A Recessive oca2 Mutation Underlies Albinism in Xiphophorus fish

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A Recessive oca2 Mutation Underlies Albinism in Xiphophorus fish | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-M677548'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results A Recessive oca2 Mutation Underlies Albinism in Xiphophorus fish Yanting Xing , William Boswell , Jessica Parker , Kang Du , Manfred Schartl , Yuan Lu doi: https://doi.org/10.1101/2025.01.20.633999 Yanting Xing 1 Institute for Molecular Life Sciences, Texas State University , San Marcos, TX, 78666 Find this author on Google Scholar Find this author on PubMed Search for this author on this site William Boswell 1 Institute for Molecular Life Sciences, Texas State University , San Marcos, TX, 78666 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jessica Parker 1 Institute for Molecular Life Sciences, Texas State University , San Marcos, TX, 78666 2 Department of Chemistry and Biochemistry, Texas State University , San Marcos, TX, 78666 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kang Du 1 Institute for Molecular Life Sciences, Texas State University , San Marcos, TX, 78666 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Manfred Schartl 1 Institute for Molecular Life Sciences, Texas State University , San Marcos, TX, 78666 2 Department of Chemistry and Biochemistry, Texas State University , San Marcos, TX, 78666 3 Developmental Biochemistry, Biocenter, University of Würzburg , Würzburg, Germany 4 Research Department for Limnology, University of Innsbruck , Mondsee, Austria Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yuan Lu 1 Institute for Molecular Life Sciences, Texas State University , San Marcos, TX, 78666 Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: y_l54{at}txstate.edu Abstract Full Text Info/History Metrics Supplementary material Preview PDF Abstract Oculocutaneous albinism (OCA) is a group of genetic disorders characterized by impaired melanin production, leading to reduced pigmentation in the skin, hair, and eyes. Xiphophorus , a genus of small freshwater fish, has been a pivotal model organism in pigmentation disorder research, providing key findings in the genetic pathways governing physiological and pathological pigment cell biology. Leveraging the well-established research framework provided by Xiphophorus , we have identified a spontaneously occurring albinism phenotype in swordtail fish Xiphophorus hellerii . Genetic mapping of albino fish showed that albinism is associated with a recessive mutation in the oca2 gene. This discovery provides a novel opportunity to explore functions of oca2 gene in pigment cell differentiation, pigment synthesis, melanosome assembly and transportation function and amelanotic melanoma development. Introduction Albinism encompasses a spectrum of inherited disorders characterized by defects in melanin production, resulting in reduced or absent pigmentation in the hair, skin, and eyes 1 . There are 7 types of oculocutaneous albinism (OCA) 2 . They are characterized by distinct phenotypes, ranging from complete lack of pigmentation in OCA1A, caused by mutations in the TYR gene, to milder hypopigmentation and variable vision issues in subtypes such as OCA2 and OCA4, which result from mutations in the OCA2 and SLC45A2 genes, respectively. OCA3, caused by mutations in the TYRP1gene, is often associated with reddish-brown skin and hair, while the rarer subtypes OCA5, OCA6, and OCA7 are associated with intermediate pigmentation and visual impairments. OCA6 is linked to mutations in the SLC24A5 gene, OCA7 is associated with mutations in C10ORF11, and the genetic cause of OCA5, mapped to chromosome 4q24, has yet to be identified. Due to their infrequency, these rarer subtypes exhibit less well-characterized phenotypic variability. 