Editing Human skin color (section)

== Genetics ==
{{See also|Human genetic variation|Race and genetics}}
To some extent, skin color is determined independently of eye and hair color, as can be seen from variation in skin coloration in human populations.<ref name=McEvoy2006>{{cite journal |journal=Human Molecular Genetics |year=2006 |volume=15 |issue=2 |pages=176–181 |doi=10.1093/hmg/ddl217 |title=The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model |last1=McEvoy |first1=B. |pmid=16987881 |doi-access=free }}</ref><ref name="Sturm2009">{{cite journal|journal=Human Molecular Genetics |year=2009 |volume=18 |issue=R1 |pages=9–17 |doi=10.1093/hmg/ddp003 |title=Molecular genetics of human pigmentation diversity|last1=Sturm |first1=R. A. |pmid=19297406|doi-access=free }}</ref><ref name=Belezal2012>{{cite journal |url=http://mbe.oxfordjournals.org/content/early/2012/08/25/molbev.mss207.short|title=The timing of pigmentation lightening in Europeans |journal=Molecular Biology and Evolution |year=2012 |doi=10.1093/molbev/mss207 |pmid=22923467 |pmc=3525146 |volume=30 |issue=1 |pages=24–35 |last2=Santos |first2=A. M. |last3=McEvoy |first3=B. |last4=Alves |first4=I. |last5=Martinho |first5=C. |last6=Cameron |first6=E. |last7=Shriver |first7=M. D. |last8=Parra |first8=E. J. |last9=Rocha |first9=J. |last1=Belezal |first1=Sandra |url-status=live |archive-url=https://web.archive.org/web/20120829050356/http://mbe.oxfordjournals.org/content/early/2012/08/25/molbev.mss207.short|archive-date=2012-08-29 }}</ref>

For skin color, [[heritability]] is very high, even though it can be modified by exposure to sunlight.<ref name="Norton2006">{{cite journal |last1=Norton |first1=H. L. |last2=Kittles |first2=R. A. |last3=Parra |first3=E. |last4=McKeigue |first4=P. |last5=Mao |first5=X. |last6=Cheng |first6=K. |last7=Canfield |first7=V. A. |last8=Bradley |first8=D. G. |last9=McEvoy |first9=B. |last10=Shriver |first10=M. D. |title=Genetic Evidence for the Convergent Evolution of Light Skin in Europeans and East Asians |journal=Molecular Biology and Evolution |volume=24 |issue=3 |pages=710–22 |year=2006 |pmid=17182896 |doi=10.1093/molbev/msl203 |doi-access=free }}</ref>

A recent systematic study found 169 genes involved in human skin coloration. Most of the genes were involved in [[melanosome]] biogenesis, [[Endosome|endosomal]] transport, and [[Regulation of gene expression|gene regulation]]. Notably, the function of these genes was verified in [[tissue culture]] experiments using [[Cas9|CRISPR-Cas9]] knockouts, showing that these genes are indeed involved in [[melanin]] production.<ref>{{Cite journal |last1=Bajpai |first1=Vivek K. |last2=Swigut |first2=Tomek |last3=Mohammed |first3=Jaaved |last4=Naqvi |first4=Sahin |last5=Arreola |first5=Martin |last6=Tycko |first6=Josh |last7=Kim |first7=Tayne C. |last8=Pritchard |first8=Jonathan K. |last9=Bassik |first9=Michael C. |last10=Wysocka |first10=Joanna |date=2023-08-11 |title=A genome-wide genetic screen uncovers determinants of human pigmentation |journal=Science |language=en |volume=381 |issue=6658 |pages=eade6289 |doi=10.1126/science.ade6289 |pmid=37561850 |s2cid=260776374 |issn=0036-8075|pmc=10901463 }}</ref>

=== Dark skin ===
{{Main|Dark skin}}
All modern humans share a [[Mitochondrial Eve|common ancestor]] who lived around 200,000 years ago in Africa.<ref name="Soares P, Ermini L, Thomson N, et al. 2009 740–59">{{cite journal |title=Correcting for purifying selection: an improved human mitochondrial molecular clock |journal=Am. J. Hum. Genet. |volume=84 |issue=6 |pages=740–59 |date=June 2009 |pmid=19500773 |pmc=2694979 |doi=10.1016/j.ajhg.2009.05.001 |last1=Soares |first1=P |last2=Ermini |first2=L |last3=Thomson |first3=N |last4=Mormina |first4=M |last5=Rito |first5=T |last6=Röhl |first6=A |last7=Salas |first7=A |last8=Oppenheimer |first8=S |last9=MacAulay |first9=V |last10=Richards |first10=M. B.}}</ref> Comparisons between known skin pigmentation genes in [[Common chimpanzee|chimpanzees]] and modern Africans show that dark skin evolved along with the loss of body hair about 1.2 million years ago and that this common ancestor had dark skin.<ref name=Rogers2004b>{{cite journal |title=Genetic Variation at the MC1R Locus and the Time since Loss of Human Body Hair |journal=Current Anthropology |volume=45 |issue=6 |pages=105–108 |year=2004b |doi=10.1086/381006 |jstor=381006|last1=Rogers |first1=Alan R. |last2=Iltis |first2=David |last3=Wooding |first3=Stephen|s2cid=224795768 }}</ref> Investigations into dark-skinned populations in South Asia and Melanesia indicate that skin pigmentation in these populations is due to the preservation of this ancestral state and not due to new variations on a previously lightened population.<ref name=Harding2000>{{cite journal |last1=Harding |first1=R |last2=Healy |first2=E |last3=Ray |first3=A |last4=Ellis |first4=N |last5=Flanagan |first5=N |last6=Todd |first6=C |last7=Dixon |first7=C |last8=Sajantila |first8=A |last9=Jackson |first9=I |last10=Birch-Machin |first10=Mark A. |last11=Rees |first11=Jonathan L. |title=Evidence for Variable Selective Pressures at MC1R |journal=The American Journal of Human Genetics |volume=66 |pages=1351–61 |year=2000 |doi=10.1086/302863 |pmid=10733465 |issue=4 |pmc=1288200}}</ref>

