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'''Sodium/potassium/calcium exchanger 5''' ('''NCKX5'''), also known as '''solute carrier family 24 member 5''' ('''SLC24A5'''), is a [[protein]] that in humans is encoded by the ''SLC24A5'' [[gene]] that has a major influence on natural skin colour variation.<ref name="pmid16357253">{{cite journal | vauthors = Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC | title = SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans | journal = Science | volume = 310 | issue = 5755 | pages = 1782–6 | date = December 2005 | pmid = 16357253 | doi = 10.1126/science.1116238 }}</ref> The NCKX5 protein is a member of the [[potassium-dependent sodium-calcium exchanger|potassium-dependent sodium/calcium exchanger]] family. Sequence variation in the ''SLC24A5'' gene, particularly a non-synonymous [[single-nucleotide polymorphism|SNP]] changing the [[amino acid]] at position 111 in NCKX5 from [[alanine]] to [[threonine]], has been associated with differences in [[human skin color|skin pigmentation]].<ref name="pmid18166528">{{cite journal | vauthors = Ginger RS, Askew SE, Ogborne RM, Wilson S, Ferdinando D, Dadd T, Smith AM, Kazi S, Szerencsei RT, Winkfein RJ, Schnetkamp PP, Green MR | title = SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis | journal = The Journal of Biological Chemistry | volume = 283 | issue = 9 | pages = 5486–95 | date = February 2008 | pmid = 18166528 | doi = 10.1074/jbc.M707521200 }}</ref> | '''Sodium/potassium/calcium exchanger 5''' ('''NCKX5'''), also known as '''solute carrier family 24 member 5''' ('''SLC24A5'''), is a [[protein]] that in humans is encoded by the ''SLC24A5'' [[gene]] that has a major influence on natural skin colour variation.<ref name="pmid16357253">{{cite journal | vauthors = Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC | title = SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans | journal = Science | volume = 310 | issue = 5755 | pages = 1782–6 | date = December 2005 | pmid = 16357253 | doi = 10.1126/science.1116238 }}</ref> The NCKX5 protein is a member of the [[potassium-dependent sodium-calcium exchanger|potassium-dependent sodium/calcium exchanger]] family. Sequence variation in the ''SLC24A5'' gene, particularly a non-synonymous [[single-nucleotide polymorphism|SNP]] changing the [[amino acid]] at position 111 in NCKX5 from [[alanine]] to [[threonine]], has been associated with differences in [[human skin color|skin pigmentation]].<ref name="pmid18166528">{{cite journal | vauthors = Ginger RS, Askew SE, Ogborne RM, Wilson S, Ferdinando D, Dadd T, Smith AM, Kazi S, Szerencsei RT, Winkfein RJ, Schnetkamp PP, Green MR | title = SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis | journal = The Journal of Biological Chemistry | volume = 283 | issue = 9 | pages = 5486–95 | date = February 2008 | pmid = 18166528 | doi = 10.1074/jbc.M707521200 }}</ref> | ||
The SLC24A5 gene's derived threonine or ''Ala111Thr'' allele (rs1426654<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1426654 Reference SNP(refSNP) Cluster Report: rs1426654 **clinically associated**]. Ncbi.nlm.nih.gov (2008-12-30). Retrieved on 2011-02-27.</ref>) has been shown to be a major factor in the light skin tone of [[Europe]]ans compared to [[Ethnic groups of Africa|African]]s, and is believed to represent as much as 25–40% of the average skin tone difference between Europeans and [[West Africa]]ns.<ref name="pmid16357253"/><ref name="Norton_2006">{{cite journal | vauthors = Norton HL, Kittles RA, Parra E, McKeigue P, Mao X, Cheng K, Canfield VA, Bradley DG, McEvoy B, Shriver MD | 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 | date = March 2007 | pmid = 17182896 | doi = 10.1093/molbev/msl203 | laysummary = http://www.sciencemag.org/content/316/5823/364.1.full | laysource = Science Magazine }}</ref> It has been the subject of recent selection in [[Europe]], and is fixed in European populations.