2 OCA2 is the most prevalent albinism worldwide, with an especially higher incidence for the African Black OCA patients 3 , 4 . Besides human, OCA is also observed in other vertebrates, including fish 5 – 7 , pig 8 , rodents 9 , 10 , water buffalo 11 , and rhesus macaque monkeys 12 , in which the same phenotypes, light body coloration along with pink or red eyes, are shared with mammals. Beyond its characteristic effects on pigmentation, albinism significantly influences both vision and sleep, as illustrated by studies in Astyanax mexicanus cavefish 13 and rhesus macaques 12 . O’Gorman et al. 13 demonstrate that OCA2 mutations in cavefish not only lead to albinism but also contribute to reduced sleep duration, a behavioral trait that likely supports increased foraging activity and survival in nutrient-scarce cave environments. In rhesus macaques with albinism 12 , research reveals that mutations in the tyrosinase (TYR) and OCA2 genes result in visual impairments, including foveal hypoplasia and retinal hypopigmentation, providing valuable insights into the genetic and clinical parallels of oculocutaneous albinism in humans. These findings highlight how OCA2 is associated with both visual and behavioral traits, contributing to adaptations necessary for survival in challenging environments. Additionally, different mutations in the OCA2 gene among humans are associated with an increased risk of melanoma 14 – 19 . Utilizing case-control studies, single nucleotide polymorphism (SNP) genotyping and sequencing, hypomorphic allele p.V443I 18 , 19 , along with p. R305W 14 and p.R419Q 15 , 17 , have been significantly associated with increased melanoma risk in specific populations. These OCA2 variants influence melanin production and pigmentary pathways, contributing not only to the pigmentation characteristics of melanomas but also to their risk and pathological diversity 14 . Evidence has been shown melanin-photosensitized radical product is the major causative step of melanoma 20 . This mechanism indicates that variations in melanin types and concentrations, influenced by OCA2 gene variants, enhance radical formation upon UV exposure. Such an increase in radicals can lead to more DNA damage, thereby raising the risk of melanoma development. Xiphophorus is a genus of 26 fresh water small fish species. They are used to study a wide range of diseases etiology or resilience 21 . The Xiphophorus species exhibit a wide array of body coloration patterns and are therefore implemented for investigation of genetics underpinning these traits. The best example refers to genetics underlying melanomagenesis 21 – 24 . However, the understanding melanophore biology, including genetics pathways affecting melanophore differentiation, proliferation, migration, melanosome assembly and intracellular trafficking, are understudied. Therefore, mutants exhibiting pigmentation pattern abnormality will offer unique opportunities to investigate the melanophore biology. In this study, we identified a spontaneously occurred albinism in swordtail fish Xiphophorus hellerii ( X. hellerii ). The albino individuals are characterized by absence of cutaneous and ocular pigmentation. We conducted genetics mapping and identified variant associated to the albino phenotype is a recessive mutation of oca2 gene. Material and Methods Research animals Fish were raised at the fish facilities of the Biocenter of the University of Würzburg and at the Xiphophorus Genetics Stock Center at Texas State University. All fish were kept and sample taken in accordance with approved experimental protocols through an authorization (568/300-1870/13) of the Veterinary Office of the District Government of Lower Franconia, Germany, and approved protocol by Texas State University IACUC (IACUC9048). The following laboratory lines were used: X. hellerii (strain hIII WLC 1336; origin in Rio Lancetilla, wild type pigmentation pattern). Albino swordtail strain (WLC 2378): the albino mutation from an ornamental swordtail strain was introduced into the genetic background of X. hellerii (hIII, WLC 1336) by repeated backcrossing. For mapping the albino locus, WLC 2378 males were crossed to females of strain WLC 534 which is heterozygous for the albino locus and the Spot Dorsal (Sd)-allele of xmrk in the genetic background of X. hellerii (hIII WLC 1336). Offspring were typed for albino (N=32) or wild type (N=59) pigmentation and absence or presence of xmrk . DNA and RNA isolation Fin clips from wild typeand albino X. hellerii males were collected and digested with Proteinase K at room temperature for 1 