==== MC1R ====
[[File:MC1R (rs885479).png|thumb|MC1R (rs885479)]]
The [[melanocortin 1 receptor]] (MC1R) gene is primarily responsible for determining whether pheomelanin and eumelanin are produced in the human body. Research shows at least 10 differences in MC1R between African and chimpanzee samples and that the gene has probably undergone a strong [[Directional selection|positive selection]] (a [[selective sweep]]) in early Hominins around 1.2 million years ago.<ref>{{cite journal|title=Genetic variation at the MC1R locus and the time since loss of human body hair|journal=Current Anthropology|year=2004a|volume=45|issue=1|pages=105–124|doi=10.1086/381006|last1=Rogers|first1=Alan R.|last2=Iltis|first2=David|last3=Wooding|first3=Stephen|s2cid=224795768 }}</ref> This is consistent with positive selection for the high-eumelanin [[phenotype]] seen in Africa and other environments with high UV exposure.<ref name=Rogers2004b/><ref name=Harding2000/>

=== Light skin ===
{{Main|Light skin}}
[[File:Archaeogenetic analysis of human skin pigmentation in Europe (with Asia geographic extension).png|thumb|History of human skin pigmentation in [[Eurasia]] based on genetics]]
For the most part, the evolution of light skin has followed different genetic paths in European and East Asian populations.

==== KITLG ====
[[File:KITLG (rs1881227).png|thumb|KITLG (rs1881227)]]
The [[KIT ligand]] (KITLG) gene is involved in the permanent survival, proliferation and migration of melanocytes.<ref name="pmid12753403">{{cite journal |last1=Wehrle-Haller |first1=Bernhard |title=The Role of Kit-Ligand in Melanocyte Development and Epidermal Homeostasis |journal=Pigment Cell Research |volume=16 |issue=3 |pages=287–96 |year=2003 |pmid=12753403 |doi=10.1034/j.1600-0749.2003.00055.x}}</ref> A mutation in this gene, ''A326G'' (rs642742<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=642742 Reference SNP(refSNP) Cluster Report: rs642742 **clinically associated**] {{webarchive|url= https://web.archive.org/web/20180328071821/https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=642742 |date=2018-03-28 }}. Ncbi.nlm.nih.gov (2008-12-30). Retrieved 2011-02-27.</ref>), has been positively associated with variations of skin color in African-Americans of mixed West African and European descent and is estimated to account for 15–20% of the melanin difference between African and European populations.<ref name=Miller2007>{{cite journal |last1=Miller |first1=Craig T. |last2=Beleza |first2=Sandra |last3=Pollen |first3=Alex A. |last4=Schluter |first4=Dolph |last5=Kittles |first5=Rick A. |last6=Shriver |first6=Mark D. |last7=Kingsley |first7=David M. |title=cis-Regulatory Changes in Kit Ligand Expression and Parallel Evolution of Pigmentation in Sticklebacks and Humans |journal=Cell |volume=131 |issue=6 |pages=1179–89 |year=2007 |pmid=18083106 |pmc=2900316 |doi=10.1016/j.cell.2007.10.055}}</ref><ref name=Pickrell2009>{{cite journal |title=Signals of recent positive selection in a worldwide sample of human populations |journal=Genome Research |year=2009 |volume=19 |pages=826–837 |doi=10.1101/gr.087577.108 |issue=5 |pmid=19307593 |pmc=2675971 |last1=Pickrell |first1=J. K. |last2=Coop |first2=G |last3=Novembre |first3=J |last4=Kudaravalli |first4=S |last5=Li |first5=J. Z. |last6=Absher |first6=D |last7=Srinivasan |first7=B. S. |last8=Barsh |first8=G. S. |last9=Myers |first9=R. M. |last10=Feldman |first10=M. W. |last11=Pritchard |first11=J. K. }}</ref> and occurs in over 80% of European and Asian samples, compared with less than 10% in African samples.<ref name=Miller2007 />

