Bo Xia,et al.

The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'1-3,with a proposed role in contributing to human bipedalism4-6.Yet,the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown.Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution.We demonstrate that this Alu element-inserted into an intron of the TBXT gene7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event.To study the effect of this splicing event,we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt,mimicking the expression pattern of its hominoid orthologue TBXT.Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud.These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype.Moreover,mice expressing the exon-skipped Tbxt isoform develop neural tube defects,a condition that affects approximately 1 in 1,000 neonates in humans10.Thus,tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects,which continue to affect human health today.