title: Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice.
abstract: Gene targeting techniques have led to the phenotypic characterization of numerous genes; however, many genes show minimal to no phenotypic consequences when disrupted, despite many having highly conserved sequences. The standard explanation for these findings is functional redundancy. A competing hypothesis is that these genes have important ecological functions in natural environments that are not needed under laboratory settings. Here we discriminate between these hypotheses by competing mice (Mus musculus) whose Hoxb1 gene has been replaced by Hoxa1, its highly conserved paralog, against matched wild-type controls in seminatural enclosures. This Hoxb1(A1) swap was reported as a genetic manipulation resulting in no discernible embryonic or physiological phenotype under standard laboratory tests. We observed a transient decline in first litter size for Hoxb1(A1) homozygous mice in breeding cages, but their fitness was consistently and more dramatically reduced when competing against controls within seminatural populations. Specifically, males homozygous for the Hoxb1(A1) swap acquired 10.6% fewer territories and the frequency of the Hoxb1(A1) allele decreased from 0.500 in population founders to 0.419 in their offspring. The decrease in Hoxb1(A1) frequency corresponded with a deficiency of both Hoxb1(A1) homozygous and heterozygous offspring. These data suggest that Hoxb1 and Hoxa1 are more phenotypically divergent than previously reported and support that sub- and/or neofunctionalization has occurred in these paralogous genes leading to a divergence of gene function and incomplete redundancy. Furthermore, this study highlights the importance of obtaining fitness measures of mutants in ecologically relevant conditions to better understand gene function and evolution.
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah 84112.
authors.forename: James S
authors.initials: JS
authors.lastname: Ruff
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Raed B
authors.initials: RB
authors.lastname: Saffarini
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Leda L
authors.initials: LL
authors.lastname: Ramoz
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Morrison
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Shambralyn
authors.initials: S
authors.lastname: Baker
authors.affiliation: Department of Mathematics and Statistics, University of Central Oklahoma, Edmond, Oklahoma 73034.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Laverty
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Petr
authors.initials: P
authors.lastname: Tvrdik
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah 84112 Potts@biology.utah.edu.
authors.forename: Wayne K
authors.initials: WK
authors.lastname: Potts
mesh_terms: D000483:Alleles; D000818:Animals; D005786:Gene Expression Regulation; D018390:Gene Targeting / Q000379:methods; D056084:Genetic Fitness; D005838:Genotype; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006720:Homozygote; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C101121:HOXB1 homeodomain protein
keywords: Hoxa1; Hoxb1; fitness assay; functional redundancy; intraspecific competition; subfunctionalization