On the genetic basis of tail-loss evolution in humans and apes [Capture-seq]

The loss of the tail is among the notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the “anthropomorphous apes”, with a hypothesized role in contributing to human bipedalism. 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 gene – pairs with a neighboring 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 mouse Tbxt, mimicking the expression pattern of its hominoid ortholog TBXT. We found that mice expressing both Tbxt isoforms can 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, supporting the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. We further noted that mice expressing the exon-skipped Tbxt isoform may develop neural tube defects, a condition that affects ~1/1,000 neonates in human. 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. Overall design: The samples are designed to perform region-specific genomic DNA sequencing for genotyping the related cell lines and mouse models. The goal is to verify whether the specific genotype was correct, and whether any off target events occurred in the samples.