<ref name=Belezal_2012>{{cite journal | vauthors = Beleza S, Santos AM, McEvoy B, Alves I, Martinho C, Cameron E, Shriver MD, Parra EJ, Rocha J | title = The timing of pigmentation lightening in Europeans | journal = Molecular Biology and Evolution | volume = 30 | issue = 1 | pages = 24–35 | date = January 2013 | pmid = 22923467 | pmc = 3525146 | doi = 10.1093/molbev/mss207 }}</ref><ref name="Soejima_2006">{{cite journal | vauthors = Soejima M, Koda Y | 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 | date = January 2007 | pmid = 16847698 | doi = 10.1007/s00414-006-0112-z }}</ref><ref name="pmid22912732">{{cite journal | vauthors = Ang KC, Ngu MS, Reid KP, Teh MS, Aida ZS, Koh DX, Berg A, Oppenheimer S, Salleh H, Clyde MM, Md-Zain BM, Canfield VA, Cheng KC | title = Skin color variation in Orang Asli tribes of Peninsular Malaysia | journal = PLoS One | volume = 7 | issue = 8 | pages = e42752 | year = 2012 | pmid = 22912732 | pmc = 3418284 | doi = 10.1371/journal.pone.0042752 | editor1-last = Kivisild | editor1-first = Toomas }}</ref> | The SLC24A5 gene's derived threonine or ''Ala111Thr'' allele (rs1426654<ref>[https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1426654 Reference SNP(refSNP) Cluster Report: rs1426654 **clinically associated**]. Ncbi.nlm.nih.gov (2008-12-30). Retrieved on 2011-02-27.</ref>) has been shown to be a major factor in the light skin tone of [[Europe]]ans compared to [[Sub-Saharan Africa|Sub-Saharan]] [[Ethnic groups of Africa|African]]s, and is believed to represent as much as 25–40% of the average skin tone difference between Europeans and [[West Africa]]ns.<ref name="pmid16357253"/><ref name="Norton_2006">{{cite journal | vauthors = Norton HL, Kittles RA, Parra E, McKeigue P, Mao X, Cheng K, Canfield VA, Bradley DG, McEvoy B, Shriver MD | 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 | date = March 2007 | pmid = 17182896 | doi = 10.1093/molbev/msl203 | laysummary = http://www.sciencemag.org/content/316/5823/364.1.full | laysource = Science Magazine }}</ref> It has been the subject of recent selection in [[Europe]], and is fixed in European populations.<ref name=Belezal_2012>{{cite journal | vauthors = Beleza S, Santos AM, McEvoy B, Alves I, Martinho C, Cameron E, Shriver MD, Parra EJ, Rocha J | title = The timing of pigmentation lightening in Europeans | journal = Molecular Biology and Evolution | volume = 30 | issue = 1 | pages = 24–35 | date = January 2013 | pmid = 22923467 | pmc = 3525146 | doi = 10.1093/molbev/mss207 }}</ref><ref name="Soejima_2006">{{cite journal | vauthors = Soejima M, Koda Y | 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 | date = January 2007 | pmid = 16847698 | doi = 10.1007/s00414-006-0112-z }}</ref><ref name="pmid22912732">{{cite journal | vauthors = Ang KC, Ngu MS, Reid KP, Teh MS, Aida ZS, Koh DX, Berg A, Oppenheimer S, Salleh H, Clyde MM, Md-Zain BM, Canfield VA, Cheng KC | title = Skin color variation in Orang Asli tribes of Peninsular Malaysia | journal = PLoS One | volume = 7 | issue = 8 | pages = e42752 | year = 2012 | pmid = 22912732 | pmc = 3418284 | doi = 10.1371/journal.pone.0042752 | editor1-last = Kivisild | editor1-first = Toomas }}</ref> | ||
== Gene == | == Gene == | ||
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== Effect on skin color == | == Effect on skin color == | ||
[[File:Ala111Thr allele frequency distribution0.png|500px|right|thumb|Global frequency distribution of the SLC24A5 gene's ancestral ''Ala111'' allele (yellow) and its derived ''Ala111Thr'' allele (blue).]] | [[File:Ala111Thr allele frequency distribution0.png|500px|right|thumb|Global frequency distribution of the SLC24A5 gene's ancestral ''Ala111'' allele (yellow) and its derived ''Ala111Thr'' allele (blue).]] | ||
''SLC24A5'' appears to have played a key role in the evolution of light skin in humans of European ancestry. The gene's function in pigmentation was discovered in zebrafish as a result of the positional cloning of the gene responsible for the " | ''SLC24A5'' appears to have played a key role in the evolution of light skin in humans of European ancestry. The gene's function in pigmentation was discovered in zebrafish as a result of the positional cloning of the gene responsible for the "golden" variety of this common pet store fish. Evidence in the [[International HapMap Project]] database of genetic variation in human populations showed that Europeans, represented by the "CEU" population, had two primary [[allele]]s differing by only one [[nucleotide]], changing the 111th [[amino acid]] from [[alanine]] to [[threonine]], abbreviated "''A111T''".