NAT2 gene diversity and its evolutionary trajectory in the Americas

Area of Science:

• Pharmacogenomics
• Human Genetics
• Population Genetics

Background:

• N-acetyltransferase 2 (NAT2) metabolizes xenobiotics, and its polymorphisms define rapid, intermediate, and slow acetylator phenotypes.
• Understanding NAT2 diversity is crucial for personalized medicine and understanding drug response variations.

Purpose of the Study:

• To investigate the genetic diversity of NAT2 in Native American populations.
• To determine the distribution of NAT2 haplotypes and acetylator phenotypes across different Native American groups.

Main Methods:

• Sequencing of NAT2 exon 2 in 286 individuals from 21 Native American and Mestizo populations.
• Analysis of the ~44 kb region surrounding NAT2 in 819 individuals from diverse global populations (Africa, East Asia, Europe, America).

Main Results:

• The NAT2*5B and NAT2*7B haplotypes, associated with slow acetylation, were prevalent in Native American agriculturalist groups.
• A novel NAT2 haplotype was identified in two Amerindian individuals.
• No significant differences in NAT2 haplotype or phenotype distributions were observed between Native American hunting/gathering and farming/herding populations.

Conclusions:

• Native American populations exhibit NAT2 diversity with a notable presence of slow acetylator haplotypes.
• The lack of significant differences between subsistence groups suggests that demographic processes and weak selection pressures may have shaped NAT2 distribution, rather than strong adaptive selection related to diet or lifestyle.