Little impact of new mutations on mammalian trait variation

Abstract

New mutations provide the source of all genetic variation but their impact on trait variation remains poorly understood. A new study published in PLOS Biology addresses this question, finding that new mutations exert only weak effects on some traits in mice.

Fig 1. Schematic of a mutation accumulation experiment in a sexually reproducing species.

Mutation accumulation (MA) provides an experimental framework for assessing mutation rates and the effects of new mutations on traits of interest. MA experiments typically initiate from a single founder pair of genetically identical individuals. This aspect of experimental design ensures that differences between replicate MA lines reflect the impacts of new mutations, rather than inherited variation. Independent MA lines are maintained for a large number of generations through strict sib-sib mating, minimizing the ability of natural selection to act on new mutations. With the exception of mutations associated with inviability or sterility, accumulated mutations therefore provide a read-out of the underlying spectrum of new mutations in a genome, independent of selection. Comparisons across replicate MA lines expose the variability of mutation accumulation across independent evolutionary trials and the amount of variation for surveyed traits that arises from new mutations at each generation. Equally important to the MA lines themselves are the control lines, which provide a baseline for the expected level of phenotype variation in the absence of accumulated mutations. Controls can be derived by freezing embryos from experimental founders and reviving them contemporaneously with the final generations of the MA experiment. Given the limited number of elapsed generations, any trait differences between experiment founders and control lines can be ascribed to factors other than new mutations, including changes in environment, epigenome, or microbiome. The schematic employs standard pedigree nomenclature, with circles indicating females and squares denoting males. The accumulation of independent mutations along each example lineage introduces phenotypic variation across lines, as illustrated by different fill colors.