{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:05:07Z","timestamp":1760238307480,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["24650233"],"award-info":[{"award-number":["24650233"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Pink-eyed dilution castaneus (Oca2p-cas) is a mutant gene on mouse chromosome 7 that arose spontaneously in wild Mus\u00a0musculus\u00a0castaneus. Homozygotes for Oca2p-cas exhibit pink eyes and a light gray coat throughout life. In an ordinary mutant strain carrying Oca2p-cas, we previously discovered a novel spontaneous mutation that gradually increases melanin pigmentation in the eyes and coat with aging, and we developed a novel mutant strain that was fixed for the novel phenotype. The purpose of this study was to map major quantitative trait loci (QTLs) for the novel pigmentation phenotype and for expression levels of four important melanogenesis genes, microphthalmia-associated transcription factor (Mitf), tyrosinase (Tyr), tyrosinase-related protein-1 (Tyrp1) and dopachrome tautomerase (Dct). We developed 69 DNA markers and created 303 F2 mice from two reciprocal crosses between novel and ordinary mutant strains. The QTL analysis using a selective genotyping strategy revealed a significant QTL for eye pigmentation between 34 and 64 Mb on chromosome 13. This QTL explained approximately 20% of the phenotypic variance. The QTL allele derived from the novel strain increased pigmentation. Although eye pigmentation was positively correlated with Dct expression, no expression QTLs were found, suggesting that the pigmentation QTL on chromosome 13 may not be directly in the pathway of any of the four melanogenesis genes. This study is the first step toward identifying a causal gene for the novel spontaneous phenotype in mice and is expected to discover a new regulatory mechanism for complex melanin biosynthesis during aging.<\/jats:p>","DOI":"10.3390\/genes13071138","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T09:00:13Z","timestamp":1656234013000},"page":"1138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["QTL Mapping for Age-Related Eye Pigmentation in the Pink-Eyed Dilution Castaneus Mutant Mouse"],"prefix":"10.3390","volume":"13","author":[{"given":"Takaya","family":"Nakano","sequence":"first","affiliation":[{"name":"Laboratory of Animal Genetics and Breeding, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Momoko","family":"Takenaka","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Genetics and Breeding, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9340-6015","authenticated-orcid":false,"given":"Makoto","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, Kitasato University School of Veterinary Medicine, Towada 034-8628, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8275-4230","authenticated-orcid":false,"given":"Akira","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Genetics and Breeding, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"D801","DOI":"10.1093\/nar\/gky1056","article-title":"Mouse Genome Database (MGD)","volume":"47","author":"Bult","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1111\/pcmr.12743","article-title":"A curated gene list for expanding the horizons of pigmentation biology","volume":"32","author":"Baxter","year":"2019","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1093\/oxfordjournals.jhered.a108473","article-title":"Greying with age: A coat-color variant in wild Australian populations of mice","volume":"65","author":"Kirby","year":"1974","journal-title":"J. Hered."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1538\/expanim1978.35.2_131","article-title":"Faded, a mutation in the KSB strain of mouse which shows age-related pigment changes","volume":"35","author":"Oh","year":"1986","journal-title":"Exp. Anim."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1038\/ng.185","article-title":"A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse","volume":"40","author":"Pielberg","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1146\/annurev-animal-031412-103659","article-title":"Genetics of pigmentation in dogs and cats","volume":"1","author":"Kaelin","year":"2013","journal-title":"Annu. Rev. Anim. Biosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"198","DOI":"10.4103\/ijt.ijt_47_18","article-title":"Premature graying of hair: Review with updates","volume":"10","author":"Kumar","year":"2018","journal-title":"Int. J. Trichol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1538\/expanim.44.347","article-title":"A new spontaneous allele at the pink-eyed dilution (p) locus discovered in Mus musculus castaneus","volume":"44","author":"Tsuji","year":"1995","journal-title":"Exp. Anim."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1538\/expanim.14-0101","article-title":"Development of a novel pink-eyed dilution mouse model showing progressive darkening of the eyes and coat hair with aging","volume":"64","author":"Ishikawa","year":"2015","journal-title":"Exp. Anim."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jdermsci.2015.10.002","article-title":"L-tyrosine induces melanocyte differentiation in novel pink-eyed dilution castaneus mouse mutant showing age-related pigmentation","volume":"80","author":"Hirobe","year":"2015","journal-title":"J. Darmatol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1586\/edm.10.70","article-title":"Update on the regulation of mammalian melanocyte function and skin pigmentation","volume":"6","author":"Kondo","year":"2011","journal-title":"Expert Rev. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1158\/0008-5472.CAN-17-0337","article-title":"Variant review with the Integrative Genomics Viewer","volume":"77","author":"Robinson","year":"2017","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"W71","DOI":"10.1093\/nar\/gkm306","article-title":"Primer3Plus, an enhanced web interface to Primer3","volume":"35","author":"Untergasser","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., and Madden, T.L. (2012). Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinfom., 13.","DOI":"10.1186\/1471-2105-13-134"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/1746-4811-8-34","article-title":"An improved allele-specific PCR primer design method for SNP marker analysis and its application","volume":"8","author":"Liu","year":"2012","journal-title":"Plant Methods"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s00335-007-9009-5","article-title":"A growth QTL (Pbwg1) region of mouse chromosome 2 contains closely linked loci affecting growth and body composition","volume":"18","author":"Ishikawa","year":"2007","journal-title":"Mamm. Genome"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1007\/s00335-001-1016-3","article-title":"Map Manager QTX, cross-platform software for genetic mapping","volume":"12","author":"Manly","year":"2001","journal-title":"Mamm. Genome"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/BF00222881","article-title":"Selective genotyping for determination of linkage between a marker locus and a quantitative trait locus","volume":"85","author":"Darvasi","year":"1992","journal-title":"Theoret. Appl. Genetics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1093\/bioinformatics\/btg112","article-title":"R\/qtl: QTL mapping in experimental crosses","volume":"19","author":"Broman","year":"2003","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1007\/s00335-005-0160-6","article-title":"Quantitative trait loci for body size components in mice","volume":"17","author":"Vaughn","year":"2006","journal-title":"Mamm. Genome"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1101\/gr.128652.111","article-title":"HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter","volume":"22","author":"Visser","year":"2012","journal-title":"Genome Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/BF00225166","article-title":"Optimum spacing of genetic markers for determining linkage between marker loci and quantitative trait loci","volume":"89","author":"Darvasi","year":"1994","journal-title":"Theor. Appl. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ishikawa, A. (2017). A strategy for identifying quantitative trait genes using gene expression analysis and causal analysis. Genes, 8.","DOI":"10.3390\/genes8120347"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s003359900353","article-title":"The effect of selective genotyping on QTL mapping accuracy","volume":"8","author":"Darvasi","year":"1997","journal-title":"Mamm. Genome"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1093\/genetics\/165.4.2259","article-title":"Theoretical basis of the Beavis effect","volume":"165","author":"Xu","year":"2003","journal-title":"Genetics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17658","DOI":"10.1038\/s41598-018-36073-0","article-title":"Genetic identification of Ly75 as a novel quantitative trait gene for resistance to obesity in mice","volume":"8","author":"Makino","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1182\/blood.V78.8.2036.2036","article-title":"Platelet storage pool deficiency associated with inherited abnormalities of the inner ear in the mouse pigment mutants muted and mocha","volume":"78","author":"Swank","year":"1991","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1093\/hmg\/11.6.697","article-title":"The gene for the muted (mu) mouse, a model for Hermansky-Pudlak syndrome, defines a novel protein which regulates vesicle trafficking","volume":"11","author":"Zhang","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1017\/S0016672300029608","article-title":"Sandy: A new mouse model for platelet storage pool deficiency","volume":"58","author":"Swank","year":"1991","journal-title":"Genet. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/ng1229","article-title":"Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1)","volume":"35","author":"Li","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1111\/pcmr.12982","article-title":"Genetics of non-syndromic and syndromic oculocutaneous albinism in human and mouse","volume":"34","author":"Hayashi","year":"2021","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1016\/j.cell.2013.10.022","article-title":"A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF\/TFAP2A Pathway","volume":"155","author":"Praetorius","year":"2013","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.ajpath.2012.02.017","article-title":"Loss of Msx2 function down-regulates the FoxE3 expression and results in anterior segment dysgenesis resembling Peters anomaly","volume":"180","author":"Zhao","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1006\/dbio.2001.0280","article-title":"Transdifferentiation of the ventral retinal pigmented epithelium to neural retina in the growth arrest specific gene 1 mutant","volume":"236","author":"Lee","year":"2001","journal-title":"Dev. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1034\/j.1600-0749.2002.02035.x","article-title":"Changes in the proliferative activity of epidermal melanocytes in serum-free primary culture during the development of ultraviolet radiation B-induced pigmented spots in hairless mice","volume":"15","author":"Furuya","year":"2002","journal-title":"Pigment Cell Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1600-0749.2004.00198.x","article-title":"Role of keratinocyte-derived factors involved in regulating the proliferation and differentiation of mammalian epidermal melanocytes","volume":"18","author":"Hirobe","year":"2005","journal-title":"Pigment Cell Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jdermsci.2019.01.004","article-title":"Dyschromatosis symmetrica hereditaria and reticulate acropigmentation of Kitamura: An update","volume":"93","author":"Kono","year":"2019","journal-title":"J. Dermatol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.jdermsci.2018.02.008","article-title":"MITF-M regulates melanogenesis in mouse melanocytes","volume":"90","author":"Chena","year":"2018","journal-title":"J. Dermatol. Sci."},{"key":"ref_40","first-page":"2649","article-title":"Knockdown of microRNA-143-5p by STTM technology affects eumelanin and pheomelanin production in melanocytes","volume":"20","author":"Qi","year":"2019","journal-title":"Mol. Med. Reports"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.matbio.2018.09.006","article-title":"Dual role of laminin-511 in regulating melanocyte migration and differentiation","volume":"80","author":"Reibetanz","year":"2019","journal-title":"Matrix Biol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1138\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:18Z","timestamp":1760139558000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/7\/1138"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,24]]},"references-count":41,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["genes13071138"],"URL":"https:\/\/doi.org\/10.3390\/genes13071138","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2022,6,24]]}}}