<ref name="pmid16357253"/><ref name="url_BBC_News">{{cite web | url = http://news.bbc.co.uk/2/hi/health/4531966.stm | title = Key gene 'controls skin colour' | author = | authorlink = | coauthors = | date = 2005-12-16 | format = | work = Health | publisher = BBC News | pages = | quote = | accessdate = 2010-10-23}}</ref><ref name="urlPenn State Live - Fish gene sheds light on human skin color variation">{{cite web| url =http://live.psu.edu/story/15166| title =Fish gene sheds light on human skin color variation| author =| authorlink =| coauthors =| date =2005-12-16| format =| work =Penn State Live| publisher =Penn State University| pages =| archiveurl =https://web.archive.org/web/20100721225430/http://live.psu.edu/story/15166| archivedate =2010-07-21| quote =| accessdate =2010-10-23| deadurl =yes| df =}}</ref> | ||
The derived threonine allele (''Ala111Thr''; also known as ''A111T'' or ''Thr111'') represented 98.7 to 100% of the alleles in European samples, while the ancestral or alanine form was found in 93 to 100% of samples of Sub-Saharan Africans, East Asians and Indigenous Americans. The variation is a [[Single nucleotide polymorphism|SNP]] polymorphism ''rs1426654'', which had been previously shown to be second among 3011 tabulated SNPs ranked as [[ancestry-informative marker]]s. This single change in SLC24A5 explains between 25 and 38% of the difference in skin [[melanin]] index between peoples of sub-Saharan African and European ancestry.<ref name="pmid16357253" /> | The derived threonine allele (''Ala111Thr''; also known as ''A111T'' or ''Thr111'') represented 98.7 to 100% of the alleles in European samples, while the ancestral or alanine form was found in 93 to 100% of samples of Sub-Saharan Africans, East Asians and Indigenous Americans. The variation is a [[Single nucleotide polymorphism|SNP]] polymorphism ''rs1426654'', which had been previously shown to be second among 3011 tabulated SNPs ranked as [[ancestry-informative marker]]s. This single change in SLC24A5 explains between 25 and 38% of the difference in skin [[melanin]] index between peoples of sub-Saharan African and European ancestry.<ref name="pmid16357253" /> | ||
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The SNP rs2470102 independently affect skin pigmentation variation among the South Asian population.<ref>{{Cite news|url=http://www.thehindu.com/todays-paper/tp-features/tp-sci-tech-and-agri/CCMB-scientists-unravel-skin-colour-genetics-of-Indians/article16660021.ece|title=CCMB scientists unravel skin colour genetics of Indians|last=Prasad|first=R.|date=2016-11-20|work=The Hindu|access-date=2017-11-08|last2=Prasad|first2=R.|language=en-IN|issn=0971-751X}}</ref> | The SNP rs2470102 independently affect skin pigmentation variation among the South Asian population.<ref>{{Cite news|url=http://www.thehindu.com/todays-paper/tp-features/tp-sci-tech-and-agri/CCMB-scientists-unravel-skin-colour-genetics-of-Indians/article16660021.ece|title=CCMB scientists unravel skin colour genetics of Indians|last=Prasad|first=R.|date=2016-11-20|work=The Hindu|access-date=2017-11-08|last2=Prasad|first2=R.|language=en-IN|issn=0971-751X}}</ref> | ||
Furthermore, the European mutation is associated with the largest region of diminished genetic variation in the CEU HapMap population, suggesting the possibility that the ''A111T'' mutation may be the subject of the single largest degree of selection in human populations of European ancestry.<ref name="pmid16357253"/> It is theorised that selection for the derived allele is based on the need for sunlight to produce the essential nutrient [[vitamin D]]. In northerly latitudes, where there is less sun, greater requirement for body coverage due to colder climate, and frequently, diets poor in vitamin D, making lighter skin more suitable for survival.<ref name="Jablonski_2000">{{cite journal | vauthors = Jablonski NG, Chaplin G | title = The evolution of human skin coloration | journal = Journal of Human Evolution | volume = 39 | issue = 1 | pages = 57–106 | date = July 2000 | pmid = 10896812 | doi = 10.1006/jhev.2000.0403 | url = http://www.bgsu.edu/departments/chem/faculty/leontis/chem447/PDF_files/Jablonski_skin_color_2000.pdf }}</ref> Tests for this variation have obvious application to forensic science. | Furthermore, the European mutation is associated with the largest region of diminished genetic variation in the CEU HapMap population, suggesting the possibility that the ''A111T'' mutation may be the subject of the single largest degree of selection in human populations of European ancestry.