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April 25, 2004

Gene controlling brain size

Got a forward about this article, Reconstructing the evolutionary history of Microcephalin, a gene controlling human brain size. Abstract & excerpts below.

Reconstructing the evolutionary history of Microcephalin, a gene controlling human brain size.

Evans PD, Anderson JR, Vallender EJ, Choi SS, Lahn BT.

Howard Hughes Medical Institute, Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA; Committee on Genetics, University of Chicago, Chicago, IL 60637, USA.

The defining process in the evolution of primates and particularly humans is the dramatic expansion of the brain. While many types of genes could potentially contribute to this process, genes that specifically regulate brain size during development may be especially relevant. Here, we examine the evolution of the Microcephalin gene, whose null mutation in humans causes primary microcephaly, a congenital defect characterized by severe reductions in brain size without other gross abnormalities. We show that the evolution of Microcephalin's protein sequence is highly accelerated throughout the lineage from simian ancestors to humans and chimpanzees, with the most pronounced acceleration seen in the early periods of this lineage. We further demonstrate that this accelerated evolution is coupled with signatures of positive selection. Statistical analysis suggests that about 45 advantageous amino acid changes in Microcephalin might have fixed during the 25-30 million years of evolution from early simian progenitors to modern humans. These observations support the notion that the molecular evolution of Microcephalin may have contributed to brain expansion in the simian lineage leading to humans. We have recently shown that ASPM, another gene linked to primary microcephaly, experienced strong positive selection in the ape lineage leading to humans. We therefore propose that genes regulating brain size during development may have the general propensity to contribute to brain evolution in primates and particularly humans.

excerpts:

"The human microcephalin gene spans 14 exons and has a deduced protein-coding region of roughly 2.5 kb (21). It contains three so-called BRCA1 C-terminal (BRCT) domains, one at its N-terminus and two at its C-terminus. This domain is found in the tumor suppressor gene BRCA1 as well as multiple other eukaryotic genes, and is implicated in protein-protein and protein-DNA interactions. Apart from the BRCT domains, however, the biochemical function of microcephalin is unknown. Expression of microcephalin is found in a variety of human and mouse tissues (21). The most prominent is found in the developing forebrain, within regions of active neurogenesis ( i.e. the walls of lateral telencephalic ventricles). Such an expression pattern is consistent with the role of this gene in regulating brain size during development. (21) "

"Curiously, the BRCA1 gene has been shown to exhibit signatures of positive selection in the human and chimpanzees lineages after they diverged from each other (37,38) It may be a mere coincidence that both Microcephalin and BRCA1 - which share the BRCT domains in common - are subject to positive selection during primate evolution. Indeed, the BRCT domains in both genes are highly conserved and are themselves not subject to positive selection. However, it is also possible that Microcephalin and BRCA1 have similar functions in regulating cell cycle and are therefore subject to similar regimes of positive selection. Consistent with this possibility, BRCA! knockout mice show profound defects in nervous system development such as failure of neural tube closure and severely retarded growth of the forebrain. These results indicate that BRCA1, like Microcephalin, has a critical function in the proliferation and differentiation of neural progenitor cells (39), raising the possibility that positive selection on BRCA1 was actually directed towards its activity in brain development rather than its function in tumor suppression. "

Posted by razib at 09:15 PM