The Genetics of Encephalization in Eight Inbred Mouse Strains and their F1 Crosses

Abstract

Increased relative brain size (encephalization) is an important feature of primate and human evolution that has been associated with increased intelligence. Although the heritability of brain size is known to be high, the extent to which different genetic factor types (e.g., additive genotype, maternal genotype, sex, nonadditive genetic interactions) contribute to measured brain size and encephalization are not as well understood. Endocast measures from a large normative sample of genetically diverse mouse lines were estimated to quantify 1) how increased encephalization impacts neurocranial shape and 2) the contribution of various genetic factors towards determining encephalization. Digital endocasts were estimated for 1182 mice representing the eight Collaborative Cross mouse inbred founder lines and 62 reciprocal F1 crosses. Endocasts were estimated by applying a single atlas image endocast segmentation to micro‐computed tomography (μCT) images of each specimen’s skull, based on the nonlinear volumetric image registration of each μCT to the representative atlas image. This method was validated by comparison of automatically extracted endocasts to endocasts that were manually segmented (using Endex software) for a large subset of the specimens. Measures of endocast volume, length, width, and height represent different aspects of endocast size. Ratios of volume over cranial base length (IRE) and volume over body weight (V2W) represent encephalization relative to cranial size and body size, respectively. Diallel analysis (BayesDiallel in R) was used to estimate the genetic influence of multiple additive and nonadditive genetic factors on each measure. The total heritability of each size and encephalization measure is between 0.82 and 0.87, with additive founder strain genotype effects accounting for the vast majority of this heritability. There are also significant inbreeding, sex, maternal genotype, and founder strain cross‐specific effects. The additive effects of founder genotypes were more pronounced for V2W than for IRE, with some of the strains showing opposite directions of effect between these encephalization measures. Care must be taken in the measure of overall size used to estimate encephalization. While inbred mice tend to have smaller overall size, they tend to have a higher encephalization, likely because the impact of inbreeding on brain volume is not as severe as the impact on skull size or body weight. In addition to the strength of genotypic effects, we quantified the influence of increased encephalization on overall cranial vault shape. As encephalization increases, endocasts display more substantial increases in cranial vault height than either length or width. Variation in the mouse cranial base size appears limited, while the shape of later ossifying vault bones strongly covaries with relative brain size. These results support the conclusion that encephalization is highly heritable and indicate which types of genetic factors contribute most strongly. Additionally, relatively large mouse brains are accommodated primarily through variation in cranial vault height, leading to a round cranial vault shape that is analogous to globular vault of modern humans.Support or Funding InformationFinancial support provided by Stony Brook University Startup Funds to CJP