<ref name="pmid16357253"/> It is theorised that selection for the derived allele is based on the need for sunlight to produce the essential nutrient [[vitamin D]]. In northerly latitudes, where there is less sun, greater requirement for body coverage due to colder climate, and frequently, diets poor in vitamin D, making lighter skin more suitable for survival.<ref name="Jablonski_2000">{{cite journal | vauthors = Jablonski NG, Chaplin G | title = The evolution of human skin coloration | journal = Journal of Human Evolution | volume = 39 | issue = 1 | pages = 57–106 | date = July 2000 | pmid = 10896812 | doi = 10.1006/jhev.2000.0403 | url = http://www.bgsu.edu/departments/chem/faculty/leontis/chem447/PDF_files/Jablonski_skin_color_2000.pdf | deadurl = yes | archiveurl = https://web.archive.org/web/20120114203210/http://www.bgsu.edu/departments/chem/faculty/leontis/chem447/PDF_files/Jablonski_skin_color_2000.pdf | archivedate = 2012-01-14 | df = }}</ref> Tests for this variation have obvious application to forensic science. | ||
The earliest known sample of the threonine allele is 13,000 years old from [[Satsurblia Cave]] in Georgia.<ref>{{cite journal | vauthors = Jones ER, Gonzalez-Fortes G, Connell S, Siska V, Eriksson A, Martiniano R, McLaughlin RL, Gallego Llorente M, Cassidy LM, Gamba C, Meshveliani T, Bar-Yosef O, Müller W, Belfer-Cohen A, Matskevich Z, Jakeli N, Higham TF, Currat M, Lordkipanidze D, Hofreiter M, Manica A, Pinhasi R, Bradley DG | title = Upper Palaeolithic genomes reveal deep roots of modern Eurasians | language = en | journal = Nature Communications | volume = 6 | pages = 8912 | date = November 2015 | pmid = 26567969 | pmc = 4660371 | doi = 10.1038/ncomms9912 | url = http://www.nature.com/articles/ncomms9912 }}</ref> The allele was widespread from Anatolia to Iran at the beginning of the Neolithic, and was introduced to Europe with the arrival of the first farmers from this region about 8,000 years ago.<ref>{{cite journal | vauthors = Broushaki F, Thomas MG, Link V, López S, van Dorp L, Kirsanow K, Hofmanová Z, Diekmann Y, Cassidy LM, Díez-del-Molino D, Kousathanas A, Sell C, Robson HK, Martiniano R, Blöcher J, Scheu A, Kreutzer S, Bollongino R, Bobo D, Davoudi H, Munoz O, Currat M, Abdi K, Biglari F, Craig OE, Bradley DG, Shennan S, Veeramah KR, Mashkour M, Wegmann D, Hellenthal G, Burger J | title = Early Neolithic genomes from the eastern Fertile Crescent | language = en | journal = Science | volume = 353 | issue = 6298 | pages = 499–503 | date = July 2016 | pmid = 27417496 | pmc = 5113750 | doi = 10.1126/science.aaf7943 | url = http://science.sciencemag.org/content/early/2016/07/13/science.aaf7943 }}</ref><ref>{{cite biorxiv|last=Mathieson|first=Iain|last2=Lazaridis|first2=Iosif|last3=Rohland|first3=Nadin|last4=Mallick|first4=Swapan|last5=Patterson|first5=Nick|last6=Roodenberg|first6=Songul Alpaslan|last7=Harney|first7=Eadaoin|last8=Stewardson|first8=Kristin|last9=Fernandes|first9=Daniel|date=2015-10-10|title=Eight thousand years of natural selection in Europe|biorxiv=016477}}</ref> | The earliest known sample of the threonine allele is 13,000 years old from [[Satsurblia Cave]] in Georgia.<ref>{{cite journal | vauthors = Jones ER, Gonzalez-Fortes G, Connell S, Siska V, Eriksson A, Martiniano R, McLaughlin RL, Gallego Llorente M, Cassidy LM, Gamba C, Meshveliani T, Bar-Yosef O, Müller W, Belfer-Cohen A, Matskevich Z, Jakeli N, Higham TF, Currat M, Lordkipanidze D, Hofreiter M, Manica A, Pinhasi R, Bradley DG | title = Upper Palaeolithic genomes reveal deep roots of modern Eurasians | language = en | journal = Nature Communications | volume = 6 | pages = 8912 | date = November 2015 | pmid = 26567969 | pmc = 4660371 | doi = 10.1038/ncomms9912 | url = http://www.nature.com/articles/ncomms9912 }}</ref> The allele was widespread from Anatolia to Iran at the beginning of the Neolithic, and was introduced to Europe with the arrival of the first farmers from this region about 8,000 years ago.