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High-Density Lipoprotein Receptor SCARB1 Is Required for Carotenoid Coloration in Birds

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High-Density Lipoprotein Receptor SCARB1 Is Required for Carotenoid Coloration in Birds High-density lipoprotein receptor SCARB1 is required for carotenoid coloration in birds Matthew B. Toomeya,1, Ricardo J. Lopesb, Pedro M. Araújob,c, James D. Johnsond,Małgorzata A. Gazdab, Sandra Afonsob, Paulo G. Motab,e, Rebecca E. Kochd, Geoffrey E. Hilld, Joseph C. Corboa,1,2, and Miguel Carneirob,f,1,2 aDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; bCIBIO/InBIO, Centro de Investigação em Biodiversidade e Recursos Genéticos, Campus Agrário de Vairão, Universidade do Porto, 4485-661 Vairão, Portugal; cCentro de Ciências do Mar e do Ambiente, Departamento de Ciências da Vida, Universidade de Coimbra, 3004-517 Coimbra, Portugal; dDepartment of Biological Sciences, Auburn University, Auburn, AL 36849; eDepartamento de Ciências da Vida, Universidade de Coimbra, 3004-517 Coimbra, Portugal; and fDepartamento de Biologia, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal Edited by David W. Russell, University of Texas Southwestern Medical Center, Dallas, TX, and approved April 13, 2017 (received for review January 13, 2017) Yellow, orange, and red coloration is a fundamental aspect of red feathers and bare parts (8, 9). In other studies, expression of avian diversity and serves as an important signal in mate choice the carotenoid-cleaving enzyme β-carotene-9′,10′-dioxygenase and aggressive interactions. This coloration is often produced (BCO2) was found to be associated with loss of yellow leg col- through the deposition of diet-derived carotenoid pigments, yet oration in chickens (10), and sequence variation around this the mechanisms of carotenoid uptake and transport are not well- same gene was associated with yellow versus white breast understood. The white recessive breed of the common canary plumage in two sister species of wood warblers (4). The discov- (Serinus canaria), which carries an autosomal recessive mutation eries of the roles that CYP2J19 and BCO2 play in the carotenoid that renders its plumage pure white, provides a unique opportu- pigmentation of birds provide important insights into the meta- nity to investigate mechanisms of carotenoid coloration. We car- bolic mechanisms that underlie carotenoid coloration. ried out detailed genomic and biochemical analyses comparing the Progress has also been made in understanding the mechanism white recessive with yellow and red breeds of canaries. Biochem- whereby carotenoids are transported via the blood to target tis- ical analysis revealed that carotenoids are absent or at very low sues. It has long been known that birds transport carotenoids in concentrations in feathers and several tissues of white recessive the circulatory and lymphatic systems via lipoproteins (11, 12), EVOLUTION canaries, consistent with a genetic defect in carotenoid uptake. and recent experimental evidence confirms a key role for lipo- Using a combination of genetic mapping approaches, we show proteins in carotenoid transport in birds. For example, the that the white recessive allele is due to a splice donor site muta- Wisconsin hypoalpha mutant chicken has a mutation in the tion in the scavenger receptor B1 (SCARB1; also known as SR-B1) ABCA1 transporter, which results in markedly reduced levels of gene. This mutation results in abnormal splicing, with the most circulating high-density lipoprotein (HDL) and a consequent abundant transcript lacking exon 4. Through functional assays, reduction in the level of carotenoids in the blood and peripheral tissues (13, 14). Despite these insights, many aspects of carot- we further demonstrate that wild-type SCARB1 promotes cellular enoid transport and delivery remain to be discovered. uptake of carotenoids but that this function is lost in the predom- Domesticated canaries (Serinus canaria) provide an ideal sys- inant mutant isoform in white recessive canaries. Our results in- tem in which to explore the mechanisms of avian carotenoid dicate that SCARB1 is an essential mediator of the expression of physiology because these birds have been selectively crossed for carotenoid-based coloration in birds, and suggest a potential link between visual displays and lipid metabolism. Significance coloration | carotenoids | lipid metabolism | Serinus canaria The yellow, orange, and red colors of birds are produced through the deposition of carotenoid pigments into feathers he yellow, orange, and red coloration of the feathers, skin, and skin, and often function as signals in aggressive interac- and beaks of birds is most commonly produced through the T tions and mate choice. These colors are hypothesized to com- deposition of carotenoid pigments (1). Carotenoid coloration of municate information about individual quality because their birds has been a focus of study in the fields of behavior, evolu- expression is linked to vital cellular processes through the tion, and physiology because it plays a key role in mate assess- mechanisms of carotenoid metabolism. To elucidate these ment in many