==== ASIP ====
Studies have found two alleles in the vicinity of ASIP [[Agouti signalling peptide]] are associated with skin color variation in humans. One, rs2424984,<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2424984 Reference SNP(refSNP) Cluster Report: rs2424984] {{webarchive|url= https://web.archive.org/web/20160501175840/http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2424984 |date=2016-05-01 }}. Ncbi.nlm.nih.gov (2008-12-30). Retrieved 2011-02-27.</ref> has been identified as an indicator of skin reflectance in a forensics analysis of human phenotypes across Caucasian, African-American, South Asian, East Asian, Hispanic and Native American populations<ref name=Valenzuela>{{cite journal |last1=Valenzuela |pages=315–22 |first1=Robert K. |issue=2 |last2=Henderson |first2=Miquia S. |last3=Walsh |first3=Monica H. |last4=Garrison |first4=Nanibaa' A. |last5=Kelch |first5=Jessica T. |last6=Cohen-Barak |first6=Orit |last7=Erickson |first7=Drew T. |last8=John Meaney |first8=F. |last9=Bruce Walsh |first9=J. |last10=Cheng |first10=Keith C. |last11=Ito |first11=Shosuke |last12=Wakamatsu |first12=Kazumasa |last13=Frudakis |first13=Tony |last14=Thomas |first14=Matthew |last15=Brilliant |first15=Murray H. |volume=55 |title=Predicting Phenotype from Genotype: Normal Pigmentation |year=2010 |pmid=20158590 |doi=10.1111/j.1556-4029.2009.01317.x |journal=Journal of Forensic Sciences |url=http://www.pennstatehershey.org/c/document_library/get_file?uuid=7b0b4263-ec43-40b2-9b76-f129ad14d4e9&groupId=101483 |pmc=3626268 |url-status=live |archive-url=https://web.archive.org/web/20130613160844/http://www.pennstatehershey.org/c/document_library/get_file?uuid=7b0b4263-ec43-40b2-9b76-f129ad14d4e9&groupId=101483 |archive-date=2013-06-13 }}</ref> and is about three times more common in non-African populations than in Africa.<ref>[http://hapmap.ncbi.nlm.nih.gov/cgi-perl/snp_details_phase3?name=rs2424984&source=hapmap3r3_B36&tmpl=snp_details_phase3 HapMap: SNP report for rs2424984]. Hapmap.ncbi.nlm.nih.gov (2009-10-19). Retrieved 2011-02-27.</ref> The other allele, ''8188G'' (rs6058017<ref>{{cite web |url=https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=6058017 |title=Reference SNP (refSNP) Cluster Report: rs6058017 ** With Pathogenic allele ** |publisher=Ncbi.nlm.nih.gov |date=2006-01-28 |access-date=2015-02-03 |url-status=live |archive-url=https://web.archive.org/web/20150203174915/http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=6058017 |archive-date=2015-02-03 }}</ref>) is significantly associated with skin color variation in African-Americans and the ancestral version occurs in only 12% of European and 28% of East Asian samples compared with 80% of West African samples.<ref name=Bonilla2005>{{cite journal |title=The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans |journal=Human Genetics |year=2005 |volume=116 |issue=5 |pages=402–6 |doi=10.1007/s00439-004-1251-2|pmid=15726415 |last1=Bonilla |first1=C |last2=Boxill |first2=L. A. |last3=Donald |first3=S. A. |last4=Williams |first4=T |last5=Sylvester |first5=N |last6=Parra |first6=E. J. |last7=Dios |first7=S |last8=Norton |first8=H. L. |last9=Shriver |first9=M. D. |last10=Kittles |first10=R. A.|s2cid=12910408 }}</ref>

==== Europe ====
A number of genes have been positively associated with the skin pigmentation difference between European and non-European populations. Mutations in SLC24A5 and SLC45A2 are believed to account for the bulk of this variation and show very strong signs of selection. A variation in TYR has also been identified as a contributor.

