18 Oral - James F. Crow Early Career Researcher Award Finalist Talks
Wednesday June 08, 2:30 PM - 2:55 PM

Authors:
Bo Xia ^1,2; Weimin Zhang ²; Aleksandra Wudzinska ²; Emily Huang ²; Ran Brosh ²; Maayan Pour ¹; Alexander Miller ⁴; Jeremy Dasen ⁴; Matthew Maurano ²; Sang Kim ⁵; Jef Boeke ^2,3,6; Itai Yanai ^1,3

Affiliations:
1) Institute for Computational Medicine, NYU Langone Health, New York, NY; 2) Institute for Systems Genetics, NYU Langone Health, New York, NY; 3) Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY; 4) Department of Neuroscience and Physiology, NYU Langone Health, New York, NY; 5) Department of Pathology, NYU Langone Health, New York, NY; 6) Department of Biomedical Engineering, NYU Tandon School of Engineering, Brooklyn, NY

Keywords:
Comparative genomics & genome evolution

The loss of the tail is one of the main anatomical changes to have occurred along the evolutionary lineage leading to modern humans. 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 humans. 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 changes. In particular, a comparative genomics approach can screen for hominoid-specific genetic elements in genomic regions associated with genes known to be involved in controlling tail development. Here, we present evidence that tail-loss evolution was mediated by the insertion of an individual transposable element (TE) – Alu element – into the intron of the TBXT gene (also called T or Brachyury) of the hominoid ancestor genome.
Unlike traditional thought that TEs in the middle of the intron are of little biological impact, we hypothesized that this Alu element could pair with a neighboring ancestral Alu element encoded in the reverse genomic orientation and thus induce the formation of a stem-loop structure in the newly transcribed pre-mRNA. We demonstrated that such an interaction pair of TEs leads to a hominoid-specific alternative splicing event, thus affecting TBXT gene function and ultimately influencing tail development and evolution.
To study the physiological 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 orthologue. We found that mice with this genotype exhibit a complete absence of the 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 propose that selection for the loss of the tail along the hominoid lineage was associated with an adaptive cost of potential neural tube defect as an evolutionary trade-off, which may thus continue to affect human health today.