A genome-wide genetic screen uncovers determinants of human pigmentation
Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes tha...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2023-08, Vol.381 (6658), p.eade6289-eade6289 |
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| creator | Bajpai, Vivek K Swigut, Tomek Mohammed, Jaaved Naqvi, Sahin Arreola, Martin Tycko, Josh Kim, Tayne C Pritchard, Jonathan K Bassik, Michael C Wysocka, Joanna |
| description | Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes that converge on melanosome biogenesis, endosomal transport, and gene regulation, of which 135 represented previously unknown associations with pigmentation. In agreement with their melanin-promoting function, the majority of screen hits were up-regulated in melanocytes from darkly pigmented individuals. We further unraveled functions of KLF6 as a transcription factor that regulates melanosome maturation and pigmentation in vivo, and of the endosomal trafficking protein COMMD3 in modulating melanosomal pH. Our study reveals a plethora of melanin-promoting genes, with broad implications for human variation, cell biology, and medicine. |
| doi_str_mv | 10.1126/science.ade6289 |
| format | Article |
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In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes that converge on melanosome biogenesis, endosomal transport, and gene regulation, of which 135 represented previously unknown associations with pigmentation. In agreement with their melanin-promoting function, the majority of screen hits were up-regulated in melanocytes from darkly pigmented individuals. We further unraveled functions of KLF6 as a transcription factor that regulates melanosome maturation and pigmentation in vivo, and of the endosomal trafficking protein COMMD3 in modulating melanosomal pH. Our study reveals a plethora of melanin-promoting genes, with broad implications for human variation, cell biology, and medicine.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.ade6289</identifier><identifier>PMID: 37561850</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Adaptation ; Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Cell Line, Tumor ; Cell lines ; Color ; CRISPR ; Deletion ; DNA damage ; Endosomes - metabolism ; Flow cytometry ; Gene regulation ; Genes ; Genetic screening ; Genetics ; Genome-Wide Association Study ; Genomes ; Hair ; Human populations ; Humans ; Kruppel-Like Factor 6 - genetics ; Kruppel-Like Factor 6 - metabolism ; Light ; Light levels ; Light scattering ; Maturation ; Melanin ; Melanins - biosynthesis ; Melanins - genetics ; Melanocytes ; Melanocytes - metabolism ; Melanosomes ; Melanosomes - metabolism ; Mice ; Optical properties ; Perturbation ; pH effects ; Physicochemical properties ; Pigmentation ; Pigments ; Polymers ; Population studies ; Populations ; Protein transport ; Refractivity ; RNA processing ; RNA transport ; Scattering ; Skin ; Skin pigmentation ; Skin Pigmentation - genetics ; Synthesis ; Transcription factors ; Variation</subject><ispartof>Science (American Association for the Advancement of Science), 2023-08, Vol.381 (6658), p.eade6289-eade6289</ispartof><rights>Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c381t-8ec023ceaf541e3d20e9d1b05edeecfc3eedd2cfb40617bcdf336d5ccfaba99b3</citedby><cites>FETCH-LOGICAL-c381t-8ec023ceaf541e3d20e9d1b05edeecfc3eedd2cfb40617bcdf336d5ccfaba99b3</cites><orcidid>0000-0002-7649-6781 ; 0000-0002-7053-5575 ; 0000-0002-6909-6544 ; 0000-0001-6549-3588 ; 0000-0001-5185-8427 ; 0000-0003-4659-3211 ; 0000-0002-4108-0575 ; 0000-0003-2635-7967 ; 0000-0002-8828-5236 ; 0009-0001-3703-4760</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,2871,2872,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37561850$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bajpai, Vivek K</creatorcontrib><creatorcontrib>Swigut, Tomek</creatorcontrib><creatorcontrib>Mohammed, Jaaved</creatorcontrib><creatorcontrib>Naqvi, Sahin</creatorcontrib><creatorcontrib>Arreola, Martin</creatorcontrib><creatorcontrib>Tycko, Josh</creatorcontrib><creatorcontrib>Kim, Tayne C</creatorcontrib><creatorcontrib>Pritchard, Jonathan K</creatorcontrib><creatorcontrib>Bassik, Michael C</creatorcontrib><creatorcontrib>Wysocka, Joanna</creatorcontrib><title>A genome-wide genetic screen uncovers determinants of human pigmentation</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes that converge on melanosome biogenesis, endosomal transport, and gene regulation, of which 135 represented previously unknown associations with pigmentation. In agreement with their melanin-promoting function, the majority of screen hits were up-regulated in melanocytes from darkly pigmented individuals. We further unraveled functions of KLF6 as a transcription factor that regulates melanosome maturation and pigmentation in vivo, and of the endosomal trafficking protein COMMD3 in modulating melanosomal pH. Our study reveals a plethora of melanin-promoting genes, with broad implications for human variation, cell biology, and medicine.