Research indicates the selection for the light-skin alleles of these genes in Europeans is comparatively recent, having occurred later than 20,000 years ago and perhaps as recently as 12,000 to 6,000 years ago.<ref name=Belezal2012 /> In the 1970s, [[Luca Cavalli-Sforza]] suggested that the selective sweep that rendered light skin ubiquitous in Europe might be correlated with the [[Neolithic Revolution|advent of farming]] and thus have taken place only around 6,000 years ago;<ref name="pmid17446367">{{cite journal |last1=Gibbons |first1=A. |doi=10.1126/science.316.5823.364a |title=European Skin Turned Pale Only Recently, Gene Suggests |year=2007 |pages=364a |volume=316 |journal=Science |issue=5823|pmid=17446367|s2cid=43290419 |url=http://galsatia.files.wordpress.com/2007/04/blanche_paleur.pdf |archive-url= https://web.archive.org/web/20101103171424/http://galsatia.files.wordpress.com//2007//04//blanche_paleur.pdf |archive-date=2010-11-03 |url-status=dead |access-date=2011-01-26}} "a suggestion made 30 years ago by Stanford University geneticist L. Luca Cavalli-Sforza … that the early immigrants to Europe … survived on ready-made sources of vitamin D in their diet. But when farming spread in the past 6,000 years, he argued, Europeans had fewer sources of vitamin D in their food and needed to absorb more sunlight to produce the vitamin in their skin."</ref> This scenario found support in a 2014 analysis of [[Mesolithic]] (7,000 years old) [[hunter-gatherer]] DNA from [[La Braña]], Spain, which showed a version of these genes not corresponding with light skin color.<ref>{{cite journal |title= Derived immune and ancestral pigmentation alleles in a 7,000-year-old Mesolithic European|journal=Nature|volume=507|issue=7491|pages=225–228 |doi=10.1038/nature12960|pmid=24463515|quote=The La Braña individual carries ancestral alleles in several skin pigmentation genes, suggesting that the light skin of modern Europeans was not yet ubiquitous in Mesolithic time|year=2014|last1=Olalde|first1=Iñigo|last2=Allentoft|first2=Morten E.|last3=Sánchez-Quinto |first3=Federico|last4=Santpere|first4=Gabriel|last5=Chiang|first5=Charleston W. K.|last6=Degiorgio |first6=Michael|last7=Prado-Martinez|first7=Javier|last8=Rodríguez|first8=Juan Antonio|last9=Rasmussen |first9=Simon|last10=Quilez |first10=Javier|last11=Ramírez|first11=Oscar|last12=Marigorta|first12=Urko M. |last13=Fernández-Callejo|first13=Marcos|last14=Prada|first14=María Encina|last15=Encinas|first15=Julio Manuel Vidal|last16=Nielsen|first16=Rasmus |last17=Netea|first17=Mihai G.|last18=Novembre|first18=John |last19=Sturm|first19=Richard A.|last20=Sabeti|first20=Pardis|author20-link=Pardis Sabeti|last21=Marquès-Bonet|first21=Tomàs |last22=Navarro|first22=Arcadi|last23=Willerslev|first23=Eske |last24=Lalueza-Fox|first24=Carles |pmc=4269527|bibcode=2014Natur.507..225O}}</ref> 

In 2015, researchers analysed for light skin genes in the DNA of 94 ancient skeletons ranging from 8,000 to 3,000 years old from Europe and Russia. They found c. 8,000-year-old hunter-gatherers in Spain, Luxembourg, and Hungary were dark skinned while similarly aged hunter gatherers in Sweden were light skinned (having predominately derived alleles of SLC24A5, SLC45A2 and also HERC2/OCA2). [[Early European Farmers|Neolithic farmers]] entering Europe at around the same time were intermediate, being nearly fixed for the derived SLC24A5 variant but only having the derived SLC45A2 allele in low frequencies. The SLC24A5 variant spread very rapidly throughout central and southern Europe from about 8,000 years ago, whereas the light skin variant of SLC45A2 spread throughout Europe after 5,800 years ago.<ref>{{cite journal |last=Gibbons |first=Ann |date=2 April 2015 |url=https://www.science.org/content/article/how-europeans-evolved-white-skin |title=How Europeans evolved white skin |doi=10.1126/science.aab2435 |archive-url=https://web.archive.org/web/20150414000323/http://news.sciencemag.org/archaeology/2015/04/how-europeans-evolved-white-skin |archive-date=2015-04-14 |journal=Science |access-date=13 April 2015 |url-status=live}}</ref><ref>{{cite bioRxiv |biorxiv=10.1101/016477|title=Eight thousand years of natural selection in Europe|year=2015 |last1=Mathieson |first1=I. |last2=Lazaridis |first2=I. |last3=Rohland |first3=N. |last4=Mallick |first4=S. |last5=Llamas |first5=B. |last6=Pickrell |first6=J. |last7=Meller |first7=H. |last8=Rojo Guerra |first8=M. A. |last9=Krause |first9=J. |last10=Anthony |first10=D. |last11=Brown |first11=D. |last12=Lalueza Fox |first12=C. |last13=Cooper |first13=A. |last14=Alt |first14=K. W. |last15=Haak |first15=W. |last16=Patterson |first16=N. |last17=Reich |first17=D.}}</ref>

Some authors have expressed caution regarding the skin pigmentation predictions. According to Ju et al. (2021), in a study addressing 40,000 years of modern human history, stated:<blockquote>"Relatively dark skin pigmentation in Early Upper Paleolithic Europe would be consistent with those populations being relatively poorly adapted to high-latitude conditions as a result of having recently migrated from lower latitudes. On the other hand, although we have shown that these populations carried few of the light pigmentation alleles that are segregating in present-day Europe, they may have carried different alleles that we cannot now detect."<ref>{{cite journal |journal=PNAS |volume=118 |issue=1 |date=2021 |title=The evolution of skin pigmentation-associated variation in West Eurasia |last1=Ju |first1=Dan |last2=Mathieson |first2=Ian|pages=e2009227118 |doi=10.1073/pnas.2009227118|pmid=33443182 |pmc=7817156 |bibcode=2021PNAS..11809227J |quote="Relatively dark skin pigmentation in Early Upper Paleolithic Europe would be consistent with those populations being relatively poorly adapted to high-latitude conditions as a result of having recently migrated from lower latitudes. On the other hand, although we have shown that these populations carried few of the light pigmentation alleles that are segregating in present-day Europe, they may have carried different alleles that we cannot now detect." |doi-access=free }}</ref></blockquote>

