The genetic control of neocortex volume and covariation with neocortical gene expression in mice

The size of the cerebral cortex varies widely within human populations, and a large portion of this variance is modulated by genetic factors. The discovery and characterization of these genes and their variants can contribute to an understanding of individual differences in brain development, behavior, and disease susceptibility. Here we use unbiased stereological techniques to map quantitative trait loci (QTLs) that modulate the volume of neocortex.

We estimated volumes bilaterally in an expanded set of BXD recombinant inbred strains (n = 56 strains and 223 animals) taken from the Mouse Brain Library http://www.mbl.org. We generated matched microarray data for the cerebral cortex in the same large panel of strains and in parental neonates to efficiently nominate and evaluate candidate genes. Volume of the neocortex varies widely, and is a heritable trait. Genome-wide mapping of this trait revealed two QTLs--one on chromosome (Chr) 6 at 88 +/- 5 Mb and another at Chr 11 (41 +/- 8 Mb). We generated both neonatal and adult neocortical gene expression databases using microarray technology. Using these databases in combination with other bioinformatic tools we have identified positional candidates on these QTL intervals.

This study is the first to use the expanded set of BXD strains to map neocortical volume, and we found that normal variation of this trait is, at least in part, genetically modulated. These results provide a baseline from which to assess the genetic contribution to regional variation in neocortical volume, as well as other neuroanatomic phenotypes that may contribute to variation in regional volume, such as proliferation, death, and number and packing density of neurons.