</description><subject>Adaptation</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Color</subject><subject>CRISPR</subject><subject>Deletion</subject><subject>DNA damage</subject><subject>Endosomes - metabolism</subject><subject>Flow cytometry</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genetic screening</subject><subject>Genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Hair</subject><subject>Human populations</subject><subject>Humans</subject><subject>Kruppel-Like Factor 6 - genetics</subject><subject>Kruppel-Like Factor 6 - metabolism</subject><subject>Light</subject><subject>Light levels</subject><subject>Light scattering</subject><subject>Maturation</subject><subject>Melanin</subject><subject>Melanins - biosynthesis</subject><subject>Melanins - genetics</subject><subject>Melanocytes</subject><subject>Melanocytes - metabolism</subject><subject>Melanosomes</subject><subject>Melanosomes - metabolism</subject><subject>Mice</subject><subject>Optical properties</subject><subject>Perturbation</subject><subject>pH effects</subject><subject>Physicochemical properties</subject><subject>Pigmentation</subject><subject>Pigments</subject><subject>Polymers</subject><subject>Population studies</subject><subject>Populations</subject><subject>Protein transport</subject><subject>Refractivity</subject><subject>RNA processing</subject><subject>RNA transport</subject><subject>Scattering</subject><subject>Skin</subject><subject>Skin pigmentation</subject><subject>Skin Pigmentation - genetics</subject><subject>Synthesis</subject><subject>Transcription factors</subject><subject>Variation</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkT1PwzAQhi0EoqUws6FILCxp7ThJkwmhCihSJRaYLed8aV01drGTIv49rhoqYLqT7rn3Pl5CrhkdM5bkEw8aDeBYKsyTojwhQ0bLLC4Tyk_JkFKexwWdZgNy4f2a0lAr-TkZ8GmWsyKjQzJ_iJZobIPxp1a4z7HVEHlwiCbqDNgdOh8pbNE12kjT-sjW0aprpIm2etmgaWWrrbkkZ7XceLzq44i8Pz2-zebx4vX5ZfawiIEXrI0LBJpwQFlnKUOuEoqlYhXNUCFCDRxRqQTqKqU5m1agas5zlQHUspJlWfERuT_obruqQQVhvpMbsXW6ke5LWKnF34rRK7G0OxEeQ1ma86Bw1ys4-9Ghb0WjPeBmIw3azoskPIazlPEyoLf_0LXtnAn3BSot0pRNi73g5ECBs947rI_bMCr2NoneJtHbFDpufh9x5H984d_OypOy</recordid><startdate>20230811</startdate><enddate>20230811</enddate><creator>Bajpai, Vivek K</creator><creator>Swigut, Tomek</creator><creator>Mohammed, Jaaved</creator><creator>Naqvi, Sahin</creator><creator>Arreola, Martin</creator><creator>Tycko, Josh</creator><creator>Kim, Tayne C</creator><creator>Pritchard, Jonathan K</creator><creator>Bassik, Michael C</creator><creator>Wysocka, Joanna</creator><general>The American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7649-6781</orcidid><orcidid>https://orcid.org/0000-0002-7053-5575</orcidid><orcidid>https://orcid.org/0000-0002-6909-6544</orcidid><orcidid>https://orcid.org/0000-0001-6549-3588</orcidid><orcidid>https://orcid.org/0000-0001-5185-8427</orcidid><orcidid>https://orcid.org/0000-0003-4659-3211</orcidid><orcidid>https://orcid.org/0000-0002-4108-0575</orcidid><orcidid>https://orcid.org/0000-0003-2635-7967</orcidid><orcidid>https://orcid.org/0000-0002-8828-5236</orcidid><orcidid>https://orcid.org/0009-0001-3703-4760</orcidid></search><sort><creationdate>20230811</creationdate><title>A genome-wide genetic screen uncovers determinants of human pigmentation</title><author>Bajpai, Vivek K ; Swigut, Tomek ; Mohammed, Jaaved ; Naqvi, Sahin ; Arreola, Martin ; Tycko, Josh ; Kim, Tayne C ; Pritchard, Jonathan K ; Bassik, Michael C ; Wysocka, Joanna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c381t-8ec023ceaf541e3d20e9d1b05edeecfc3eedd2cfb40617bcdf336d5ccfaba99b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Adaptation</topic><topic>Adaptor Proteins, Signal Transducing - 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In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes that converge on melanosome biogenesis, endosomal transport, and gene regulation, of which 135 represented previously unknown associations with pigmentation. In agreement with their melanin-promoting function, the majority of screen hits were up-regulated in melanocytes from darkly pigmented individuals. We further unraveled functions of KLF6 as a transcription factor that regulates melanosome maturation and pigmentation in vivo, and of the endosomal trafficking protein COMMD3 in modulating melanosomal pH. 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| subjects | Adaptation Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Cell Line, Tumor Cell lines Color CRISPR Deletion DNA damage Endosomes - metabolism Flow cytometry Gene regulation Genes Genetic screening Genetics Genome-Wide Association Study Genomes Hair Human populations Humans Kruppel-Like Factor 6 - genetics Kruppel-Like Factor 6 - metabolism Light Light levels Light scattering Maturation Melanin Melanins - biosynthesis Melanins - genetics Melanocytes Melanocytes - metabolism Melanosomes Melanosomes - metabolism Mice Optical properties Perturbation pH effects Physicochemical properties Pigmentation Pigments Polymers Population studies Populations Protein transport Refractivity RNA processing RNA transport Scattering Skin Skin pigmentation Skin Pigmentation - genetics Synthesis Transcription factors Variation |
| title | A genome-wide genetic screen uncovers determinants of human pigmentation |
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