<ref>{{cite journal | vauthors = Broushaki F, Thomas MG, Link V, López S, van Dorp L, Kirsanow K, Hofmanová Z, Diekmann Y, Cassidy LM, Díez-del-Molino D, Kousathanas A, Sell C, Robson HK, Martiniano R, Blöcher J, Scheu A, Kreutzer S, Bollongino R, Bobo D, Davoudi H, Munoz O, Currat M, Abdi K, Biglari F, Craig OE, Bradley DG, Shennan S, Veeramah KR, Mashkour M, Wegmann D, Hellenthal G, Burger J | title = Early Neolithic genomes from the eastern Fertile Crescent | language = en | journal = Science | volume = 353 | issue = 6298 | pages = 499–503 | date = July 2016 | pmid = 27417496 | pmc = 5113750 | doi = 10.1126/science.aaf7943 | url = http://science.sciencemag.org/content/early/2016/07/13/science.aaf7943 }}</ref><ref>{{cite biorxiv|last=Mathieson|first=Iain|last2=Lazaridis|first2=Iosif|last3=Rohland|first3=Nadin|last4=Mallick|first4=Swapan|last5=Patterson|first5=Nick|last6=Roodenberg|first6=Songul Alpaslan|last7=Harney|first7=Eadaoin|last8=Stewardson|first8=Kristin|last9=Fernandes|first9=Daniel|date=2015-10-10|title=Eight thousand years of natural selection in Europe|biorxiv=016477}}</ref> | ||
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== See also == | == See also == | ||
*[[Human skin color]] | *[[Human skin color]] | ||
* [[SLC45A2]] | |||
== References == | == References == | ||
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* {{cite journal | vauthors = Cook AL, Chen W, Thurber AE, Smit DJ, Smith AG, Bladen TG, Brown DL, Duffy DL, Pastorino L, Bianchi-Scarra G, Leonard JH, Stow JL, Sturm RA | title = Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci | journal = The Journal of Investigative Dermatology | volume = 129 | issue = 2 | pages = 392–405 | date = February 2009 | pmid = 18650849 | doi = 10.1038/jid.2008.211 }} | * {{cite journal | vauthors = Cook AL, Chen W, Thurber AE, Smit DJ, Smith AG, Bladen TG, Brown DL, Duffy DL, Pastorino L, Bianchi-Scarra G, Leonard JH, Stow JL, Sturm RA | title = Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci | journal = The Journal of Investigative Dermatology | volume = 129 | issue = 2 | pages = 392–405 | date = February 2009 | pmid = 18650849 | doi = 10.1038/jid.2008.211 }} | ||
* {{cite journal | vauthors = Nan H, Kraft P, Hunter DJ, Han J | title = Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians | journal = International Journal of Cancer | volume = 125 | issue = 4 | pages = 909–17 | date = August 2009 | pmid = 19384953 | pmc = 2700213 | doi = 10.1002/ijc.24327 }} | * {{cite journal | vauthors = Nan H, Kraft P, Hunter DJ, Han J | title = Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians | journal = International Journal of Cancer | volume = 125 | issue = 4 | pages = 909–17 | date = August 2009 | pmid = 19384953 | pmc = 2700213 | doi = 10.1002/ijc.24327 }} | ||
* {{cite journal | vauthors = Meda SA, Jagannathan K, Gelernter J, Calhoun VD, Liu J, Stevens MC, Pearlson GD | title = A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia | journal = NeuroImage | volume = 53 | issue = 3 | pages = 1007–15 | date = November 2010 | pmid = 19944766 | doi = 10.1016/j.neuroimage.2009.11.052 }} | * {{cite journal | vauthors = Meda SA, Jagannathan K, Gelernter J, Calhoun VD, Liu J, Stevens MC, Pearlson GD | title = A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia | journal = NeuroImage | volume = 53 | issue = 3 | pages = 1007–15 | date = November 2010 | pmid = 19944766 | doi = 10.1016/j.neuroimage.2009.11.052 | pmc = 3968678 }} | ||
* {{cite journal | vauthors = Stokowski RP, Pant PV, Dadd T, Fereday A, Hinds DA, Jarman C, Filsell W, Ginger RS, Green MR, van der Ouderaa FJ, Cox DR | title = A genomewide association study of skin pigmentation in a South Asian population | journal = American Journal of Human Genetics | volume = 81 | issue = 6 | pages = 1119–32 | date = December 2007 | pmid = 17999355 | pmc = 2276347 | doi = 10.1086/522235 }} | * {{cite journal | vauthors = Stokowski RP, Pant PV, Dadd T, Fereday A, Hinds DA, Jarman C, Filsell W, Ginger RS, Green MR, van der Ouderaa FJ, Cox DR | title = A genomewide association study of skin pigmentation in a South Asian population | journal = American Journal of Human Genetics | volume = 81 | issue = 6 | pages = 1119–32 | date = December 2007 | pmid = 17999355 | pmc = 2276347 | doi = 10.1086/522235 }} | ||