===== SLC24A5 =====
[[SLC24A5|Solute carrier family 24 member 5]] (SLC24A5) regulates calcium in melanocytes and is important in the process of melanogenesis.<ref name="pmid18166528">{{cite journal |last1=Ginger |first1=R. S. |last2=Askew |first2=S. E. |last3=Ogborne |first3=R. M. |last4=Wilson |first4=S. |last5=Ferdinando |first5=D. |last6=Dadd |first6=T. |last7=Smith |first7=A. M. |last8=Kazi |first8=S. |last9=Szerencsei |first9=R. T. |last10=Winkfein |first10=R. J. |last11=Schnetkamp |first11=P. P. M. |last12=Green |first12=M. R. |title=SLC24A5 Encodes a trans-Golgi Network Protein with Potassium-dependent Sodium-Calcium Exchange Activity That Regulates Human Epidermal Melanogenesis |journal=Journal of Biological Chemistry |volume=283 |issue=9 |pages=5486–95 |year=2007 |pmid=18166528 |doi=10.1074/jbc.M707521200|doi-access=free }}</ref> The SLC24A5 gene's derived ''Ala111Thr'' allele (rs1426654<ref name="ncbi_rs14">{{Cite web |title=rs1426654 RefSNP Report |author= |work=ncbi.nlm.nih.gov |date= |access-date=15 February 2021 |url= https://www.ncbi.nlm.nih.gov/snp/rs1426654 |quote=}}</ref>) has been shown to be a major factor in light skin pigmentation and is common in Western [[Eurasia]].<ref name=Valenzuela /> Recent studies have found that the variant represents as much as 25–40% of the average skin tone difference between Europeans and West Africans.<ref name=Norton2006 /><ref name="pmid16357253">{{cite journal |last1=Lamason |first1=R. L. |last2=Mohideen |first2=MA |last3=Mest |first3=JR |last4=Wong |first4=AC |last5=Norton |first5=HL |last6=Aros |first6=MC |last7=Jurynec |first7=MJ |last8=Mao |first8=X |last9=Humphreville |first9=VR |last10=Humbert |first10=J. E. |last11=Sinha |first11=S |last12=Moore |first12=J. L. |last13=Jagadeeswaran |first13=P |last14=Zhao |first14=W |last15=Ning |first15=G |last16=Makalowska |first16=I |last17=McKeigue |first17=P. M. |last18=O'Donnell |first18=D |last19=Kittles |first19=R |last20=Parra |first20=E. J. |last21=Mangini |first21=N. J. |last22=Grunwald |first22=D. J. |last23=Shriver |first23=M. D. |last24=Canfield |first24=V. A. |last25=Cheng |first25=K. C. |title=SLC24A5, a Putative Cation Exchanger, Affects Pigmentation in Zebrafish and Humans |journal=Science |volume=310 |issue=5755 |pages=1782–6 |year=2005 |pmid=16357253 |doi=10.1126/science.1116238 |bibcode=2005Sci...310.1782L |s2cid=2245002}}</ref> This derived allele is a reliable predictor of phenotype across a range of populations.<ref name=Lopez>{{cite journal |last1=López |first1=Saioa |title=The Interplay between Natural Selection and Susceptibility to Melanoma on Allele 374F of SLC45A2 Gene in a South European Population |journal=PLOS ONE |volume=9 |issue=8 |pages=e104367 |date=5 August 2014 |doi=10.1371/journal.pone.0104367 |pmid=25093503 |pmc=4122405 |bibcode=2014PLoSO...9j4367L |doi-access=free }}</ref><ref name=Stokowski2007 /> It has been the subject of recent selection in Western Eurasia, and is fixed in European populations.<ref name=Belezal2012 /><ref name=Soejima2006>{{cite journal |last1=Soejima |first1=Mikiko |last2=Koda |first2=Yoshiro |title=Population differences of two coding SNPs in pigmentation-related genes SLC24A5 and SLC45A2 |journal=International Journal of Legal Medicine |volume=121 |issue=1 |pages=36–9 |year=2006 |pmid=16847698 |doi=10.1007/s00414-006-0112-z|s2cid=11192076 }}</ref><ref name=Khai2012>{{cite journal |title=Skin Color Variation in Orang Asli Tribes of Peninsular Malaysia |journal=PLOS ONE |volume=7 |issue=8 |pages=e42752 |doi=10.1371/journal.pone.0042752 |year=2012 |pmid=22912732 |pmc=3418284 |bibcode=2012PLoSO...742752A |last1=Ang |first1=K. C. |last2=Ngu |first2=M. S. |last3=Reid |first3=K. P. |last4=Teh |first4=M. S. |last5=Aida |first5=Z. S. |last6=Koh |first6=D. X. |last7=Berg |first7=A |last8=Oppenheimer |first8=S |last9=Salleh |first9=H |last10=Clyde |first10=M. M. |last11=Md-Zain |first11=B. M. |last12=Canfield |first12=V. A. |last13=Cheng |first13=K. C. |doi-access=free }}</ref>

