Abstract
The molecular, developmental, and evolutionary bases of human brain asymmetry are almost completely unknown. Genetic linkage and association mapping have pin-pointed a gene called LRRTM1 (leucine-rich repeat transmembrane neuronal 1) that may contribute to variability in human handedness. Here I describe how LRRTM1's involvement in handedness was discovered, and also the latest knowledge of its functions in brain development and disease. The association of LRRTM1 with handedness was derived entirely from the paternally inherited gene, and follow-up analysis of gene expression confirmed that LRRTM1 is one of a small number of genes that are imprinted in the human genome, for which the maternally inherited copy is suppressed. The same variation at LRRTM1 that was associated paternally with mixed-/left-handedness was also over-transmitted paternally to schizophrenic patients in a large family study.
LRRTM1 is expressed in specific regions of the developing and adult forebrain by post-mitotic neurons, and the protein may be involved in axonal trafficking. Thus LRRTM1 has a probable role in neurodevelopment, and its association with handedness suggests that one of its functions may be in establishing or consolidating human brain asymmetry.
LRRTM1 is the first gene for which allelic variation has been associated with human handedness. The genetic data also suggest indirectly that the epigenetic regulation of this gene may yet prove more important than DNA sequence variation for influencing brain development and disease.
Intriguingly, the parent-of-origin activity of LRRTM1 suggests that men and women have had conflicting interests in relation to the outcome of lateralized brain development in their offspring.