hour. The lysates were transferred to 2.0 mL collection tubes, and DNA was isolated using the QIAcube HT automated bio-sample isolation system (Qiagen, Valencia, CA, USA) with reagents from the QIAamp 96 DNA QIAcube HT Kit. The system features a robotic arm equipped with eight pipettes capable of picking and ejecting pipette tips, self-cleaning, and transferring liquids between wells, columns, or reservoirs in standard 96-well plate formats. Each sample was handled independently throughout the isolation process. DNA concentrations were measured using a Qubit 2.0 fluorometer (Life Technologies, Grand Island, NY, USA) and adjusted for sequencing library preparation. Skin samples were homogenized in TRI-reagent (Sigma Inc., St. Louis, MO, USA), followed by the addition of 200 μL/mL chloroform, vigorous shaking, and centrifugation at 12,000 g for 5 minutes at 4°C. Total RNA was purified using the RNeasy Mini RNA Isolation Kit (Qiagen, Valencia, CA, USA), with on-column DNase digestion performed at 25°C for 15 minutes to eliminate residual DNA. RNA concentrations were determined using a Qubit 2.0 fluorometer (Life Technologies, Grand Island, NY, USA), and RNA quality was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA). Only samples with RIN scores above 7.0 were used for subsequent gene expression profiling. Genome wide association study DNA sequencing reads were mapped to X. hellerii genome (GenBank assembly accession: GCA_003331165.2) using Bowtie2 25 . Mpileup files were made using samtools and genotyping was processed using Bcftools 26 , 27 Genotype in this study refers to inheritance of wild type or mutant alleles, with heterozygous meaning that a locus exhibited both allele calls, and homozygous means that a locus exhibited only mutant allele calls. Genotypes calls with high statistical confidence were kept for following analyses (i.e., Bcftools: MAPQ□ ≥ □30, Phred score of genotype call□=□0, with alternative genotype call Phred score□ ≥ □20). Per polymorphic locus, a Chisq test was used to test if genotype distribution is biased from an expected 50%-50% distribution of heterozygotes and homozygotes in both wild type and albino population. The Chisq test p-values were adjusted using Bonferroni method to for multiple test correction and were converted to −10*Log10p-value for Manhattan plot. Sequence analyses and polymerase chain reaction RNA sequencing reads were mapped to X. hellerii genome (GenBank assembly accession: GCA_003331165.2) using Tophat2. 28 The short read mapping results in BAM format were indexed and visualized using table genome browser IGV that is configured for X. hellerii genome. 26 , 29 Each homozygous variant in albino samples were manually analyzed for codon-change mutation. Sashimi plot was made using IGV to show sequencing reads density at exon-exon junctions. Total RNA was isolated from skin of both wild type and albino fish. Reverse transcription was conducted using total RNA with random primers. To amplify exon 16, primers were designed on oca2 (RefSeq: NC_045680.1) exon 16. The forward primer sequence is: 5’-AACTGAAGCATGAGATCCTG-3’; The reverse primer sequence is: 5’-CTCTGGAAGGTTTTCATCAT-3’. Electrophoresis was performed to test the PCR amplicon size, followed by amplicons recovered and Sanger Sequencing performed (Azenta Life Sciences, Burlington, MA, USA). Protein structure prediction The amino acid sequence of the Xiphophorus wild type oca2 was retrieved from NCBI (XP_014326265.1). The mutant allele protein sequence was translated from coding sequencing that is constructed by adding sanger sequencing recovered insertion into wild type oca2 protein sequence. Both wild type and mutant OCA2 protein structures were modeled using AlphaFold3 30 . The amino acid sequences were formatted in FASTA and put into Alphafold3 to generated structural prediction for each isoform. The models with the highest Predicted Template Modeling (pTM) scores were selected for further analysis. Structural alignments and visualizations were conducted using PyMol to assess the impact of the alterations on the protein structure. Results X. hellerii albinism is a monogenic recessive coloration disorder The X. hellerii exhibits three main types of chromatophores: melanophores, which synthesize black or dark-brown eumelanin; xanthophores, which contain carotenoid-based yellow pigments; and erythrophores, which contain pteridine-based red pigments 31 . Additionally, iridophores produce iridescent blue, green, or silver colors through the reflection of light by guanine crystals. The melanophores usually locate between fin rays and at the edge of scales, erythrophores locates around the lateral line, and xanthophores are in the dorsal fin and also caudal fin. The albino X. hellerii exhibit no melanophore pigmentation pattern but intact erythrophores and xanthophore pigmentation patterns. In addition, there is no ocular pigmentation and the fish have red eyes ( Fig. 1B ). Download figure Open in new tab Figure 1. Wild type and albino X. hellerii (A) Wild type X. hellerii exhibit macromelanophores (black) in the eyes, at the edge of scale, and between fin rays. Erythrophores (red) appear along the body side lateral line and between fin rays. (B) Albino X. hellerii exhibit no macromelanophore pigmentation patterns in the eye, skin and fins. Download figure Open in new tab Figure 2. Genetic mapping of genetic locus underlying albinism Hybrids were produced by reciprocally crossing albino animal to heterozygous animal for the albino locus. A total of 32 albino and 59 heterozygous animals were sequenced, detected for genetic variants, and genotyped for polymorphic sites. Manhattan plot showing –log10 P value of χ2 test across the genome. The y axis represents –log 10 P value and the x axis represents polymorphism coordinates on each chromosome, which is labeled as red (odd number chromosomes) or blue (even number chromosomes). χ2 test P values were corrected using FDR method across the genome-wide data. The black dashed line represents adjusted P value of 0.05. Hybrids between albino animal to wild type animal exhibit normal pigmentation pattern, suggesting the genetics variant underlying the albinism is recessive. In order to identify the albino-associated genetic variants, we created a hybrid population by first crossing albino X. hellerii with a xmrk - introgressed X. hellerii , which was established by repetitively backcrossing xmrk -bearing interspecies hybrids between X. maculatus and X. hellerii to X. hellerii . The rationale of using xmrk introgressed line as parental is to rely on xmrk mapping as positive control for genetic mapping. In successive breeding pair setup, we used individuals showing normal body and ocular coloration (albino locus heterozygotes) with xmrk -associated melanophore and erythrophore pigmentation pattern enhancement, and homozygous albino xmrk -negative individuals as parentals. We generated a total of 91 hybrids, including 32 albino (35%) and 59 wild type (65%; Table 1 ). View this table: View inline View popup Download powerpoint Table 1. Genotype and phenotype distribution Genetics Mapping of Albinism Inheritance of the xmrk gene leads to expansion of erythrophore and melanophore pigmentation pattern. Therefore, the hybrids inherited the xmrk exhibit red coloration on the body side and expanded dorsal fin melanophore pigmentation pattern. Since the xmrk introgression is known to be on Chr21, it allows us to test the accuracy of genetics mapping. Genetics mapping of genetic locus underlying the enhanced red pigmentation pattern resulted peaks at the region encoding xmrk (Fig. S1). There is a single locus identified that is associated to the albinism (multiple test corrected p -value < 0.05; Chr 9: 24,167,249 bp – 24,380,394 bp). Allelic inheritance analyses of the hybrid population within this candidate region showed that all albino individuals are homozygous for variant allele, and all wild type individuals are heterozygous (Table S1). This candidate region from the genetics mapping include 6 genes: herc2, oca2 , LOC116725874, gabrg3, gabra5 , and gabrb3 . Manual curation of genetics variant analyses showed all albino-associated single nucleotide variants (SNVs) within these genes are intronic (25 of 28), intergenic (2 of 28), or synonymous (1 of 28; Table S1). Mutations in oca2 underlie Xiphophorus albinism RNA-sequencing of wild type and albino individuals showed all genes within the peak