===== SLC45A2 =====
[[SLC45A2|Solute carrier family 45 member 2]] (SLC45A2 or MATP) aids in the transport and processing of tyrosine, a precursor to melanin. It has also been shown to be one of the significant components of the skin color of modern Europeans through its ''Phe374Leu'' ([[rs16891982]]<ref>{{Cite web |title=rs16891982 RefSNP Report - dbSNP - NCBI |url=https://www.ncbi.nlm.nih.gov/snp/rs16891982 |access-date=2022-10-02 |website=www.ncbi.nlm.nih.gov}}</ref>) allele that has been directly correlated with skin color variation across a range of populations.<ref>{{cite journal |last1=Adhikari |first1=Kaustubh |title=A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia |journal=Nature Communications |volume=10 |issue=1 |pages=358 |date=21 January 2019 |doi=10.1038/s41467-018-08147-0 |pmid=30664655 |pmc=6341102 |bibcode=2019NatCo..10..358A }}</ref><ref>{{cite journal |last1=Deng |first1=Lian |title=Adaptation of human skin color in various populations |journal=Hereditas |volume=155 |pages=1 |date=15 June 2017 |doi=10.1186/s41065-017-0036-2 |pmid=28701907 |pmc=5502412 |doi-access=free }}</ref><ref name=Lopez/><ref name=Valenzuela /><ref name=Stokowski2007 /> This variation is ubiquitous in European populations but extremely rare elsewhere and shows strong signs of selection.<ref name=Soejima2006 /><ref name=Khai2012 /><ref>{{cite journal |title=Evidence for Recent Positive Selection at the Human AIM1 Locus in a European Population |journal=Molecular Biology and Evolution |date=January 2006 |volume=23 |issue=1 |pages=179–188 |doi=10.1093/molbev/msj018 |pmid=16162863 |last1=Soejima |first1=M |last2=Tachida |first2=H |last3=Ishida |first3=T |last4=Sano |first4=A |last5=Koda |first5=Y }}</ref>

===== TYR =====
The [[TYR gene]] encodes the enzyme tyrosinase, which is involved in the production of melanin from tyrosine. It has an allele, ''Ser192Tyr'' (rs1042602<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1042602 Reference SNP(refSNP) Cluster Report: rs1042602 **clinically associated**] {{webarchive|url= https://web.archive.org/web/20160416220943/http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1042602 |date=2016-04-16 }}. Ncbi.nlm.nih.gov (2008-12-30). Retrieved 2011-02-27.</ref>), found solely in 40–50% of Europeans<ref name="Norton2006" /><ref name=Belezal2012 /> and linked to light-colored skin in studies of South Asian<ref name=Stokowski2007>{{cite journal |last1=Stokowski |first1=R |last2=Pant |first2=P |last3=Dadd |first3=T |last4=Fereday |first4=A |last5=Hinds |first5=D |last6=Jarman |first6=C |last7=Filsell |first7=W |last8=Ginger |first8=R |last9=Green |first9=M |last10=Van Der Ouderaa |first10=Frans J. |last11=Cox |first11=David R. |title=A Genomewide Association Study of Skin Pigmentation in a South Asian Population |journal=The American Journal of Human Genetics |volume=81 |pages=1119–32 |year=2007 |doi=10.1086/522235 |pmid=17999355 |issue=6 |pmc=2276347 }}</ref> and African-American<ref name=Shriver2003>{{cite journal|url=http://dl.dropbox.com/u/38568440/admixture/shriver01.pdf |title=Skin pigmentation, biogeographical ancestry and admixture mapping |journal=Human Genetics |year=2003 |volume=112 |issue=4 |pages=387–399 |doi=10.1007/s00439-002-0896-y |pmid=12579416 |last1=Shriver|first1=MD |last2=Parra|first2=EJ |last3=Dios|first3=S |last4=Bonilla |first4=C |last5=Norton|first5=H |last6=Jovel|first6=C |last7=Pfaff |first7=C |last8=Jones|first8=C |last9=Massac|first9=A |last10=Cameron|first10=N |last11=Baron|first11=A |last12=Jackson|first12=T |last13=Argyropoulos|first13=G |last14=Jin|first14=L |last15=Hoggart|first15=CJ |last16=McKeigue|first16=PM |last17=Kittles|first17=RA |s2cid=7877572 |url-status=dead |archive-url= https://web.archive.org/web/20120415112141/http://dl.dropbox.com/u/38568440/admixture/shriver01.pdf |archive-date=2012-04-15}}</ref> populations.

==== East Asia ====
A number of genes known to affect skin color have alleles that show signs of positive selection in East Asian populations. Of these, only OCA2 has been directly related to skin color measurements, while DCT, MC1R and ATRN are marked as [[candidate gene]]s for future study.

