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Current Biology 23, 1031–1035, June 3, 2013 ª2013 Elsevier Ltd All rights 4ReportThe Genetic Basis of White TigersXiao Xu,1 Gui-Xin Dong,4 Xue-Song Hu,1 Lin Miao,1Xue-Li Zhang,4 De-Lu Zhang,4 Han-Dong Yang,4Tian-You Zhang,4 Zheng-Ting Zou,1 Ting-Ting Zhang,1Yan Zhuang,1 Jong Bhak,5 Yun Sung Cho,5 Wen-Tao Dai,6Tai-Jiao Jiang,6 Can Xie,2 Ruiqiang Li,3,* and Shu-Jin Luo1,*1Peking-Tsinghua Center for Life Sciences, Laboratory ofGenomic Diversity and Evolution, College of Life Sciences2State Key Laboratory of Biomembrane and MembraneBiotechnology, Laboratory of Receptor Biology, College ofLife Sciences3Peking-Tsinghua Center for Life Sciences, BiodynamicOptical Imaging Center and College of Life SciencesPeking University, Beijing 100871, China4Chimelong Safari Park, Chimelong Group Co., Panyu,Guangzhou 511430, China5Personal Genomics Institute, Genome Research Foundation,Suwon 443-270, South Korea6Key Laboratory of Protein and Peptide Pharmaceuticals,Institute of Biophysics, Chinese Academy of Sciences,Beijing 100101, ChinaSummaryThe white tiger, an elusive Bengal tiger (Panthera tigristigris) variant with white fur and dark stripes, has fascinatedhumans for centuries ever since its discovery in the junglesof India [1]. Many white tigers in captivity are inbred in orderto maintain this autosomal recessive trait [2–5] and consequently suffer some health problems, leading to the controversial speculation that the white tiger mutation is perhaps agenetic defect [6]. However, the genetic basis of this phenotype remains unknown. Here, we conducted genome-wideassociation mapping with restriction-site-associated DNAsequencing (RAD-seq) in a pedigree of 16 captive tigerssegregating at the putative white locus, followed by wholegenome sequencing (WGS) of the three parents. Validationin 130 unrelated tigers identified the causative mutation tobe an amino acid change (A477V) in the transporter proteinSLC45A2. Three-dimensional homology modeling suggeststhat the substitution may partially block the transporterchannel cavity and thus affect melanogenesis. We demonstrate the feasibility of combining RAD-seq and WGS torapidly map exotic variants in nonmodel organisms. Our results identify the basis of the longstanding white tiger mystery as the same gene underlying color variation in human,horse, and chicken and highlight its significance as part ofthe species’ natural polymorphism that is viable in the wild.Results and DiscussionThe White Tiger Is Not a True AlbinoCoat color and pattern are prominent morphological featuresin mammals and play an essential role in survival. Individualsof the same species are often defined by shared morphological characteristics, and most species present an overall uniform coat color. Tigers are characterized by their iconicpattern of black stripes against an orange background;*Correspondence: [email protected] (R.L.), [email protected] (S.-J.L.)however, they are also among the several known mammaliantaxa that display natural intraspecific coat color polymorphism(Figure 1A). The white tiger is a rare variant of the Bengal tiger(Panthera tigris tigris) that has dark or sepia brown stripes onwhite fur, blue eyes, a pink nose, and pink paw pads [2, 4, 5].They were once observed sporadically in the wild on the Indiansubcontinent, with the oldest record dating back to the 1500s[1]. In 1951, a male white tiger named Mohan was captured inRewa, now part of Madhya Pradesh in India, from whichnumerous white tigers were bred for captivity [2–6]. The whitetiger provides a precious opportunity to better understandmammalian coat color formation and adaptive pigmentation;however, except for the monogenetic autosomal recessivemode of inheritance, its genetic basis remains unknown.Melanin is the pigment determining skin, hair, and eye colorand has two major types: pheomelanin produces red to yellowcolors, and eumelanin produces black to brown. Repression ofeither of these pigments influences specific color formation[7]. Melanin can be found in a variety of pigmented tissuesand plays diverse roles in multiple biological pathways. Severemelanin deficiency or alterations have been connected to anumber of human diseases such as oculocutaneous