region are expressed between albino and wild type individuals. However, we found a large region on exon 16 of oca2 showing absence of sequencing read mapping for albino individuals ( Fig. 3A ). We hypothesize that oca2 has a large structural change, e.g., insertion or deletion. Download figure Open in new tab Figure 3. An insertion in oca2 exon 16 is associated to albinism in Xiphophorus (A) Sashimi plot showing quantification of junction reads connecting exons. The top and middle panel respectively shows quantities of RNA sequencing reads spanning the exon-exon junction (numbers) and mapping locations (density bar graphs) of wild type and albino fish. Bottom panel shows partial oca2 gene model, with thick lines represented exons. Arrows point to exon 16. (B) Electrophoresis gel images of RT-PCR amplicons representing exon 16 of two albino and two wild type fish. To test this hypothesis, we sequenced oca2 exon 16 of both wild type and albino individuals. The results revealed that the albinism-associated oca2 allele contains an approximate 480 bp insertion compared to the wild type allele ( Fig. 3B ). Structural analyses of oca2 mutation This insertion introduces a stop codon ( Fig. 4A ). Structural alignment of the wild type and albino OCA2 proteins ( Fig. 4 ) shows that the mutant allele has a truncation that extend beyond the cytoplasmic region, resulting in the loss of the OCA2 function ( Fig. 4C ). Download figure Open in new tab Figure 4. Protein structure analyses of albino allele of Xiphophorus OCA2 (A) Peptide sequences wild type and albino OCA2 translated from exon 16 sequences. The mutation in the albino allele introduces an early stop codon, and truncated OCA2 protein. (B) Wild type and (C) mutant protein structures were generated from the Alphafold and the pTM scores are 0.67 and 0.58 respectively. Discussion The gene underlying the OCA2 in human is known as OCA2 (also known as pink-eyed dilution locus in mice) 9 , 32 , which encodes an integral melanosomal protein with 12 predicted transmembrane domains 33 , 34 . Although the precise function of the OCA2 is not fully understood, it is known to play two role: 1. Melanin biosynthesis: OCA2 is involved in the transport of melanosomal proteins and pH regulation within the melanosome 35 . The melanogenesis pathway relies on TYR activity to initiate melanin synthesis by converting tyrosine to dihydroxyphenylalanine (DOPA) and then to dopaquinone. These reactions occur in an acidic environment, while the following steps of melanogenesis require a neutral pH for TYR to catalyze intermediates that lead to pigment production 36 . OCA2 contributes to a melanosome-specific anion current that modulates melanosomal pH for optimal TYR activity required for melanogenesis 37 . Hence, inhibition of OCA2 functioning is expected to cause changes in melanin synthesis and impact melanosome morphology and quantity 34 . 2. Pigment cell lineage differentiation: The number of pigmented melanosomes decreased in the Oca2 mutant porcine compared to the wild type pigs 8 . The Oca2 has been reported to affect proliferation of mouse melanocytes through regulating the expression and activity of melanosomal proteins 38 . The oca2 knockdown in the wild type pigmented embryos of the surface conspecifics of Mexican cavefish delays the development of pigmented melanophores 6 . The oca2 mutant in zebrafish shows a reduction in the number of differentiated melanophores and significantly higher numbers of differentiated iridophores than wild type siblings 39 . In this study, we identified a spontaneous large truncation in the OCA2 protein is associated with albinism in X. hellerii . The truncation is expected to affect the protein function significantly by eliminating key structural regions and altering its overall conformation, and may play a role in pigment biosynthesis and/or melanophore differentiation. The Xiphophorus fishes are best recognized for their variations in pigmentation patterns, and elucidating negative genetic interactions underlying spontaneous melanoma development in interspecies hybrids. 