability have been uncovered [38][39][40][41][42] . A recent study uncovered a three-way interaction in both mice and humans between sex, genetics (AVPR1A genotype (AVPR1A encodes the vasopressin 1A receptor)) and acute stress 43 .…”

A systematic review of animal models for experimental neuroma

“…65 Furthermore, nerve regeneration is more efficient in females due to hormonal influences 61,63,64 ; Kovavic et al reported a larger number of myelinated axons in the anastomosed nerve segment in females, which could be related to a higher sprouting capacity of thin myelinated sensory axons. 66 Nerve Despite the fact that neuromas and nerve injuries in general are far more common in the upper limb, most of the experimental models are designed on the hindlimb.…”

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2

“…With this in mind, we ran a second experiment in which background autotomy levels were enhanced. Prior studies have shown that the tendency to autotomize is enhanced by social interactions in a group caging paradigm (Devor and Raber 1990;Devor et al 2007). Therefore, in a second, independent F 2 population (47 mice), phenotyping was done in cages containing one or two F 2 animals and one same-sex mouse of a high autotomy strain (C3H/Hen) that was nerve-injured and performed autotomy.…”