* {{cite journal | vauthors = Dagle JM, Lepp NT, Cooper ME, Schaa KL, Kelsey KJ, Orr KL, Caprau D, Zimmerman CR, Steffen KM, Johnson KJ, Marazita ML, Murray JC | title = Determination of genetic predisposition to patent ductus arteriosus in preterm infants | journal = Pediatrics | volume = 123 | issue = 4 | pages = 1116–23 | date = April 2009 | pmid = 19336370 | pmc = 2734952 | doi = 10.1542/peds.2008-0313 }} | * {{cite journal | vauthors = Dagle JM, Lepp NT, Cooper ME, Schaa KL, Kelsey KJ, Orr KL, Caprau D, Zimmerman CR, Steffen KM, Johnson KJ, Marazita ML, Murray JC | title = Determination of genetic predisposition to patent ductus arteriosus in preterm infants | journal = Pediatrics | volume = 123 | issue = 4 | pages = 1116–23 | date = April 2009 | pmid = 19336370 | pmc = 2734952 | doi = 10.1542/peds.2008-0313 }} | ||
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{{Membrane transport proteins}} | {{Membrane transport proteins}} | ||
[[Category:Solute carrier family]] | [[Category:Solute carrier family]] | ||
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Sodium/potassium/calcium exchanger 5 (NCKX5), also known as solute carrier family 24 member 5 (SLC24A5), is a protein that in humans is encoded by the SLC24A5 gene that has a major influence on natural skin colour variation.[1] The NCKX5 protein is a member of the potassium-dependent sodium/calcium exchanger family. Sequence variation in the SLC24A5 gene, particularly a non-synonymous SNP changing the amino acid at position 111 in NCKX5 from alanine to threonine, has been associated with differences in skin pigmentation.[2]
The SLC24A5 gene's derived threonine or Ala111Thr allele (rs1426654[3]) has been shown to be a major factor in the light skin tone of Europeans compared to Sub-Saharan Africans, and is believed to represent as much as 25–40% of the average skin tone difference between Europeans and West Africans.[1][4] It has been the subject of recent selection in Europe, and is fixed in European populations.[5][6][7]
Gene
The SLC24A5 gene, in humans, is located on the long (q) arm of chromosome 15 on position 21.1, from base pair 46,200,461 to base pair 46,221,881.[1]
Protein
NCKX5 is 43 kDa protein that is partially localized to the trans-Golgi network in melanocytes. Removal of the NCKX5 protein disrupts melanogenesis in human and mouse melanocytes, causing a significant reduction in melanin pigment production. Site-directed mutagenesis corresponding to a non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue in NCKX5 (A111T) that is important for NCKX5 sodium-calcium exchanger activity.[2]
Effect on skin color
SLC24A5 appears to have played a key role in the evolution of light skin in humans of European ancestry. The gene's function in pigmentation was discovered in zebrafish as a result of the positional cloning of the gene responsible for the "golden" variety of this common pet store fish. Evidence in the International HapMap Project database of genetic variation in human populations showed that Europeans, represented by the "CEU" population, had two primary alleles differing by only one nucleotide, changing the 111th amino acid from alanine to threonine, abbreviated "A111T".[1][8][9]
The derived threonine allele (Ala111Thr; also known as A111T or Thr111) represented 98.7 to 100% of the alleles in European samples, while the ancestral or alanine form was found in 93 to 100% of samples of Sub-Saharan Africans, East Asians and Indigenous Americans. The variation is a SNP polymorphism rs1426654, which had been previously shown to be second among 3011 tabulated SNPs ranked as ancestry-informative markers. This single change in SLC24A5 explains between 25 and 38% of the difference in skin melanin index between peoples of sub-Saharan African and European ancestry.[1]
The SNP rs2470102 independently affect skin pigmentation variation among the South Asian population.[10]
Furthermore, the European mutation is associated with the largest region of diminished genetic variation in the CEU HapMap population, suggesting the possibility that the A111T mutation may be the subject of the single largest degree of selection in human populations of European ancestry.[1] It is theorised that selection for the derived allele is based on the need for sunlight to produce the essential nutrient vitamin D. In northerly latitudes, where there is less sun, greater requirement for body coverage due to colder climate, and frequently, diets poor in vitamin D, making lighter skin more suitable for survival.[11] Tests for this variation have obvious application to forensic science.