albinism,Hermansky-Pudlak syndrome, Griscelli syndrome, and melanoma [7].The white tiger is not a true albino, in that although pheomelanin is largely absent, eumelanin is present in the eyes andin the hairs of stripes [2, 5]. Some white tigers also showstrabismus, probably due to the reduction of pigment in theretinal epithelium and iris during eye development [8]. Robinson [2, 3] postulated that the white tiger mutation resemblesa chinchilla allele at the albino locus because of its phenotypicsimilarity to the chinchilla variant in rodents and the Burmesebreed of domestic cat. We therefore began by examiningpreviously reported mammalian coat color-determininggenes, including MC1R, ASIP, TYR (the albino gene), TYRP1,and SLC7A11, in both white and orange tigers. No variationassociated with the white tiger was observed (see Table S2available online), disproving Robinson’s proposed geneticmechanism.A Single Amino Acid Change in SLC45A2 Causes the WhiteTiger PhenotypeWe refer to the white tiger-determining gene as a distinct‘‘white locus’’ with two alleles: W, the wild-type, is dominantover w, the recessive mutant [5]. We recruited a Ww 3 wwcaptive tiger pedigree (n 16) including seven white and ninewild-type tigers (Figures 1B and S1; Table S1). We performedwhole-genome sequencing (WGS) in the three parents (TablesS3 and S4) at 303 genome coverage each and restriction-siteassociated DNA sequencing (RAD-seq) [9–12] in the 13offspring (Table S4). A total of 509,220 SNP markers were identified and aligned to the tiger reference genome (http://tigergenome.org), among which 172,554 contained data fromat least 15 of the 16 individuals and were used for a genomewide association study (GWAS) at an approximate markerdensity of 1 SNP per 14 kb. SNPs from scaffolds 75, 188,and 1458 showed significant association (p 0.001) with thewhite phenotype (Figure 2A; Table S5). Scaffold 188 wasdiscarded, as it failed to fit the recessive inheritance pattern.Scaffolds 75 and 1458 demonstrate conserved syntenywith human chromosome 5 (19.71–36.04 Mb, hg19) and cat

Current Biology Vol 23 No 111032AOrange tigerFigure 1. Tiger Coat Color and PedigreeWhite tiger(A) The white tiger mutant (ww, right) is recessiveto the orange (WW or Ww).(B) The SLC45A2 A477V substitution cosegregates with the white phenotype in a pedigreethat includes seven white and nine orange tigers(W wild-type A477 allele; w mutant A477Vallele).See also Table S1.BwwGZXJ34WwwwGZXJ39GZXJ35Orange tigerWwWwwwvertebrate species, including mouse,horse, chicken, and medaka fish (Figure 3A) [18–21]. These results supportthat SLC45A2 is the tiger white gene,and that the single amino acid changeA477V is causative for the recessivewhite phenotype.SLC45A2 Homology ModelingSuggests the Functional Effect of theA477V SubstitutionGZXJ33 GZXJ05 GZXJ06Residue A477 of the 560 amino acids ofSLC45A2 is highly conserved amongvertebrates (Figures 3A and 3B), and awwWwwwWwwwWwWwwwWwWwmutation at the same position (A477T)has been reported only once in humans,in an OCA4 German with pale skin andGZXJ04 GZXJ03 GZXJ32 GZXJ26 GZXJ38 GZXJ27 GZXJ30 GZXJ31 GZXJ28 GZXJ29dark blonde hair [15]. To decipher thepotential functional impact of theA477V substitution, we generated achromosome A1 (210.57–223.49 Mb, felCat5) and are adjacent three-dimensional protein structure homology model ofSLC45A2. The modeled SLC45A2 structure consists of 12to each other on the same chromosome (Figure 2B).Linkage analysis in these two candidate scaffolds revealed transmembrane helices connected by loop regions, formingone haplotype block of 3.3 Mb at complete linkage disequilib- a transporter protein-like structure (Figure 3C). The substraterium (LD, r2 1; Figure 2C). All white tigers examined in the transportation cavity is surrounded by four transmembranepedigree were fixed for a single haplotype spanning 52 SNPs helices: TM4, TM5, TM10, and TM11 (Figure 3D). Residuefrom position 871,133 to 4,192,353 in scaffold 75 (Figure 2C; A477 is located on TM11 facing the inner surface of the transTable S6). All wild-type tigers (Ww at the white locus) from porter cavity toward the cytoplasm, and the two additionalmethyl groups introduced in the valine substitution of A477the pedigree were heterozygous