The mammalian brain has undergone significant expansion in its evolution to man, and is over 3 times bigger than our closest primate relatives (1). The longterm research interests of the Jackson laboratory are in brain size. Head circumference is highly correlated with brain size, and is used clinically as a proxy measurement for brain volume. To date our major work has been in the identification and functional analysis of genes causing marked reduction in head circumference/brain size (Primary Microcephaly/Seckel syndrome,ref. 2-6). Several genes have been identified, all of which have centrosomal functions (6-8). Two of these, ASPM and MCPH1 have been found to undergo significant adaptive evolution in primates (9,10). However, to date, variants in these genes have not been found to be associated with normal population variation in head circumference/brain size (11).

Following on from the identification of Mendelian genes for these disorders of extreme reduction in head circumference (-4 to -10sd), it is now of interest to identify the factors responsible for variation in head circumference and brain size in the general population.

Within the Human Genetics Unit, head circumference has been measured as a QTL in ongoing GWAS studies in Croatia and Orkneys. To increase the power of these studies we now plan to perform metaanalyses in conjunction with other cohorts to identify SNPs associated with determining head circumference in the general population. The ALSPAC cohort provides an ideal cohort to combine with our studies, particularly given that genotyping has been performed on the same 317 platform, and the availability of a larger cohort for replication/confirmation, of positive hits. (If required, such validation work through genotyping of candidate SNPs would be performed by Nic Timpson on the ALSPAC cohort for within cohort replication/confirmation)

Once identified, and validated, such genes contributing to variation in head cirucmference, will be functionally characterised at the cellular level and in model organisms, using approaches already established in ongoing work in the lab to characterise the MCPH1 and PCNT genes. Such work, will address whether such variants are acting in developmental pathways already implicated by mendelian genetics in brain size determination.

1. Ponting, C. & Jackson, A.P. Evolution of primary microcephaly genes and the enlargement of primate brains. Curr Opin Genet Dev 15, 241-8 (2005).

2. Griffith, E. et al. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet 40, 232-6 (2008).

3. Brunk, K. et al. Microcephalin coordinates mitosis in the syncytial Drosophila embryo. J Cell Sci 120, 3578-88 (2007).

4. Alderton, G.K. et al. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Nat Cell Biol 8, 725-33 (2006).

5. Trimborn, M. et al. Mutations in Microcephalin Cause Aberrant Regulation of Chromosome Condensation. Am J Hum Genet 75, 261-266 (2004).

6. Jackson, A.P. et al. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71, 136-42 (2002).

7. Bond, J. et al. Protein-Truncating Mutations in ASPM Cause Variable Reduction in Brain Size. Am J Hum Genet 73, 1170-7 (2003).

8. Bond, J. et al. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 37, 353-5 (2005).

9. Evans, P.D. et al. Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 13, 489-94 (2004).

10. Evans, P.D., Anderson, J.R., Vallender, E.J., Choi, S.S. & Lahn, B.T. Reconstructing the evolutionary history of microcephalin, a gene controlling human brain size. Hum Mol Genet 13, 1139-45 (2004).

11. Timpson, N., Heron, J., Smith, G.D. & Enard, W. Comment on papers by Evans et al. and Mekel-Bobrov et al. on Evidence for Positive Selection of MCPH1 and ASPM. Science 317, 1036; author reply 1036 (2007).