On the genetic basis of tail-loss evolution in humans and apes

Bo Xia (), Weimin Zhang, Guisheng Zhao, Xinru Zhang, Jiangshan Bai, Ran Brosh, Aleksandra Wudzinska, Emily Huang, Hannah Ashe, Gwen Ellis, Maayan Pour, Yu Zhao, Camila Coelho, Yinan Zhu, Alexander Miller, Jeremy S. Dasen, Matthew T. Maurano, Sang Y. Kim, Jef D. Boeke () and Itai Yanai ()
Additional contact information
Bo Xia: NYU Langone Health
Weimin Zhang: NYU Langone Health
Guisheng Zhao: NYU Langone Health
Xinru Zhang: Broad Institute of MIT and Harvard
Jiangshan Bai: Broad Institute of MIT and Harvard
Ran Brosh: NYU Langone Health
Aleksandra Wudzinska: NYU Langone Health
Emily Huang: NYU Langone Health
Hannah Ashe: NYU Langone Health
Gwen Ellis: NYU Langone Health
Maayan Pour: NYU Langone Health
Yu Zhao: NYU Langone Health
Camila Coelho: NYU Langone Health
Yinan Zhu: NYU Langone Health
Alexander Miller: NYU Langone Health
Jeremy S. Dasen: NYU Langone Health
Matthew T. Maurano: NYU Langone Health
Sang Y. Kim: NYU Langone Health
Jef D. Boeke: NYU Langone Health
Itai Yanai: NYU Langone Health

Nature, 2024, vol. 626, issue 8001, 1042-1048

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07095-8

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