21 In our future studies, we will leverage on the newly found natural oca2 mutation and investigate oca2 function in chromophore lineages differentiation and development. In addition, we will cross the albino fish to Xiphophorus fish with melanoma driving gene to study how oca2 affect genetic pathways promoting the melanoma development. Supplemental Figure Figure S1. Genetic mapping of xmrk A total of 59 animals exhibiting red coloration enhancement and 32 animals exhibit wild type erythrophore pigmentation pattern were sequenced, detected for genetic variants, and genotyped for polymorphic sites. Manhattan plot showing –log10 P value of χ2 test across the genome. The y axis represents –log 10 P value and the x axis represents polymorphism coordinates on each chromosome, which is labeled as red (odd number chromosomes) or blue (even number chromosomes). Supplemental Table Table S1. Genetic Variants in Albino vs. Wild type Acknowledgements This work was supported by the National Institutes of Health, National Cancer Institute, R15 CA -223964 to Y. Lu, Office of Director R24 OD-031467 to Y. Lu and M. Schartl, R2R1 accelerator award from Texas State University to Y. Lu and M. Schartl. References 1. ↵ Oetting , W. S. , Brilliant , M. H. & King , R. A. The clinical spectrum of albinism in humans . Mol. Med. Today 2 , 330 – 335 ( 1996 ). OpenUrl CrossRef PubMed Web of Science 2. ↵ Kamaraj , B. & Purohit , R. Mutational Analysis of Oculocutaneous Albinism: A Compact Review . BioMed Res. Int . 2014 , e905472 ( 2014 ). OpenUrl 3. ↵ Grønskov , K. , Ek , J. & Brondum-Nielsen , K. Oculocutaneous albinism . Orphanet J. Rare Dis . 2 , 43 ( 2007 ). OpenUrl CrossRef PubMed 4. ↵ Mabula , J. B. et al. Skin cancers among Albinos at a University teaching hospital in Northwestern Tanzania: a retrospective review of 64 cases . BMC Dermatol . 12 , 5 ( 2012 ). OpenUrl CrossRef PubMed 5. ↵ Protas , M. E. et al. Genetic analysis of cavefish reveals molecular convergence in the evolution of albinism . Nat. Genet . 38 , 107 – 111 ( 2006 ). OpenUrl CrossRef PubMed Web of Science 6. ↵ BilandŽija , H. , Ma , L. , Parkhurst , A. & Jeffery , W. R. A Potential Benefit of Albinism in Astyanax Cavefish: Downregulation of the oca2 Gene Increases Tyrosine and Catecholamine Levels as an Alternative to Melanin Synthesis . PLOS ONE 8 , e80823 ( 2013 ). OpenUrl CrossRef PubMed 7. ↵ Kratochwil , C. F. , Urban , S. & Meyer , A. Genome of the Malawi golden cichlid fish (Melanochromis auratus) reveals exon loss of oca2 in an amelanistic morph . Pigment Cell Melanoma Res . 32 , 719 – 723 ( 2019 ). OpenUrl CrossRef PubMed 8. ↵ Zhang , Y. et al. A novel porcine model reproduces human oculocutaneous albinism type II . Cell Discov . 5 , 1 – 3 ( 2019 ). OpenUrl CrossRef PubMed 9. ↵ H. Brilliant , M. The Mouse p (pink-eyed dilution) and Human P Genes, Oculocutaneous Albinism Type 2 (OCA2), and Melanosomal pH . Pigment Cell Res . 14 , 86 – 93 ( 2001 ). OpenUrl CrossRef PubMed Web of Science 10. ↵ Blaszczyk , W. M. , Arning , L. Hoffmann , K.-P. & Epplen , J. T. A Tyrosinase missense mutation causes albinism in the Wistar rat . Pigment Cell Res . 18 , 144 – 145 ( 2005 ). OpenUrl CrossRef PubMed Web of Science 11. ↵ Damé , M. C. F. et al. A nonsense mutation in the tyrosinase gene causes albinism in water buffalo . BMC Genet . 13 , 62 ( 2012 ). OpenUrl CrossRef PubMed 12. ↵ Wu , K.-C. et al. Nonhuman Primate Model of Oculocutaneous Albinism with TYR and OCA2 Mutations . Research 2020 , ( 2020 ). 13. ↵ O’Gorman , M. et al. Pleiotropic function of the oca2 gene underlies the evolution of sleep loss and albinism in cavefish . Curr. Biol . 31 , 3694 - 3701 .e4 ( 2021 ). OpenUrl CrossRef PubMed 14. ↵ Jannot , A.-S. et al. Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma . Eur. J. Hum. Genet . 13 , 913 – 920 ( 2005 ). OpenUrl CrossRef PubMed Web of Science 15. ↵ Fernandez , L. P. et al. Pigmentation-related genes and their implication in malignant melanoma susceptibility . Exp. Dermatol . 18 , 634 – 642 ( 2009 ). OpenUrl CrossRef PubMed Web of Science 16. Ibarrola-Villava , M. et al. Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A, MC1R and HERC2/OCA2 . Exp. Dermatol . 19 , 836 – 844 ( 2010 ). OpenUrl CrossRef PubMed 17. ↵ Duffy , D. L. et al. Multiple Pigmentation Gene Polymorphisms Account for a Substantial Proportion of Risk of Cutaneous Malignant Melanoma . J. Invest. Dermatol . 