Evolutionary history of sex-linked mammalian amelogenin genes

Amelogenin (AMEL) arose prior to the emergence of tetrapods and transposed into an intron of the Rho GTPase-activating protein 6 gene. In the mammalian lineage leading to eutherians, a pair of homologous autosomes with this nested gene structure fused with the then already differentiating sex chromosomes by suppressing homologous recombination. As sex-chromosomal differentiation extended to the fused region, a pair of homologous AMEL genes too differentiated from each other in two steps; first in the 5' region (the promoter region to transposon MER5 in intron 2) and second in the remaining 3' region. This resulted in gametologous AMELX and AMELY in the eutherian sex chromosomes. Although the early differentiation of the 5' region between AMELX and AMELY is consistent with the lowered expression level of AMELY, there is no indication for deterioration of AMELY at the amino acid level. Rather, both AMELX and AMELY in particular lineages might undergo positive selection, followed by negative selection to preserve established function. Based on patterns and levels of AMELX and AMELY polymorphisms in the human population, it is also argued that a recombination cold spot near AMELX might be related to the cause of the ancient pseudoautosomal boundary.