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Researchers investigated whether a specific genetic regulatory element near the Shox2 gene in jerboas, rodents with extremely elongated hindlimbs, could alter limb bone length when introduced into mice. Despite identifying a 139 base pair sequence in jerboas that replaced a ~1 kilobase deletion found in other mammals, replicating this genetic change in mice produced no detectable change in limb proportions. A comprehensive genome-wide analysis revealed 7,445 similar regulatory regions specific to jerboa metatarsals, suggesting that limb proportion evolution likely involves many small-effect mutations rather than single large-effect changes in a few candidate genes.
Why it matters
This study challenges the common research approach of focusing on a small number of candidate genes to explain evolutionary changes in body proportions. The findings suggest that understanding limb development and potentially treating skeletal disorders will require unbiased genome-wide approaches rather than targeted investigations of historically favored genes, as many small genetic changes likely work together to produce morphological diversity.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.