for this haplotype.Annotation of the tiger reference genome suggested 23 lead to a reduction in cavity size (Figure 3D). We speculategenes in this candidate LD interval (Figure 2C). Through scan- that the A477V substitution might partially block the cavity,ning all SNPs among the three WGS parent genomes within the hindering substrate transport of SLC45A2.candidate region, we identified seven genes displaying polymorphisms in the coding regions between white and wild- Mutation in SLC45A2 Primarily Affects Pheomelanintype tigers (Table S7). Nonsynonymous substitutions in two Pigmentation in the Tigergenes were considered putative mutations, including the C- The SLC45A2 missense mutation in the white tiger primarily into-T transition in exon 7 in SLC45A2 (solute carrier family 45 hibits the synthesis of red/yellow pheomelanin, with no or onlymember 2, also known as MATP or AIM-1), which corresponds minor effect on black eumelanin, a specific phenotypic featureto alanine-to-valine substitution at amino acid residue 477 also observed in SLC45A2 mutant cream horses and silverchickens [20, 21]. It is intriguing that some recessive null allele(A477V), and the D1125A substitution in ADAMTS12.The two genes are tightly linked, are approximately 300 kb mutations in SLC45A2, such as the underwhite allele in mouseapart on the chromosome, and are perfectly segregated in and the sex-linked imperfect albinism allele in chicken [18, 20],the five white and eight wild-type first-generation offspring. inhibit both eumelanin and pheomelanin pigmentation,In an extended study that included 130 unrelated tigers from whereas some missense mutations, such as the chicken Silvervarious sources, the phenotype correlated exactly with the allele, are dominant and cause a specific inhibition of pheomeA477V substitution in SLC45A2, but not the D1125A substitu- lanin in homozygotes or heterozygotes. The Cream allele oftion in ADAMTS12 (Table 1). SLC45A2 is a pigmentation- SLC45A2 in horses primarily affects pheomelanin in heterorelated gene in humans, whose polymorphisms are associated zygotes, yet it inhibits both eumelanin and pheomelaninwith light skin color in modern Europeans and pathogenic mu- synthesis in homozygotes [21]. Although the white tigertations known to cause oculocutaneous albinism type 4 mutation mimics the effects of SLC45A2 mutations in chickens(OCA4; Figure 3A) [13–18]. Mutations in SLC45A2 also cause and horses, it is apparently a missense yet recessive allele.lightened skin and/or hair pigmentation in several other Further studies on these missense mutations in the tiger,White tiger

The Genetic Basis of White Tigers1033AFigure 2. Genetic Mapping of the White TigerMutation Based on RAD-Seq and WholeGenome Sequencing-lg(p)5scaffold754(A) Genome-wide p values (y axis) of 172,554SNPs are plotted every 500 kb based on thereference tiger genome scaffold numeric order(x axis). SNPs within one scaffold are arrangedby level of significance, and those from highlyassociated scaffolds are marked in red.(B) Conserved synteny of tiger genome scaffolds75 and 1458 to the cat and human genomes.(C) Haplotype block at linkage disequilibrium (LD)with the white phenotype based on 186 restriction-site-associated DNA SNPs. Regions withoutSNP coverage are gray. The diagram below indicates all genes within the candidate region in thetiger genome. See also Figure S1 and Tables S3,S4, S5, S6, and 0175020002250Human (Chr5, hg19)studies have suggested that SLC45A2may be a sucrose or proton transporter19.71because it shares structural similarityand the signature RXGRR motif withsucrose/proton symporters in plants[18, 19]. This is supported by the recent223.49discovery of the Drosophila melanogaster sucrose/proton cotransporterSCRT, which phylogenetically clusterswith the SLC45 protein family and exhibits the highest degree of aminor2 1acid similarity with SLC45A2 [23].0.75Tyrosinase processing and trafficking0.5is regulated by organellar pH [24], andin addition, the crenate melanosome0.25found in the uw mouse mutant [22, 25]0implies disruption of osmotic balancingthat is probably due to the disruption ofsucrose transportation [22]. Taking theevidence together, it is plausible thatSLC45A2 is a sucrose/proton symporter and mediates melanin synthesisScaffold14581 Mbby regulating organellar pH and/orosmotic balancing.A recent study on feline coat patterns proposed that the patterned coatis sustained by the comparativelyhigh expression of EDN3 in darkmarking regions (e.g., cats’ tabbystripes and cheetahs’ spots), whichstimulates region-specific eumelanogenesis (TYR, TYRP1, DCT, SILVupregulated) through the EDNRB pathway [26]. The mechanism may be conserved in the Felidae and explains why thewhite tiger retains dark stripes despite its melanogenesisbeing affected by SLC45A2.