130 , 520 – 528 ( 2010 ). OpenUrl CrossRef PubMed Web of Science 18. ↵ Hawkes , J. E. et al. Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree . J. Dermatol. Sci . 69 , 30 – 37 ( 2013 ). OpenUrl CrossRef PubMed 19. ↵ Rayner , J. E. et al. Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants . PLOS ONE 15 , e0238529 ( 2020 ). OpenUrl CrossRef PubMed 20. ↵ Wood , S. R. et al. UV causation of melanoma in Xiphophorus is dominated by melanin photosensitized oxidant production . Proc. Natl. Acad. Sci . 103 , 4111 – 4115 ( 2006 ). OpenUrl Abstract / FREE Full Text 21. ↵ Schartl , M. & Lu , Y. Validity of Xiphophorus fish as models for human disease . Dis. Model. Mech . 17 , dmm050382 ( 2024 ). OpenUrl CrossRef PubMed 22. Lu , Y. et al. Oncogenic allelic interaction in Xiphophorus highlights hybrid incompatibility . Proc. Natl. Acad. Sci . 117 , 29786 – 29794 ( 2020 ). OpenUrl Abstract / FREE Full Text 23. Powell , D. L. et al. Natural hybridization reveals incompatible alleles that cause melanoma in swordtail fish . Science 368 , 731 – 736 ( 2020 ). OpenUrl Abstract / FREE Full Text 24. ↵ Soria , E. et al. Segregation Between an Ornamental and a Disease Driver Gene Provides Insights Into Pigment Cell Regulation . Pigment Cell Melanoma Res . n/a ,. 25. ↵ Langmead , B. & Salzberg , S. L. Fast gapped-read alignment with Bowtie 2 . Nat. Methods 9 , 357 – 359 ( 2012 ). OpenUrl CrossRef PubMed Web of Science 26. ↵ Li , H. & Durbin , R. Fast and accurate short read alignment with Burrows-Wheeler transform . Bioinforma. Oxf. Engl . 25 , 1754 – 1760 ( 2009 ). OpenUrl 27. ↵ Li , H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data . Bioinforma. Oxf. Engl . 27 , 2987 – 2993 ( 2011 ). OpenUrl 28. ↵ Kim , D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions . Genome Biol . 14 , R36 ( 2013 ). OpenUrl CrossRef PubMed 29. ↵ Robinson , J. T. et al. Integrative genomics viewer . Nat. Biotechnol . 29 , 24 – 26 ( 2011 ). OpenUrl CrossRef PubMed Web of Science 30. ↵ Abramson , J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3 . Nature 630 , 493 – 500 ( 2024 ). OpenUrl CrossRef PubMed 31. ↵ Schartl , M. et al. What is a vertebrate pigment cell? Pigment Cell Melanoma Res . 29 , 8 – 14 ( 2016 ). OpenUrl CrossRef PubMed 32. ↵ Rinchik , E. M. et al. A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism . Nature 361 , 72 – 76 ( 1993 ). OpenUrl CrossRef PubMed 33. ↵ Rosemblat , S. et al. Identification of a melanosomal membrane protein encoded by the pink-eyed dilution (type II oculocutaneous albinism) gene . Proc. Natl. Acad. Sci . 91 , 12071 – 12075 ( 1994 ). OpenUrl Abstract / FREE Full Text 34. ↵ Park , S. et al. Unrevealing the role of P-protein on melanosome biology and structure, using siRNA-mediated down regulation of OCA2 . Mol. Cell. Biochem . 403 , 61 – 71 ( 2015 ). OpenUrl CrossRef PubMed 35. ↵ Rimoldi , V. et al. Functional characterization of two novel splicing mutations in the OCA2 gene associated with oculocutaneous albinism type II . Gene 537 , 79 – 84 ( 2014 ). OpenUrl CrossRef PubMed Web of Science 36. ↵ Wiriyasermkul , P. , Moriyama , S. & Nagamori , S. Membrane transport proteins in melanosomes: Regulation of ions for pigmentation . Biochim. Biophys. Acta BBA - Biomembr . 1862 , 183318 ( 2020 ). OpenUrl CrossRef 37. ↵ Bellono , N. W. , Escobar , I. E. , Lefkovith , A. J. , Marks , M. S. & Oancea , E. An intracellular anion channel critical for pigmentation . eLife 3 , e04543 ( 2014 ). OpenUrl CrossRef PubMed 38. ↵ Hirobe , T. , Kawa , Y. , Mizoguchi , M. , Ito , S. & Wakamatsu , K. Effects of genic substitution at the pink-eyed dilution locus on the proliferation and differentiation of mouse epidermal melanocytes in vivo and in vitro . J. Exp. Zool . 292 , 351 – 366 ( 2002 ). OpenUrl CrossRef PubMed Web of Science 39. ↵ Beirl , A. J. , Linbo , T. H. , Cobb , M. J. & Cooper , C. D. oca2 regulation of chromatophore differentiation and number is cell type specific in zebrafish . Pigment Cell Melanoma Res . 27 , 178 – 189 ( 2014 ). OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted January 23, 2025. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. 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