species. In addition, it is frequently an indicator of – mechanisms, we carried out genomic and biochemical analyses individual quality, and can signal species identity (2 4). Birds of the white recessive canary breed, which carries a heritable cannot synthesize carotenoids de novo and must acquire them defect in carotenoid uptake. We identified a mutation in the through their diet (1), potentially linking coloration to the ac- SCARB1 gene in this breed that disrupts carotenoid transport quisition of pigments from the environment (3). Thus, key hy- function. Our study implicates SCARB1 as a key mediator of potheses related to honest signaling and sexual selection have carotenoid-based coloration and suggests a link between ca- been shaped by and are currently being tested in carotenoid- rotenoid coloration and lipid metabolism. ornament systems (5, 6). Ultimately, the information content and evolutionary trajectories of carotenoid ornaments are a Author contributions: M.B.T., J.C.C., and M.C. designed research; M.B.T., R.J.L., P.M.A., M.A.G., function of the physiological mechanisms underlying color ex- S.A., P.G.M., R.E.K., and M.C. performed research; M.B.T., R.J.L., P.M.A., J.D.J., M.A.G., S.A., P.G.M., pression, yet our understanding of these mechanisms is limited. and M.C. analyzed data; and M.B.T., G.E.H., J.C.C., and M.C. wrote the paper. The expression of carotenoid coloration in birds involves four The authors declare no conflict of interest. distinct physiological steps: uptake in the gut, transport in cir- This article is a PNAS Direct Submission. culatory and lymphatic systems, metabolism either at the site of Data deposition: The sequences reported in this paper have been deposited in the deposition or in the liver, and deposition in the integument (7). GenBank (BioProject PRJNA300534)andDryad(doi:10.5061/dryad.bt816) databases. Recent progress has been made in understanding how caroten- 1To whom correspondence may be addressed. Email: [email protected], jcorbo@ oids are metabolized to novel forms. In 2016, two studies in- pathology.wustl.edu, or [email protected]. dependently identified a key carotenoid metabolism enzyme, 2J.C.C. and M.C. contributed equally to this work. CYP2J19, that mediates the oxidation of yellow carotenoids into This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. red ketocarotenoids and is used by many bird species to produce 1073/pnas.1700751114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1700751114 PNAS Early Edition | 1of6 Downloaded by guest on September 29, 2021 − centuries to produce breeds with fixed expression of distinct wild-type: 13.39 ± 1.70 μg·g 1 protein; t = −6.26, df = 3.89, P = carotenoid-based plumage color phenotypes (15, 16). Wild ca- 0.0036; Fig. 1C and SI Appendix, Table S1). Carotenoids were not naries and typical domesticated varieties pigment their feathers detectable in the retinas of white recessive canaries but were with yellow carotenoids (Fig. 1A) (17, 18). The white recessive present at very high concentrations in the retinas of typical yellow − canary has entirely white plumage (Fig. 1B) as well as congenital birds (622.57 ± 131.73 μg·g 1 protein; Fig. 1C and SI Appendix, vitamin A deficiency that is inherited as an autosomal recessive Table S1). Together, these results indicate that the levels of trait (19, 20). It is hypothesized that the white recessive pheno- carotenoids are greatly reduced across multiple tissues in white type is the result of a mutation affecting carotenoid uptake (19, recessive canaries. 20), but the specific gene(s) involved remains unknown. Thus, the white recessive canary presents an opportunity to discover Identification of the Genomic Region Associated with White Recessive mechanisms of carotenoid uptake that are necessary for carot- Coloration. The white recessive breed was created through fixa- enoid coloration in birds. tion of a spontaneous mutation by artificial selection (19, 22, 23). In crosses with typical yellow canaries, this white phenotype is Results transmitted in a manner consistent with the existence of a single Carotenoids Are Absent or at Very Low Concentrations in the Tissues recessive allele. It is thus expected that the genomic region un- of White Recessive Canaries. The white recessive canary is char- derlying white feather coloration will show elevated differentia- acterized by completely white plumage that appears to lack the tion in allele frequency between white and colored canaries yellow carotenoid pigmentation typical of wild-type canaries compared with the remainder of the genome. To search for such (Fig. 1 A and B). To better understand the carotenoid physiology regions in the white recessive genome, we used whole-genome se- of the white recessive canary breed, we used high-performance quencing data of pooled DNA samples (detailed in SI Appendix, liquid chromatography (HPLC) to identify and quantify caroten- Table S2). We compared white recessive canaries with other oids in the feathers, skin, liver, and retina, tissues that are im- domestic breeds and one wild population, all characterized by portant sites of carotenoid accumulation in birds (1, 7, 21) (Fig.
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