(Mb)36.0428.99Cat (Chr A1, felCat5)210.57216.13Scaffold75Tiger ARSwhite tiger LD (3.3 RSLC45A2RXFP32500 (Mb)chicken, and horse may shed light on the specific function ofSLC45A2 associated with the eumelanin and pheomelaninpathways.The various phenotypic outcomes of SLC45A2 mutationscannot be explained based on the current limited understanding of its function. Because cysteine is essential forpheomelanin production, it has been speculated that onefunction of SLC45A2 might be to transport cysteine into themelanosome, and that this function may be disrupted bymissense mutations at the locus [20]. Alternatively, mouseSLC45A2 was reported to be involved in pigmentation byregulating the processing and trafficking of tyrosinase,the enzyme critical for melanin biosynthesis [22]. PreviousCDH60Implications for Tiger ConservationAll tested white tigers were homozygous for the SLC45A2A477V allele, and only one orange tiger carried the mutantallele in the heterozygous form (Table 1; see also Table S1),consistent with the idea that the white mutation has evolvedonly once and that its frequency is probably never high.The last known free-ranging white tiger was shot in 1958,before which sporadic sightings were made in India [27].

Current Biology Vol 23 No 111034Table 1. Correlation between Tiger Coat Color Phenotypes and eSLC45A2A477V/A477VA477V/ / D1125A/D1125AD1125A/ / missing data20 (7)0020 (7)00020 (7)01 (9)1091930 (9)601110 (9)ADAMTS12TotalNumbers represent unrelated individuals used in the extended validationstudy. Numbers in parentheses represent related individuals from the pedigree shown in Figure 1B. See also Tables S1, S2, and S7.Reasons for the extinction of wild white tigers were likely thesame as those accounting for the dramatic decline in wildtigers in general: uncontrolled trophy hunting, habitat loss,and habitat fragmentation [28].Public admiration for exotic animals has driven the captivebreeding of white tigers from only a few individuals, whichare highly inbred in order to preserve this recessive trait.Inbreeding depression has thus become the primary causeof many health problems for white tigers in captivity, such aspremature death, stillbirth, and deformities [6, 8]. This hasled to speculation that the white tiger trait is a genetic deformity. However, the fact that many white tigers captured orshot in the wild were mature adults suggests that a white tigerin the wild is able to survive without its fitness being substantially compromised [6]. The undesirable traits often associatedwith captive white tigers are thus most likely due to humaninduced inbreeding. Indeed, SLC45A2 mutations in humanand chicken (e.g., the White Leghorn breed) worldwide rarelycause phenotypic features other than hypopigmentation [13–18, 20]. Therefore, we argue that the SLC45A2 A477V substitution in the tiger primarily affects only pigmentation, and thatthe white tiger morph is a viable natural genetic polymorphism.Despite its low frequency, this polymorphism has persisted forat least several hundred years and should be considered a partof the genetic diversity of tigers that is worth conserving.AFigure 3. The White Tiger Causative Mutation inSLC45A2B(A) Schematic diagram depicting variations inSLC45A2 reported in human and other mammalianspecies previously (selected list) and in this study.Periplasmic or cytoplasmic regions (white boxes)and the 12 transmembrane domains (yellowboxes) of SLC45A2 are shown.(B) Partial alignment of SLC45A2 amino acidsequence among vertebrate species. Dots (,)represent residues identical to the tiger referencesequence, and dashes (2) represent deletions.The 11th transmembrane domain is boxed in yellow, with the white tiger mutation A477V in red.(C) Ribbon representation of the structure modelof tiger SLC45A2 viewed from within the membrane. Residue A477 is located at the end of thesubstrate-translocation pathway, close to thecytosol side.(D) Periplasmic (top) view of the homology modelof SLC45A2 (with A477V substitution) in surfacerepresentation. The 12 transmembrane a helicesare shown as ribbons. A477V is shown with thetwo additional methyl group carbons as greenspheres.CD

