Population genetic analysis of N-acylsphingosine amidohydrolase gene associated with mental activity in humans

¹ The Graduate University for Advanced studies
² The Graduate University for Advanced Studies

^* To whom correspondence should be addressed. E-mail: sattayk{at}soken.ac.jp.

Submitted on October 25, 2007
Revised on December 2, 2007
Accepted on 21 December 2007

	Abstract

To understand the evolution of human mental activity, we performed population genetic analyses of nucleotide sequences (~ 11 kb) from a world-wide sample of 60 chromosomes of the N-acylsphingosine amidohydrolase (ASAH1) gene. ASAH1 hydrolyzes ceramides and regulates neuronal development, and its deficiency often results in mental retardation. In the region (~ 4.4 kb) encompassing exons 3 and 4 of this gene, there are two distinct lineages (V and M) that have been segregating in the human population for 2.4 ± 0.4 million years (my). The persistence of these two lineages is attributed to ancient population structure of humans in Africa. However, all haplotypes belonging to the V lineage exhibit strong linkage disequilibrium, a high frequency (62%), and small nucleotide diversity ( = 0.05%). These features indicate a signature of positive Darwinian selection for the V lineage. Compared with the orthologs in mammals and birds, it is only Val at amino acid site 72 that is found exclusively in the V lineage in humans, suggesting that this Val is a likely target of positive selection. Computer simulation confirms that demographic models of modern humans except for the ancient population structure cannot explain the presence of two distinct lineages, and neutrality is incompatible with the observed small genetic variation of the V lineage at ASAH1. Based on the above observations, it is argued that ASAH1 provides unequivocal evidence for positive selection in the modern human population.

Key Words: ASAH1, coalescence time, mental activity, population structure, positive selection