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The genetic basis of tail-loss evolution in humans and apes

View ORCID ProfileBo Xia, View ORCID ProfileWeimin Zhang, Aleksandra Wudzinska, View ORCID ProfileEmily Huang, View ORCID ProfileRan Brosh, View ORCID ProfileMaayan Pour, View ORCID ProfileAlexander Miller, Jeremy S. Dasen, View ORCID ProfileMatthew T. Maurano, Sang Y. Kim, View ORCID ProfileJef D. Boeke, View ORCID ProfileItai Yanai
doi: https://doi.org/10.1101/2021.09.14.460388
Bo Xia
1Institute for Computational Medicine, NYU Langone Health, New York, NY 10016, USA
2Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA
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  • For correspondence: Bo.Xia@nyulangone.edu Jef.Boeke@nyulangone.org Itai.Yanai@nyulangone.org
Weimin Zhang
2Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA
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Aleksandra Wudzinska
2Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA
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Emily Huang
2Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA
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Ran Brosh
2Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA
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Maayan Pour
1Institute for Computational Medicine, NYU Langone Health, New York, NY 10016, USA
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Alexander Miller
4Department of Neuroscience and Physiology, NYU Langone Health, New York, NY 10016, USA
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Jeremy S. Dasen
4Department of Neuroscience and Physiology, NYU Langone Health, New York, NY 10016, USA
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Matthew T. Maurano
2Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA
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Sang Y. Kim
5Department of Pathology, NYU Langone Health, New York, NY 10016, USA
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Jef D. Boeke
2Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA
3Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY 10016, USA
6Department of Biomedical Engineering, NYU Tandon School of Engineering, Brooklyn, NY, 11201, USA
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  • For correspondence: Bo.Xia@nyulangone.edu Jef.Boeke@nyulangone.org Itai.Yanai@nyulangone.org
Itai Yanai
1Institute for Computational Medicine, NYU Langone Health, New York, NY 10016, USA
3Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY 10016, USA
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  • For correspondence: Bo.Xia@nyulangone.edu Jef.Boeke@nyulangone.org Itai.Yanai@nyulangone.org
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Abstract

The loss of the tail is one of the main anatomical evolutionary changes to have occurred along the lineage leading to humans and to the “anthropomorphous apes”1,2. This morphological reprogramming in the ancestral hominoids has been long considered to have accommodated a characteristic style of locomotion and contributed to the evolution of bipedalism in humans3–5. Yet, the precise genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Primate genome sequencing projects have made possible the identification of causal links between genotypic and phenotypic changes6–8, and enable the search for hominoid-specific genetic elements controlling tail development9. Here, we present evidence that tail-loss evolution was mediated by the insertion of an individual Alu element into the genome of the hominoid ancestor. We demonstrate that this Alu element – inserted into an intron of the TBXT gene (also called T or Brachyury10–12) – 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 a mouse model that mimics the expression of human TBXT products by expressing both full-length and exon-skipped isoforms of the mouse TBXT ortholog. We found that mice with this genotype exhibit the complete absence of a tail or a shortened tail, supporting the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype, albeit with incomplete penetrance. We further noted that mice homozygous for the exon-skipped isoforms exhibited embryonic spinal cord malformations, resembling a neural tube defect condition, which affects ∼1/1000 human neonates13. We propose that selection for the loss of the tail along the hominoid lineage was associated with an adaptive cost of potential neural tube defects and that this ancient evolutionary trade-off may thus continue to affect human health today.

Competing Interest Statement

J.D.B is a Founder and Director of CDI Labs, Inc., a Founder of and consultant to Neochromosome, Inc, a Founder, SAB member of and consultant to ReOpen Diagnostics, LLC and serves or served on the Scientific Advisory Board of the following: Sangamo Inc., Modern Meadow Inc., Sample6 Inc., Tessera Therapeutics Inc. and the Wyss Institute. The other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 16, 2021.
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The genetic basis of tail-loss evolution in humans and apes
Bo Xia, Weimin Zhang, Aleksandra Wudzinska, Emily Huang, Ran Brosh, Maayan Pour, Alexander Miller, Jeremy S. Dasen, Matthew T. Maurano, Sang Y. Kim, Jef D. Boeke, Itai Yanai
bioRxiv 2021.09.14.460388; doi: https://doi.org/10.1101/2021.09.14.460388
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The genetic basis of tail-loss evolution in humans and apes
Bo Xia, Weimin Zhang, Aleksandra Wudzinska, Emily Huang, Ran Brosh, Maayan Pour, Alexander Miller, Jeremy S. Dasen, Matthew T. Maurano, Sang Y. Kim, Jef D. Boeke, Itai Yanai
bioRxiv 2021.09.14.460388; doi: https://doi.org/10.1101/2021.09.14.460388

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