SSADH Variation in Primates: Intra- and Interspecific Data on a Gene with a Potential Role in Human Cognitive Functions

Abstract

Abstract. In the present study we focus on the nucleotide and the inferred amino acid variation occurring in humans and other primate species for mitochondrial NAD + -dependent succinic semialdehyde dehydrogenase, a gene recently supposed to contribute to cognitive performance in humans. We determined 2527 bp of coding, intronic, and flanking sequences from chimpanzee, bonobo, gorilla, orangutan, gibbon, and macaque. We also resequenced the entire coding sequence on 39 independent chromosomes from Italian families. Four variable coding sites were genotyped in additional populations from Europe, Africa, and Asia. A test for constancy of the nonsynonymous vs. synonymous rates of nucleotide changes revealed that primates are characterized by largely variable d N /d S ratios. On a background of strong conservation, probably controlled by selective constraints, the lineage leading to humans showed a ratio increased to 0.42. Human polymorphic levels fall in the range reported for other genes, with a pattern of frequency and haplotype structure strongly suggestive of nonneutrality. The comparison with the primate sequences allowed inferring the ancestral state at all variable positions, suggesting that the c.538(C) allele and the associated functional variant is indeed a derived state that is proceeding to fixation. The unexpected pattern of human polymorphism compared to interspecific findings outlines the possibility of a recent positive selection on some variants relevant to new cognitive capabilities unique to humans.

A human derived SSADH coding variant is replacing the ancestral allele shared with primates

“…In the first one, SSADH exon 3 was amplified with specific primers (Blasi et al 2002), spotted on nylon membranes and hybridized with 32-P labelled ASO probes as described (Blasi et al 2006).…”

“…The complete dataset consists of the Human Genome Diversity Project (HGDP) Panel (Cann et al 2002) with 147 subjects already reported by Blasi et al (2006); 218 newly typed Italian, UK and Nigerian subjects; and 101 subjects from six populations reported here for the first time (Table I). The total amounts to 1574 individuals representing 60 populations from the five continents.…”

“…c.545 C > T and c.538 T > C. In particular, the latter causes the replacement of a tyrosine residue conserved in primates and rodents with a histidine never observed in other eukaryotes. We hypothesized that the high frequencies of c.538C are the result of positive selection (Blasi et al 2006). …”

Cognitive Functioning and Survival in the Elderly: The SSADH C538T Polymorphism

“…1). It is worth noticing that we cannot rule out the possibility that the T allele is not directly responsible of the observed phenomena but in Linkage Disequilibrium with other activity-altering SNPs, especially considering the high proportion of Non Synonymous changes characterizing this human gene (Blasi et al 2006). …”

Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ‐hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1−/− mice and characterization of γ‐hydroxybutyric acid pharmacology

“…In Aldh5a1 j/j mice the heterozygous animals are apparently normal (Gibson et al 2002. Comparative studies on polymorphisms between humans and baboons suggest a putative role for the SSADH gene in the evolution of cognitive capabilities unique to humans (Blasi et al 2006).…”