Regulatory and disruptive variants in the CLCN2 gene are associated with modified skin color pattern phenotypes in the corn snake

Article Article scientifique Article Regulatory and disruptive variants in the CLCN2 gene are associated with modified skin color pattern phenotypes in the corn snake eng 2025-03-26 author Montandon Sophie Laboratory of Artificial and Natural Evolution, Department of Genetics & Evolution, University of Geneva, Geneva, Switzerland.,Present address: Bracco Suisse S.A., Plan-les-Ouates, Switzerland. 641811 author Beaudier Pierre 0000-0003-3812-7966 Laboratory of Artificial and Natural Evolution, Department of Genetics & Evolution, University of Geneva, Geneva, Switzerland. 418316 Département de génétique et évolution (Genev) (BIANI) author Ullate Agote Asier 0000-0002-8595-7703 Laboratory of Artificial and Natural Evolution, Department of Genetics & Evolution, University of Geneva, Geneva, Switzerland.,Present address: Biomedical Engineering Program, Center for Applied Medical Research (CIMA), Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. 775242 author Helleboid Pierre-Yves Laboratory of Artificial and Natural Evolution, Department of Genetics & Evolution, University of Geneva, Geneva, Switzerland. 405252 Département de génétique et évolution (Genev) (BIANI) author Kummrow Maya 0000-0002-5343-1336 Tierspital, University of Zurich, Zurich, Switzerland. author Roig Puiggros Sergi 0000-0001-5909-218X Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland. 931871 Département de neurosciences fondamentales (NEUFO) author Jabaudon Denis 0000-0003-2438-4769 Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland.,Clinic of Neurology, Geneva University Hospital, Geneva, Switzerland. 682473 Département de neurosciences fondamentales (NEUFO) author Andersson Leif Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.,Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA. author Milinkovitch Michel C. Laboratory of Artificial and Natural Evolution, Department of Genetics & Evolution, University of Geneva, Geneva, Switzerland. michel.milinkovitch@unige.ch. 679786 Département de génétique et évolution (Genev) (BIANI) author Tzika Athanasia 0000-0002-0831-5221 Laboratory of Artificial and Natural Evolution, Department of Genetics & Evolution, University of Geneva, Geneva, Switzerland. athanasia.tzika@unige.ch. 683179 Département de génétique et évolution (Genev) (BIANI) 73 10.1186/s13059-025-03539-0 40140900 1474-7596 PMC11948899 https://genomebiology.biomedcentral.com/articles/10.1186/s13059-025-03539-0 Background: Snakes exhibit a broad variety of adaptive colors and color patterns, generated by the spatial arrangement of chromatophores, but little is known of the mechanisms responsible for these spectacular traits. Here, we investigate a mono-locus trait with two recessive alleles, motley and stripe, that both cause pattern aberrations in the corn snake. Results: We use mapping-by-sequencing to identify the genomic interval where the causal mutations reside. With our differential gene expression analyses, we find that CLCN2 (Chloride Voltage-Gated Channel 2), a gene within the genomic interval, is significantly downregulated in Motley embryonic skin. Furthermore, we identify the stripe allele as the insertion of an LTR-retrotransposon in CLCN2, resulting in a disruptive mutation of the protein. We confirm the involvement of CLCN2 in color pattern formation by producing knock-out snakes that present a phenotype similar to Stripe. In humans and mice, disruption of CLCN2 results in leukoencephalopathy, as well as retinal and testes degeneration. Our single-cell transcriptomic analyses in snakes reveal that CLCN2 is indeed expressed in chromatophores during embryogenesis and in the adult brain, but the behavior and fertility of Motley and Stripe corn snakes are not impacted. Conclusions: Our genomic, transcriptomic, and functional analyses identify a plasma membrane anion channel to be involved in color pattern development in snakes and show that an active LTR-retrotransposon might be a key driver of trait diversification in corn snakes. CLCN2 Chromatophores Coloration Reptiles Skin Dewey 590 Zeno Karl Schindler Foundation Sara Borrell grant CD22/00027 Human Frontier Science Program RGP0037/2022 Ernst and Lucie Schmidheiny Foundation 10_2023 Fonds Général de l’Université de Genève 23_28 Emile Plantamour Fund 2024/12 Swiss National Science Foundation Evolutionary developmental genetics of ?phenotypic novelties and convergences 140785 CH 44 Département de génétique et évolution 162 false 819 Groupe Milinkowitch Genome biology 26 1 c81c786d-7dc8-4f42-b3b5-f74146ff3096 Article (Published version) Public Article_scientifique_from_crossref.pdf 3742984 application/pdf CC BY-4.0 5f6570b0a7ed17a2cc31bd3bab6a1e05c73a8e098a2a9a4ad121e2b94dc3d1b1 openAccess Faculté des sciences / Section de biologie / Département de génétique et évolution

Title	Published in	Year	Views	Downloads

Regulatory and disruptive variants in the CLCN2 gene are associated with modified skin color pattern phenotypes in the corn snake	Genome biology	2025	6	84
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Helleboid, Pierre-Yves