The variation seen in overall brain size within and among species in relation to the size of different brain parts and of body size has been the focus of a large research effort because these fundamental relations reveal much about the constraints, adaptations and even candidate mechanisms that lead to micro- and macro-evolutionary change1,2,3,4. Several hypotheses based on comparative data have been developed to answer two fundamental questions about brain evolution4,5,6,7,8,9. The first is the degree to which the different functional brain systems evolve independently of each other and the brain as a whole. Under the mosaic evolutionary hypothesis, the size of different systems evolves independently due to differential selective pressures associated with different tasks4,6. In contrast, under a concerted evolutionary paradigm, promoted by Finlay and Darlington1, different regions are constrained or canalized by developmental factors and thus evolve predominantly as a whole. The distinction between these two hypotheses is central to our understanding of brain evolution and our interpretation of the underlying genetic, developmental and ecological mechanisms on which selection is presumed to operate. Comparative analyses of brain size have provided evidence for both hypotheses1,6,10. For example, the seminal data set collated and first analysed by Stephan et al. (for example, ref. 11) on brain and brain part sizes in primates and insectivores has provided the basis for much of the comparative analyses2. However, few studies, in particular in mammals, have investigated the genetic architecture of the brain to address the microevolutionary and genetic underpinnings of brain evolution12.

Mosaic evolution of brain regions predicts that heritable variation in the size of different brain parts should be modulated by independent genetic loci and gene variants, and that phenotypic correlations among different brain parts may be low or absent. In contrast, under concerted evolution overlapping sets of loci should modulate the size of multiple parts of the brain with high levels of positive covariation. Quantitative genetic studies in the cave fish have demonstrated independent loci regulating the evolution of different eye phenotypes and argue in favour of a mosaic model12. A quantitative genetic approach offers the further advantage that the degree of mosaic versus concerted evolution may be inferred by comparing the level of variation explained by loci that are shared across many brain parts versus the level of variation explained by unique loci specific to brain parts. Although macroevolutionary patterns (for example, phylogenetic patterns seen above the species level including the occurrence of higher taxa) arise from microevolutionary mechanisms, that is, changes occurring within species13, it remains unclear whether specific brain parts can respond individually to selective pressure or are constrained in their response imposed by other brain parts or overall brain size.

A second fundamental question is how phylogenetic differences in brain:body ratios have evolved. What are the mechanisms underlying the strong allometry between brain and body? Overall, brain size scales with body size due to linked processes very early during development14. After this initial phase, however, body size increases while brain size remains relatively constant14. Evolutionarily, the large relative brain to body size ratio, especially seen in many vertebrates, could in principle be due to changes in overall brain size or be secondary to changes in body size. It is evident that macroevolutionary trends among major vertebrate taxa have often involved a genuine increase in relative brain size at a constant body size, and that this has been made possible due to major changes in bioenergetics and life history5. However, at a microevolutionary level within species, brain size may be free to change independently of body size, with different genetic loci accounting for variation in the two traits and low phenotypic correlation between them.

Here, we address these two key questions and present results of a 15-year research effort into the genetic architecture of brain and body size using a massive neuro-morphometric data set for ~10,000 mice belonging to a large set of recombinant inbred strains. The BXD family consists of ~100 lines derived from parental strains that differ at ~5 million single-nucleotide polymorphisms (SNPs), indels, transposons and copy-number variants15. This model system harbours naturally occurring genetic variation at a level approximating that of human populations. Our study utilizes a high-density linkage analysis16,17 to map loci modulating phenotypic variation in overall brain size, body size and the size of seven major brain parts: the neocortex, cerebellum, striatum, olfactory bulb, hippocampus, lateral geniculate nucleus and basolateral complex of the amygdala. We scanned the entire genome, except the Y chromosome, using interval mapping as implemented in GeneNetwork (http://www.genenetwork.org17). Mapping relies on a set of 3,800 fully informative SNPs and microsatellite markers. In a second analysis, we scan the genome for all two-way epistatic interactions between loci.