title: 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.
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: James S
authors.identifier: http://orcid.org/0000-0002-8292-8640
authors.initials: JS
authors.lastname: Ruff
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Raed B
authors.initials: RB
authors.lastname: Saffarini
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Leda L
authors.initials: LL
authors.lastname: Ramoz
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Morrison
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Shambralyn
authors.initials: S
authors.lastname: Baker
authors.affiliation: Department of Mathematics and Statistics, University of Central Oklahoma, Edmond, Oklahoma, United States of America.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Laverty
authors.affiliation: Department of Neurosurgery, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Petr
authors.initials: P
authors.lastname: Tvrdik
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Wayne K
authors.initials: WK
authors.lastname: Potts
mesh_terms: D000483:Alleles; D000818:Animals; D001947:Breeding; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D056084:Genetic Fitness / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C101121:HOXB1 homeodomain protein