Genetic Control of Tissue Remodeling by a Non‐Coding SNP in ITGA8 Explains Carotenoid‐Based Color Polymorphism in Marine Mollusks

ABSTRACT Biological color polymorphism represents a widespread form of phenotypic diversity in nature; however, the multi‐scale regulatory mechanisms of carotenoid‐based coloration, from genetic control to cell states and tissue architecture, remain poorly understood. Here, using the orange‐muscle giant abalone ( Haliotis gigantea ) as a model, we demonstrate that a non‐coding single nucleotide polymorphism (SNP) in the integrin subunit alpha 8 ( ITGA8 ) gene induces alternative splicing, thereby promoting carotenoid‐based coloration through the regulation of tissue remodeling processes, including cell state transitions and reconstruction of the physical microenvironment. Through chromosome‐level genome assembly and genome‐wide association studies (GWAS), we identified a SNP that disrupts the interaction between ITGA8 pre‐mRNA and the splicing factor ILF2, leading to altered ITGA8 splicing. Multi‐omics analyses and transmission electron microscopy reveal that these splicing changes promote carotenoid accumulation in abalone muscle by weakening cell adhesion and enlarging intercellular spaces. Functional validation supports the role of ITGA8 in regulating cell adhesion and carotenoid uptake. Our study uncovers a cross‐scale mechanism by which genetic variation drives macroscopic phenotypic diversity in carotenoid‐based color polymorphism through the regulation of cell state transitions and tissue remodeling. These findings provide novel insights into the genotype‐phenotype relationship and advance our understanding of color diversity in multicellular organisms.