Population Genetic Analysis of the N-Acylsphingosine Amidohydrolase Gene Associated With Mental Activity in Humans

Abstract

To understand the evolution of human mental activity, we performed population genetic analyses of nucleotide sequences ($11 kb) from a worldwide 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, two distinct lineages (V and M) have been segregating in the human population for 2.4 6 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 (p ¼ 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. On the basis of the above observations, it is argued that positive selection is possibly operating on ASAH1 in the modern human population.

Long-Standing Balancing Selection in theTHBS4Gene: Influence on Sex-Specific Brain Expression and Gray Matter Volumes in Alzheimer Disease

“…Nonetheless, introgression and selection are not mutually exclusive, as a haplotype introduced by admixture may have higher chances to be detected in modern populations when subjected to a selective event (that opposes its chances of being lost by drift). This has been shown to be the case for other genes involved in brain development, such as MCPH1 and ASAH1 [Evans et al, ; Kim and Satta, ].…”

Genetic Structure in African Populations: Implications for Human Demographic History

“…This approach has been used in a variety of studies during the past decade (Harris and Hey 1999; Jaruzelska et al 1999; Yu et al 2002; Barreiro et al 2005; Hayakawa et al 2006; Yotova et al 2007). To provide statistical evidence of population structure, some authors have also tested assumptions of panmixia directly using customdesigned coalescent simulations (Garrigan et al 2005a; Kim and Satta 2008). In particular, Kim and Satta (2008) tested 22 sets of demographic parameters to examine models of panmixia, bottlenecks, expansions, and population structure (both ancient and recent) for an 11kb region of the ASAH gene and found that a model of ancient structure in Africa best explained their data.…”

Complex Haplotypes of GSTM1 Gene Deletions Harbor Signatures of a Selective Sweep in East Asian Populations

“…In parallel to the allele frequency based analyses described above, we conducted tests based on haplotype similarity. We first followed the reasoning outlined by Kim and Satta ( Kim and Satta 2008 ). Briefly, if a recent sweep indeed increased the allele frequency of a particular existing haplotype group, we expect that the nucleotide diversity would decrease among the haplotypes that were sweeped, but not the others.…”