The earliest known sample of the threonine allele is 13,000 years old from Satsurblia Cave in Georgia.[12] The allele was widespread from Anatolia to Iran at the beginning of the Neolithic, and was introduced to Europe with the arrival of the first farmers from this region about 8,000 years ago.[13][14]
See also
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC (December 2005). "SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans". Science. 310 (5755): 1782–6. doi:10.1126/science.1116238. PMID 16357253.
- ↑ 2.0 2.1 Ginger RS, Askew SE, Ogborne RM, Wilson S, Ferdinando D, Dadd T, Smith AM, Kazi S, Szerencsei RT, Winkfein RJ, Schnetkamp PP, Green MR (February 2008). "SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis". The Journal of Biological Chemistry. 283 (9): 5486–95. doi:10.1074/jbc.M707521200. PMID 18166528.
- ↑ Reference SNP(refSNP) Cluster Report: rs1426654 **clinically associated**. Ncbi.nlm.nih.gov (2008-12-30). Retrieved on 2011-02-27.
- ↑ Norton HL, Kittles RA, Parra E, McKeigue P, Mao X, Cheng K, Canfield VA, Bradley DG, McEvoy B, Shriver MD (March 2007). "Genetic evidence for the convergent evolution of light skin in Europeans and East Asians". Molecular Biology and Evolution. 24 (3): 710–22. doi:10.1093/molbev/msl203. PMID 17182896. Lay summary – Science Magazine.
- ↑ Beleza S, Santos AM, McEvoy B, Alves I, Martinho C, Cameron E, Shriver MD, Parra EJ, Rocha J (January 2013). "The timing of pigmentation lightening in Europeans". Molecular Biology and Evolution. 30 (1): 24–35. doi:10.1093/molbev/mss207. PMC 3525146. PMID 22923467.
- ↑ Soejima M, Koda Y (January 2007). "Population differences of two coding SNPs in pigmentation-related genes SLC24A5 and SLC45A2". International Journal of Legal Medicine. 121 (1): 36–9. doi:10.1007/s00414-006-0112-z. PMID 16847698.
- ↑ Ang KC, Ngu MS, Reid KP, Teh MS, Aida ZS, Koh DX, Berg A, Oppenheimer S, Salleh H, Clyde MM, Md-Zain BM, Canfield VA, Cheng KC (2012). Kivisild T, ed. "Skin color variation in Orang Asli tribes of Peninsular Malaysia". PLoS One. 7 (8): e42752. doi:10.1371/journal.pone.0042752. PMC 3418284. PMID 22912732.
- ↑ "Key gene 'controls skin colour'". Health. BBC News. 2005-12-16. Retrieved 2010-10-23.
- ↑ "Fish gene sheds light on human skin color variation". Penn State Live. Penn State University. 2005-12-16. Archived from the original on 2010-07-21. Retrieved 2010-10-23.
- ↑ Prasad, R.; Prasad, R. (2016-11-20). "CCMB scientists unravel skin colour genetics of Indians". The Hindu. ISSN 0971-751X. Retrieved 2017-11-08.
- ↑ Jablonski NG, Chaplin G (July 2000). "The evolution of human skin coloration" (PDF). Journal of Human Evolution. 39 (1): 57–106. doi:10.1006/jhev.2000.0403. PMID 10896812. Archived from the original (PDF) on 2012-01-14.
- ↑ Jones ER, Gonzalez-Fortes G, Connell S, Siska V, Eriksson A, Martiniano R, McLaughlin RL, Gallego Llorente M, Cassidy LM, Gamba C, Meshveliani T, Bar-Yosef O, Müller W, Belfer-Cohen A, Matskevich Z, Jakeli N, Higham TF, Currat M, Lordkipanidze D, Hofreiter M, Manica A, Pinhasi R, Bradley DG (November 2015). "Upper Palaeolithic genomes reveal deep roots of modern Eurasians". Nature Communications. 6: 8912. doi:10.1038/ncomms9912. PMC 4660371. PMID 26567969.
