Dietary change and adaptive evolution of enamelin in humans and among primates

Abstract

Scans of the human genome have identified many loci as potential targets of recent selection, but exploration of these candidates is required to verify the accuracy of genomewide scans and clarify the importance of adaptive evolution in recent human history. We present analyses of one such candidate, enamelin, whose protein product operates in tooth enamel formation in 100 individuals from 10 populations. Evidence of a recent selective sweep at this locus confirms the signal of selection found by genomewide scans. Patterns of polymorphism in enamelin correspond with population-level differences in tooth enamel thickness, and selection on enamel thickness may drive adaptive enamelin evolution in human populations. We characterize a high-frequency nonsynonymous derived allele in non-African populations. The polymorphism occurs in codon 648, resulting in a nonconservative change from threonine to isoleucine, suggesting that the allele may affect enamelin function. Sequences of exons from 12 primate species show evidence of positive selection on enamelin. In primates, it has been documented that enamel thickness correlates with diet. Our work shows that bursts of adaptive enamelin evolution occur on primate lineages with inferred dietary changes. We hypothesize that among primate species the evolved differences in tooth enamel thickness are correlated with the adaptive evolution of enamelin.

Figure 1.—

Unrooted species tree (Boffelli et al. 2003) for the primates sequenced at the enamelin locus. Corresponding dietary preferences are noted by each species name. Branches with inferred diet changes are indicated with an asterisk.

Figure 2.—

Visual genotype of enamelin locus from targeted resequencing. Individuals are represented in rows by population. For combined populations: EUR, European; NS, north Saharan African; SS, sub-Saharan African; ASN, Asian; SA, South American. For individual populations, NE, Northern European; RU, Russian; ME, Middle Eastern; NA, North American; NS, Africans north of Sahara; SS, Africans south of the Sahara; MT, Mbuti tribe; JP, Japanese; TW, Taiwanese; SA, South American. Each column represents a polymorphic site and is classified on the basis of location in the gene sequence, numbered from the first base 5′-UTR. Each rectangle indicates the genotypic state for the corresponding individual and SNP location; blue indicates homozygous for the ancestral allele, yellow indicates heterozygous, red indicates homozygous for the derived allele, and white indicates missing data. All populations, except the south Saharan Africans, have low nucleotide variation.

Figure 3.—

Gene structure for enamelin. Predicted cleavage sites are denoted with vertical bars and the corresponding cleavage products are drawn below. Synonymous SNPs (▿) and nonsynonymous SNPs (▾) identified in the human polymorphism are indicated above the gene diagram. Additionally, we have indicated the sites predicted to be under positive selection by codeml with an asterisk.