Recent studies demonstrate that 5-HTTLPR is more highly polymorphic than previously believed and that a reassessment of 5-HTTLPR as functionally tri-allelic is premature for at least two reasons. First, despite our reference to an XL allele, several studies, including our own, find that XL comprises variants with different numbers of repeats, at minimum 18, 19, 20 and 22 repeats. Second, SNP and other variations have been identified within the S and L alleles. Nakamura et al. [7] found several novel variants consisting of different combinations of the 14- and 16-repeats. Hu et al. [32] failed to detect most of Nakamura’s novel variants in an ethnically diverse sample but demonstrated a large difference in transcriptional efficiency resulting from a single base substitution in an L allele, with one of the L variants having a similar degree of 5-HTT expression as the S allele. Wendland et al. [40] demonstrated that this SNP (rs25531) occurs in the S allele—albeit very rarely—as well as the L allele. Such findings raise the question of whether these variants are at least as important functionally as differences in the tandem repeat structure.