The Genetic Basis of White Tigers1035ConclusionMapping the white mutation in the tiger to the A477V substitution in the transporter protein SLC45A2 proves the efficiency ofusing pedigree-based GWAS followed by WGS to identifycausative genes and mutations based upon next-generationRAD-seq in an exotic species. For the variety of charismaticnonmodel organisms carrying unique or significant phenotypes that are controlled by single genes, this approach promises to be a simple, efficient, and cost-effective means of geneand mutation mapping. Because the SLC45A2 A477V substitution affects the white tiger’s pigmentation only, withoutcausing severe physiological defects, we argue that the whitetiger morph is a naturally occurring and viable feature of genetic diversity in tigers.Accession NumbersGenome resequencing and RAD-seq reads have been deposited in theNCBI BioProject database (SRP017677) under the accession numbersSRS381413–SRS381428 and SRS381821.Supplemental InformationSupplemental Information includes one figure, seven tables, and Supplemental Experimental Procedures and can be found with this article onlineat ledgmentsAll biological samples were recruited in full compliance with the Conventionon International Trade in Endangered Species (CITES) and other relevantpermissions issued to S.-J.L. and the College of Life Sciences, PekingUniversity, by the State Forestry Administration of China. We are gratefulto all the institutes, zoos, and private donors listed in Table S1 for providingbiological specimens upon which this study is based. In particular, we thankD. Smith, J.Q. Zheng, Y.H. Yuan, and R.Z. Yang for their contributions to theproject. We acknowledge Chimelong Safari Park for animal studbookinformation and photos, as well as animal handling assistance fromY.S. Zhong, R.A. Qiu, B.H. Li, Z.Q. Lei, W.H. Yang, and J. Dong. Weappreciate the technical assistance provided by F.C. Tang, Y. Zhang, andW.P. Ma in genome sequencing and E. Johnson, B. Peterson, K. Emerson,and Y. Surget-Groba for helpful discussions regarding RAD-seq. We thankC. Yeung for editing the manuscript and S.J. O’Brien for insights. Thisresearch was supported by Peking University (PKU, to S.-J.L.), thePeking-Tsinghua Center for Life Sciences (CLS, through a grant to S.-J.L.and an Outstanding Postdoctoral Fellowship to X.X.), the 973 Program(no. 2009CB918503, to T.-J.J.), and National Science Foundation China(NSFC no. 31271320, to S.-J.L.).Received: January 11, 2013Revised: March 19, 2013Accepted: April 18, 2013Published: May 23, 2013References1. Jackson, P. (1988). Earliest record of a white tiger. Cat News 8, 6–7.2. Robinson, R. (1969). The white tigers of Rewa and gene homology in theFelidae. Genetica 40, 198–200.3. Robinson, R. (1976). Homologous genetic variation in the Felidae.Genetica 46, 1–31.4. Thornton, I.W.B. (1978). White tiger genetics—further evidence. J. Zool.185, 389–394.5. Thornton, I.W.B., Yeung, K.K., and Sankhala, K.S. (1967). The geneticsof white tiger of Rewa. J. Zool. 152, 127–135.6. Maruska, E.J. (1987). White tiger: Phantom or freak? 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Many white tigers in captivity are inbred in order to maintain this autosomal recessive trait [2–5] and conse- . white fur, blue eyes, a pink nose, and pink paw pads [2, 4, 5]. . eumelanin is present in the eyes and in the hairs of stripes [2, 5]. Some white tigers also showFile Size: 1MBPage Count: 5Explore furtherScientists Find One Gene Responsible For All White Tigerswww.popsci.comThe Genetic Basis of White Tigers - ScienceDirectwww.sciencedirect.comThe Genetic Basis of White Tigerswww.luo-lab.orgThe Genetic Basis of White Tigers - COREcore.ac.uk(PDF) Understanding "Tiger Parenting" Through the Perceptions www.researchgate.netRecommended to you b