===== OCA2 =====
[[File:OCA2 (rs12913832).png|thumb|OCA2 (rs12913832)]]
[[OCA2|Oculocutaneous albinism II]] (OCA2) assists in the regulation of [[pH]] in melanocytes. The OCA2 gene's derived ''His615Arg'' (rs1800414<ref name="ncbi_rs18">{{Cite web |title=rs1800414 RefSNP Report |author= |work=ncbi.nlm.nih.gov |date= |access-date=15 February 2021 |url= https://www.ncbi.nlm.nih.gov/snp/rs1800414 |quote=}}</ref>) allele has been shown to account for about 8% of the skin tone difference between African and East Asian populations in studies of an East Asian population living in Toronto and a Chinese [[Han Chinese|Han]] population. This variant is essentially restricted to East Asia, with highest frequencies in Eastern East Asia (49–63%), midrange frequencies in Southeast Asia, and the lowest frequencies in Western China and some Eastern European populations.<ref name="Edwards2010">{{cite journal |last1=Edwards |first1=Melissa |last2=Bigham |first2=Abigail |last3=Tan |first3=Jinze |last4=Li |first4=Shilin |last5=Gozdzik |first5=Agnes |last6=Ross |first6=Kendra |last7=Jin |first7=Li |last8=Parra |first8=Esteban J. |editor1-last=McVean |editor1-first=Gil |title=Association of the OCA2 Polymorphism His615Arg with Melanin Content in East Asian Populations: Further Evidence of Convergent Evolution of Skin Pigmentation |journal=PLOS Genetics |volume=6 |issue=3 |pages=e1000867 |year=2010 |pmid=20221248 |pmc=2832666 |doi=10.1371/journal.pgen.1000867 |doi-access=free }}</ref><ref>{{cite journal|title=A global view of the OCA2-HERC2 region and pigmentation |year=2012 |url=http://medicine.yale.edu/labs/kidd/www/511.pdf |last1=Donnelly |doi=10.1007/s00439-011-1110-x |journal=Human Genetics |volume=131 |issue=5 |pages=683–696 |first1=Michael P. |pmid=22065085 |pmc=3325407 |last2=Paschou |first2=Peristera |last3=Grigorenko |first3=Elena |last4=Gurwitz |first4=David |last5=Barta |first5=Csaba |last6=Lu |first6=Ru-Band |last7=Zhukova |first7=Olga V. |last8=Kim |first8=Jong-Jin |last9=Siniscalco |first9=Marcello |last10=New |first10=Maria |last11=Li |first11=Hui |last12=Kajuna |first12=Sylvester L. B. |last13=Manolopoulos |first13=Vangelis G. |last14=Speed |first14=William C. |last15=Pakstis |first15=Andrew J. |last16=Kidd |first16=Judith R. |last17=Kidd |first17=Kenneth K. |archive-url=https://web.archive.org/web/20131103050619/http://medicine.yale.edu/labs/kidd/www/511.pdf |archive-date=2013-11-03 |url-status=dead}}</ref>

===== Candidate genes =====
A number of studies have found genes linked to human skin pigmentation that have alleles with statistically significant frequencies in Chinese and East Asian populations. While not linked to measurements of skin tone variation directly, [[dopachrome tautomerase]] (DCT or TYRP2 rs2031526<ref name="ncbi_rs20">{{Cite web |title=rs2031526 RefSNP Report |author= |work=ncbi.nlm.nih.gov |date= |access-date=15 February 2021 |url= https://www.ncbi.nlm.nih.gov/snp/rs2031526 |quote=}}</ref><ref>{{cite journal |title=Identifying genes underlying skin pigmentation differences among human populations|year=2006 |journal=Human Genetics|volume=120|issue=5|pages=613–621|doi=10.1007/s00439-006-0256-4 |pmid=16977434 |last1=Myles|first1=S |last2=Somel|first2=M |last3=Tang|first3=K |last4=Kelso|first4=J |last5=Stoneking|first5=M |s2cid=32371450}}</ref>), [[melanocortin 1 receptor]] (MC1R) ''Arg163Gln'' (rs885479<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=885479 Reference SNP(refSNP) Cluster Report: rs885479] {{webarchive|url= https://web.archive.org/web/20160919022256/http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=885479 |date=2016-09-19 }}. Ncbi.nlm.nih.gov (2008-12-30). Retrieved 2011-02-27.</ref><ref>{{cite journal |last1=Shi |first1=Peng |last2=Lu |first2=Xue Mei |last3=Luo |first3=Huai Rong |last4=Xiang-Yu |first4=Jin-Gong |last5=Zhang |first5=Ya Ping |title=Melanocortin-1 receptor gene variants in four Chinese ethnic populations |journal=Cell Research |volume=11 |issue=1 |pages=81–4 |year=2001 |pmid=11305330 |doi=10.1038/sj.cr.7290070|doi-access=free }}</ref>) and [[ATRN|attractin]] (ATRN<ref name="Norton2006" />) have been indicated as potential contributors to the evolution of light skin in East Asian populations.

