Mouse fitness measures reveal incomplete functional redundancy of Hox paralogous group 1 proteins

Abstract

Here we assess the fitness consequences of the replacement of the Hoxa1 coding region with its paralog Hoxb1 in mice (Mus musculus) residing in semi-natural enclosures. Previously, this Hoxa1B1 swap was reported as resulting in no discernible embryonic or physiological phenotype (i.e., functionally redundant), despite the 51% amino acid sequence differences between these two Hox proteins. Within heterozygous breeding cages no differences in litter size nor deviations from Mendelian genotypic expectations were observed in the outbred progeny; however, within semi-natural population enclosures mice homozygous for the Hoxa1B1 swap were out-reproduced by controls resulting in the mutant allele being only 87.5% as frequent as the control in offspring born within enclosures. Specifically, Hoxa1B1 founders produced only 77.9% as many offspring relative to controls, as measured by homozygous pups, and a 22.1% deficiency of heterozygous offspring was also observed. These data suggest that Hoxa1 and Hoxb1 have diverged in function through either sub- or neo-functionalization and that the HoxA1 and HoxB1 proteins are not mutually interchangeable when expressed from the Hoxa1 locus. The fitness assays conducted under naturalistic conditions in this study have provided an ultimate-level assessment of the postulated equivalence of competing alleles. Characterization of these differences has provided greater understanding of the forces shaping the maintenance and diversifications of Hox genes as well as other paralogous genes. This fitness assay approach can be applied to any genetic manipulation and often provides the most sensitive way to detect functional differences.

A six-amino-acid motif is a major determinant in functional evolution of HOX1 proteins

“…The occupancy of HOXB1 and HOXA1 correlates with downstream target genes involved in different biological processes (Supplemental Fig. S5) and functional differences in their roles in mouse development and fitness (Tvrdik and Capecchi 2006;Ruff et al 2017). These observations suggest neofunctionalization of HOXB1 and HOXD1 during the duplication and divergence of HOX1 genes in evolution of vertebrates.…”

What happens when lab animals go wild

“…So the pair teamed up with Potts and discovered that in the barn males with this genetic manipulation produced 64% as many offspring as controls (13). Replacing Hoxa1 with Hoxb1 had similar effects (14).…”