Large Genomic Insertion At The Shh Locus Results In Hammer Toes Through Enhancer Adoption

Enhancers are cis -regulatory elements which control the expression of genes in a defined spatiotemporal pattern, enabling the normal morphogenesis of organs and structures during embryogenesis. Enhancers control their target genes independently of their orientation or distance through chromosomal looping and are thought to evolve through various mutational mechanisms (1). A critical biological process that leads to the acquisition of new gene expression domains as well as pathological outcomes is termed “enhancer adoption,” whereby a gene is regulated by an enhancer that is not normally its own (2). Enhancer adoption can derive from the insertion of transposable elements (TEs) with regulatory capacities or genomic structural variants (SVs). In particular, many studies have demonstrated the importance of SVs, including deletions, inversions, duplications, and translocations, with regard to 3D genome organization, gene regulation, and disease (3⇓–5). Recent advances in genome engineering and in sequencing technologies have contributed to a deeper understanding of the molecular mechanisms behind genomic rearrangements and their role in evolution and pathology. Therefore, researchers have seized the opportunity to reinterpret old mouse alleles obtained by spontaneous mutations like X-irradiation-induced phocomelia, Hemimelic extra toes ( Hx ), Ulnaless , and so on, in the light of modern molecular tools (6⇓–8). In PNAS, Mouri et al. (10) set out to reanalyze a mouse mutant with syndactyly and interdigital webbing, known as Hammer toe ( Hm ), first described in 1964 (9). The authors found that a genomic insertion of an interdigital regulatory region in the vicinity of the gene Sonic hedgehog ( Shh ) results in its ectopic expression and the Hm phenotype. The authors use chromatin technologies and CRISPR/Cas9 genetic engineering to dissect the regulatory function of … [↵][1]1To whom correspondence should be addressed. Email: andrey{at}molgen.mpg.de. [1]: #xref-corresp-1-1