Repurposing of a gill gene regulatory program for outer-ear evolution

Mathi Thiruppathy, Lauren Teubner, Ryan R. Roberts, Micaela C. Lasser, Alessandra Moscatello, Ya-Wen Chen, Christian Hochstim, Seth Ruffins, Arijita Sarkar, Jade Tassey, Denis Evseenko, Thomas P. Lozito, Helen Rankin Willsey, J. Andrew Gillis and J. Gage Crump ()
Additional contact information
Mathi Thiruppathy: University of Southern California
Lauren Teubner: University of Southern California
Ryan R. Roberts: University of Southern California
Micaela C. Lasser: University of California, San Francisco
Alessandra Moscatello: New York Medical College
Ya-Wen Chen: Icahn School of Medicine at Mount Sinai
Christian Hochstim: Children’s Hospital Los Angeles
Seth Ruffins: University of Southern California
Arijita Sarkar: University of Southern California
Jade Tassey: University of Southern California
Denis Evseenko: University of Southern California
Thomas P. Lozito: University of Southern California
Helen Rankin Willsey: University of California, San Francisco
J. Andrew Gillis: Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory
J. Gage Crump: University of Southern California

Nature, 2025, vol. 639, issue 8055, 682-690

Abstract: Abstract How new structures emerge during evolution has long fascinated biologists. An example is how the diminutive bones of the mammalian middle ear arose from ancestral fish jawbones1. By contrast, the evolutionary origin of the outer ear, another mammalian innovation, remains a mystery, partly because it is supported by non-mineralized elastic cartilage, which is rarely recovered in fossils. Whether the outer ear arose de novo or through the reuse of ancestral developmental programs has remained unknown. Here we show that the outer ear shares gene regulatory programs with the gills of fishes and amphibians for both its initial outgrowth and the later development of the elastic cartilage. Comparative single-nucleus multiomics of the human outer ear and zebrafish gills reveals conserved gene expression and putative enhancers enriched for common transcription factor binding motifs. This is reflected by the transgenic activity of human outer-ear enhancers in gills, and of fish gill enhancers in the outer ear. Furthermore, single-cell multiomics of the cartilaginous book gills of horseshoe crabs reveals a developmental program shared with the distal-less homeobox (DLX)-mediated gill program of vertebrates, with a book-gill distal-less enhancer driving expression in zebrafish gills. We propose that elements of an invertebrate gill program were reutilized in vertebrates to generate first gills and then the outer ear.

Date: 2025
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DOI: 10.1038/s41586-024-08577-5

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