Individual odortypes: interaction of MHC and background genes

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.