=== Tanning response ===
Tanning response in humans is controlled by a variety of genes. ''MC1R'' variants ''Arg151Sys'' (rs1805007<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1805007 Reference SNP(refSNP) Cluster Report: rs1805007] {{webarchive|url= https://web.archive.org/web/20161108195136/https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1805007 |date=2016-11-08 }}. Ncbi.nlm.nih.gov (2008-12-30).</ref>), ''Arg160Trp'' (rs1805008<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1805008 Reference SNP(refSNP) Cluster Report: rs1805008] {{webarchive|url= https://web.archive.org/web/20161108140647/https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1805008 |date=2016-11-08 }}. Ncbi.nlm.nih.gov (2008-12-30).</ref>), ''Asp294Sys'' (rs1805009<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1805009 Reference SNP(refSNP) Cluster Report: rs1805009] {{webarchive|url= https://web.archive.org/web/20161108135958/https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1805009 |date=2016-11-08 }}. Ncbi.nlm.nih.gov (2008-12-30).</ref>), ''Val60Leu'' (rs1805005<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1805005 Reference SNP(refSNP) Cluster Report: rs1805005] {{webarchive|url= https://web.archive.org/web/20180328064754/https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1805005 |date=2018-03-28 }}. Ncbi.nlm.nih.gov (2008-12-30).</ref>) and ''Val92Met'' (rs2228479<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2228479 Reference SNP(refSNP) Cluster Report: rs2228479] {{webarchive|url= https://web.archive.org/web/20180328111055/https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2228479 |date=2018-03-28 }}. Ncbi.nlm.nih.gov (2008-12-30).</ref>) have been associated with reduced tanning response in European and/or East Asian populations. These alleles show no signs of positive selection and only occur in relatively small numbers, reaching a peak in Europe with around 28% of the population having at least one allele of one of the variations.<ref name=Harding2000 /><ref>{{cite journal |title=Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans|journal=Nature Genetics |year=1995 |volume=11 |issue=3 |pages=328–30 |doi=10.1038/ng1195-328|pmid=7581459 |last1=Valverde|first1=P|last2=Healy|first2=E|last3=Jackson|first3=I|last4=Rees|first4=J. L.|last5=Thody|first5=A. J.|s2cid=7980311 }}</ref> A study of self-reported tanning ability and skin type in American non-[[Hispanic]] [[White American|Caucasians]] found that ''SLC24A5 Phe374Leu'' is significantly associated with reduced tanning ability and also associated ''TYR Arg402Gln'' (rs1126809<ref>{{cite web |url=https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=1126809 |title=Reference SNP (refSNP) Cluster Report: rs1126809 ** With Pathogenic allele ** |publisher=Ncbi.nlm.nih.gov |date=2006-01-28 |access-date=2015-02-03 |archive-url=https://web.archive.org/web/20150722102440/http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=1126809 |archive-date=2015-07-22 |url-status=live}}</ref>), ''OCA2 Arg305Trp'' (rs1800401<ref>{{cite web |url=https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1800401 |title=Reference SNP (refSNP) Cluster Report: rs1800401 ** With Pathogenic allele ** |publisher=Ncbi.nlm.nih.gov |date=2006-01-28 |access-date=2015-02-03 |url-status=live |archive-url=https://web.archive.org/web/20150203171523/http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1800401 |archive-date=2015-02-03 }}</ref>) and a 2-[[Single-nucleotide polymorphism|SNP]] [[haplotype]] in ''ASIP'' (rs4911414<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=4911414 Reference SNP(refSNP) Cluster Report: rs4911414 **clinically associated**] {{webarchive|url= https://web.archive.org/web/20180328061736/https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=4911414 |date=2018-03-28 }}. Ncbi.nlm.nih.gov (2008-12-30). Retrieved 2011-02-27.</ref> and rs1015362<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1015362 Reference SNP(refSNP) Cluster Report: rs1015362 **clinically associated**] {{webarchive|url= https://web.archive.org/web/20180328105513/https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1015362 |date=2018-03-28 }}. Ncbi.nlm.nih.gov (2008-12-30). Retrieved 2011-02-27.</ref>) to skin type variation within a "fair/medium/olive" context.<ref name=Nan2009>{{cite journal |last1=Nan |first1=Hongmei |last2=Kraft |first2=Peter |last3=Hunter |first3=David J. |last4=Han |first4=Jiali |title=Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians |journal=International Journal of Cancer |volume=125 |pages=909–17 |year=2009 |doi=10.1002/ijc.24327 |pmid=19384953 |issue=4 |pmc=2700213}}</ref>

=== Albinism ===
{{Main|Albinism in humans}}
[[Oculocutaneous albinism]] (OCA) is a lack of pigment in the eyes, skin and sometimes hair that occurs in a very small fraction of the population. The four known types of ''OCA'' are caused by mutations in the ''TYR'', ''OCA2'', ''[[TYRP1]]'', and ''SLC45A2'' genes.<ref name="ncbi.nlm.nih.gov">[https://www.ncbi.nlm.nih.gov/omim/203100 Albinism, Oculocutaneous, Type IA; OCA1A] {{webarchive|url= https://web.archive.org/web/20100803161806/http://www.ncbi.nlm.nih.gov/omim/203100 |date=2010-08-03 }}, Johns Hopkins University</ref>