Knockout of Hermansky-Pudlak Syndrome 4 (hps4) leads to silver-white tilapia lacking melanosomes

Body color is a major factor determining the economic value of farmed tilapia. In the present study, we engi-neered a silver-white tilapia by mutation of hps4 using CRISPR/Cas9 gene editing of a target site in exon 2. Homozygous mutation of hps4 led to a truncated protein of only 80 amino acids. Disruption of HPS4 led to a significant decrease (even absence at the adult stage) of melanophores and melanin, and a significant increase of iridophores, xanthophores and erythrophores. A sub-group of melanophores, even though very few in number, was found in the early embryonic stages. White iridophores without iridescence, hypertrophic xanthophores, and erythrophores with plenty of pigments were detected in the scales and caudal fins of the mutants, indicating enrichment of guanine, pteridine and carotenoids. To our knowledge, this is the first report on disruption of HPS4 in teleosts, and the first report demonstrating that HPS4 regulates iridophore, xanthophore and erythrophore numbers. Hps4 plays a fundamental role in LROs (lysosome-related organelles)-pigment development, mela-nophore survival and melanin biosynthesis. Our hps4 mutants provide a new model for studies of HPS4 function in vertebrates, and might be used as new germplasm for aquaculture.