A putative cis-regulatory element near Shox2 in the jerboa genome (Jaculus jaculus) is not sufficient to alter mouse limb bone lengths
- 1University of California, San Diego
Abstract
Vertebrate limb bones grow at different rates within and between species to achieve a striking variety of proportions and functions. However, most coding mutations that alter bone growth in mice and humans affect the entire skeleton, pointing to cis-regulatory modularity as the primary mechanism to diversify proportion. In a search for causative loci, we previously identified 1,755 disproportionately differentially expressed genes associated with the extreme hindlimb elongation in bipedal jerboas, Jaculus jaculus, compared to laboratory mice. We then took a focused approach to identify putative cis-regulatory elements near select candidate genes in a highly fragmented draft Jaculus jaculus genome assembly. We identified an ATAC-seq peak near Shox2 that was reproducible in jerboa metatarsals and not in radius/ulna. Shox2 gained a novel expression domain in jerboa metatarsals and is both necessary and sufficient to modulate mouse limb bone length. This 139 bp putative enhancer in the jerboa genome centers on a ~1 kb deletion of sequence found broadly throughout placental mammals. Here, we show that replicating the deletion and replacement with the 139 bp jerboa sequence in mice causes no detected phenotype. A genome-wide analysis of our ATAC-seq data using a high-quality Jaculus jaculus genome assembly replicated the peak called at this location but also identified 7,445 peaks that are similarly reproducible in metatarsals and not in radius/ulna. Certainly not all of these peaks are causative, but it is likely that many small-effect mutations diversified proportion. It is therefore crucial to apply unbiased filters to genome-wide analyses and to not assume that the few historically favored genes will have the largest effect.
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BibTeX
@misc{guerrero2026putative,
title = {{A putative cis-regulatory element near Shox2 in the jerboa genome (Jaculus jaculus) is not sufficient to alter mouse limb bone lengths}},
author = {G. Guerrero and A. Y. Liu and A. J. Weitzel and E. Gacasan and M. Hiller and R. Sah and K. L. Cooper},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752424},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752424v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A putative cis-regulatory element near Shox2 in the jerboa genome (Jaculus jaculus) is not sufficient to alter mouse limb bone lengths
AU - G. Guerrero
AU - A. Y. Liu
AU - A. J. Weitzel
AU - E. Gacasan
AU - M. Hiller
AU - R. Sah
AU - K. L. Cooper
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752424
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752424v1
AB - Vertebrate limb bones grow at different rates within and between species to achieve a striking variety of proportions and functions. However, most coding mutations that alter bone growth in mice and humans affect the entire skeleton, pointing to cis-regulatory modularity as the primary mechanism to diversify proportion. In a search for causative loci, we previously identified 1,755 disproportionately differentially expressed genes associated with the extreme hindlimb elongation in bipedal jerboas, Jaculus jaculus, compared to laboratory mice. We then took a focused approach to identify putative cis-regulatory elements near select candidate genes in a highly fragmented draft Jaculus jaculus genome assembly. We identified an ATAC-seq peak near Shox2 that was reproducible in jerboa metatarsals and not in radius/ulna. Shox2 gained a novel expression domain in jerboa metatarsals and is both necessary and sufficient to modulate mouse limb bone length. This 139 bp putative enhancer in the jerboa genome centers on a ~1 kb deletion of sequence found broadly throughout placental mammals. Here, we show that replicating the deletion and replacement with the 139 bp jerboa sequence in mice causes no detected phenotype. A genome-wide analysis of our ATAC-seq data using a high-quality Jaculus jaculus genome assembly replicated the peak called at this location but also identified 7,445 peaks that are similarly reproducible in metatarsals and not in radius/ulna. Certainly not all of these peaks are causative, but it is likely that many small-effect mutations diversified proportion. It is therefore crucial to apply unbiased filters to genome-wide analyses and to not assume that the few historically favored genes will have the largest effect.
ER -