NAT2 gene diversity and its evolutionary trajectory in the Americas.

N-acetyltransferase 2 (NAT2) is responsible for metabolizing xenobiotics; NAT2 polymorphisms lead to three phenotypes: rapid, intermediate and slow acetylators. We aimed to investigate NAT2 diversity in Native Americans. NAT2 exon 2 was sequenced for 286 individuals from 21 populations (Native American and American Mestizos). Excluding the basal/rapid haplotype NAT2*4, the most frequent haplotypes are NAT2*5B (35.95%) in hunter-gatherers and NAT2*7B (20.61%) and NAT2*5B (19.08%) in agriculturalists that were related to the slow phenotype. A new haplotype was identified in two Amerindians. Data from the ~44 kb region surrounding NAT2 in 819 individuals from Africa, East-Asia, Europe and America were used in additional analyses. No significant differences in the acetylator NAT2 haplotype and phenotype distributions were found between Native American populations practicing farming and/or herding and those practicing hunting and gathering, probably because of the absence or weakness of selection pressures and presence of demographic and random processes preventing detection of any selection signal.

Ocular and craniofacial phenotypes in a large Brazilian family with congenital aniridia.

Congenital aniridia is a rare genetic disorder characterized by varying degrees of iris hypoplasia that are associated with additional ocular abnormalities. More than 90% of the causal mutations identified are found in the PAX6 gene, a transcription factor of critical importance in the process of neurogenesis and ocular development. Here, we investigate clinical, molecular, and craniofacial features of a large Brazilian family with congenital aniridia. Among the 56 eyes evaluated, phenotype variation encompassed bilateral total aniridia to mild iris defects with extensive variation between eyes of the same individual. PAX6 molecular screening indicated a heterozygous splice mutation (c.141 + 1G>A). Thus, we hypothesize that this splicing event may cause variation in the expression of the wild-type transcript, which may lead to the observed variation in phenotype. Affected individuals were more brachycephalic, even though their face height and cephalic circumference were not significantly different when compared to those of non-affected relatives. From this, we infer that the head shape of affected subjects may also be a result of the PAX6 splice-site mutation. Our data summarize the clinical variability associated with the ocular phenotype in a large family with aniridia, and help shed light on the role of PAX6 in neurocranial development.

Molecular evolution of the melanocortin 1-receptor pigmentation gene in rodents.

Adaptive variation in the melanocortin 1-receptor gene (MC1R), a key locus in melanogenesis, has been identified in some species of rodents. However, in others, MC1R has no causative role in pigmentation phenotypes despite their coat color variation. In this study, we characterized the rates and patterns of MC1R nucleotide and amino acid sequence evolution and, particularly, selective pressures in the separated domains of the protein using a comparative analysis of 43 species representing three major lineages of rodents with variable coat colors. We found high amino acid variation (44% of sites) throughout the protein. Most substitutions were observed in extracellular and transmembrane domains; the intracellular segment was conserved across species. Pairwise non-synonymous substitutions did not vary significantly in different domains among the rodent lineages - i.e., variation was not associated with phylogenetic distance. Phylogeny-based likelihood analysis suggested that purifying selection has mostly shaped the evolutionary course of MC1R. However, a high proportion of sites (27%) were under relaxation of functional constraints (ω = 0.38), and four sites (3, 14, 26, and 251) clearly evolved under positive selection (ω ≅ 2.9). Thus, our data indicate a high proportion of sites evolving under relaxed evolutionary constraints, which might indicate the evolvability of the system in the generation of adaptive changes in specific taxa in rodent lineages.