Individual odortypes: interaction of MHC and background genes

Abstract

Genes of the major histocompatibility complex (MHC) influence the urinary odors of mice. Behavioral studies have shown (1) that mice differing only at MHC have distinct urinary odors, suggesting an MHC odor phenotype or odortype; (2) that the MHC odortype can be recognized across different background strains; and (3) that the MHC odortype is not an additive trait. Very little is known about the odorants underlying this behavioral phenotype. We compared urinary volatile profiles of two MHC haplotypes (H2(b) and H2(k)) and their heterozygous cross (H2(b) x H2(k)) for two different background strains (C57BL/6J and BALB/c) using solid phase micro-extraction (SPME) headspace analysis and gas chromatography/mass spectrometry (GC/MS). Both MHC and background genes substantially influence the volatile profile. Of 148 compounds screened, 108 of them significantly differ between the six genotypes. Surprisingly, for numerous compounds, their MHC associations are moderated by background genes (i.e., there is a significant MHC x background interaction effect in the statistical model relating genotype to relative compound concentration). These interactions account for nearly 30% of the total genetic effect on the volatile profile. MHC heterozygosity further extends the odortype diversity. For many compounds, the volatile expression for the heterozygote is more extreme than the expression for either homozygote, suggesting a heterozygous-specific odortype. The remarkable breadth of effects of MHC variation on concentrations of metabolites and the interaction between MHC and other genetic variation implies the existence of as yet unknown processes by which variation in MHC genes gives rise to variation in volatile molecules in body fluids.

In search of the chemical basis for MHC odourtypes

“…The mode of inheritance was also investigated in the same study (Willse et al 2006) by breeding heterozygous mice carrying two different sets of MHC genes (one set from female parent and the other set from male parent) in the two different background strains. It was not known whether the metabolic phenotypes of MHC heterozygote are an additive trait (an average of the two different MHC groups) or exhibited a different form of inheritance.…”

“…Several compounds (e.g. dimethyl sulphone) that have been reported as MHC-regulated metabolites in later studies (Willse et al 2005(Willse et al , 2006Kwak et al 2008) were previously ignored based on bioassay results of the fraction obtained by anion exchange chromatography, which theoretically captures only negatively charged compounds such as organic acids (Singer et al 1997).…”

“…To evaluate this conjecture, several groups examined the urinary volatile profiles of MHC-congenic mice derived from different background strains (Eggert et al 1996;Willse et al 2006;Novotny et al 2007;Zomer et al 2009). Eggert et al (1996) investigated the urinary volatile metabolic profiles of BALB/c (H2 d ), BALB/k (H2 k ) and C3H (H2 k ) mice.…”

“…No compounds, however, were structurally identified. Willse et al (2006) examined the urinary volatile metabolic profiles of two MHC haplotypes (H2 b and H2 k ) and their heterozygous cross (H2 b  H2 k ) in two different background strains (B6 and BALB/c). Although a large proportion of the background genes are shared between these strains, thereby limiting potential between-strain genetic variability, substantial genetic variation is observed that is mainly derived from the variability in founders from the main wild source, Mus musculus domesticus (Yang et al 2007).…”

“…In an attempt to understand this apparent contradiction, Willse et al (2006) developed a multivariate or combinatorial odour-recognition approach (olfaction is also thought to employ an analogous combinatorial code; reviewed in Johnson & Leon (2007) and references therein). Individual volatile metabolites influenced by the interaction of MHC and background genes, if considered individually, may not underlie MHC odourtype recognition, but they may do so in combination.…”