- ↑ Broushaki F, Thomas MG, Link V, López S, van Dorp L, Kirsanow K, Hofmanová Z, Diekmann Y, Cassidy LM, Díez-del-Molino D, Kousathanas A, Sell C, Robson HK, Martiniano R, Blöcher J, Scheu A, Kreutzer S, Bollongino R, Bobo D, Davoudi H, Munoz O, Currat M, Abdi K, Biglari F, Craig OE, Bradley DG, Shennan S, Veeramah KR, Mashkour M, Wegmann D, Hellenthal G, Burger J (July 2016). "Early Neolithic genomes from the eastern Fertile Crescent". Science. 353 (6298): 499–503. doi:10.1126/science.aaf7943. PMC 5113750. PMID 27417496.
- ↑ Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Roodenberg, Songul Alpaslan; Harney, Eadaoin; Stewardson, Kristin; Fernandes, Daniel (2015-10-10). "Eight thousand years of natural selection in Europe". bioRxiv 016477.
Further reading
- Grønskov K, Ek J, Sand A, Scheller R, Bygum A, Brixen K, Brondum-Nielsen K, Rosenberg T (March 2009). "Birth prevalence and mutation spectrum in danish patients with autosomal recessive albinism". Investigative Ophthalmology & Visual Science. 50 (3): 1058–64. doi:10.1167/iovs.08-2639. PMID 19060277.
- Cook AL, Chen W, Thurber AE, Smit DJ, Smith AG, Bladen TG, Brown DL, Duffy DL, Pastorino L, Bianchi-Scarra G, Leonard JH, Stow JL, Sturm RA (February 2009). "Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci". The Journal of Investigative Dermatology. 129 (2): 392–405. doi:10.1038/jid.2008.211. PMID 18650849.
- Nan H, Kraft P, Hunter DJ, Han J (August 2009). "Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians". International Journal of Cancer. 125 (4): 909–17. doi:10.1002/ijc.24327. PMC 2700213. PMID 19384953.
- Meda SA, Jagannathan K, Gelernter J, Calhoun VD, Liu J, Stevens MC, Pearlson GD (November 2010). "A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia". NeuroImage. 53 (3): 1007–15. doi:10.1016/j.neuroimage.2009.11.052. PMC 3968678. PMID 19944766.
- Stokowski RP, Pant PV, Dadd T, Fereday A, Hinds DA, Jarman C, Filsell W, Ginger RS, Green MR, van der Ouderaa FJ, Cox DR (December 2007). "A genomewide association study of skin pigmentation in a South Asian population". American Journal of Human Genetics. 81 (6): 1119–32. doi:10.1086/522235. PMC 2276347. PMID 17999355.
- Dagle JM, Lepp NT, Cooper ME, Schaa KL, Kelsey KJ, Orr KL, Caprau D, Zimmerman CR, Steffen KM, Johnson KJ, Marazita ML, Murray JC (April 2009). "Determination of genetic predisposition to patent ductus arteriosus in preterm infants". Pediatrics. 123 (4): 1116–23. doi:10.1542/peds.2008-0313. PMC 2734952. PMID 19336370.
- Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP, Manolescu A, Karason A, Palsson A, Thorleifsson G, Jakobsdottir M, Steinberg S, Pálsson S, Jonasson F, Sigurgeirsson B, Thorisdottir K, Ragnarsson R, Benediktsdottir KR, Aben KK, Kiemeney LA, Olafsson JH, Gulcher J, Kong A, Thorsteinsdottir U, Stefansson K (December 2007). "Genetic determinants of hair, eye and skin pigmentation in Europeans". Nature Genetics. 39 (12): 1443–52. doi:10.1038/ng.2007.13. PMID 17952075.
- Cai X, Lytton J (February 2004). "Molecular cloning of a sixth member of the K+-dependent Na+/Ca2+ exchanger gene family, NCKX6". The Journal of Biological Chemistry. 279 (7): 5867–76. doi:10.1074/jbc.M310908200. PMID 14625281.
- Chi A, Valencia JC, Hu ZZ, Watabe H, Yamaguchi H, Mangini NJ, Huang H, Canfield VA, Cheng KC, Yang F, Abe R, Yamagishi S, Shabanowitz J, Hearing VJ, Wu C, Appella E, Hunt DF (November 2006). "Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes". Journal of Proteome Research. 5 (11): 3135–44. doi:10.1021/pr060363j. PMID 17081065.
- Soejima M, Koda Y (January 2007). "Population differences of two coding SNPs in pigmentation-related genes SLC24A5 and SLC45A2". International Journal of Legal Medicine. 121 (1): 36–9. doi:10.1007/s00414-006-0112-z. PMID 16847698.
- Dimisianos G, Stefanaki I, Nicolaou V, Sypsa V, Antoniou C, Poulou M, Papadopoulos O, Gogas H, Kanavakis E, Nicolaidou E, Katsambas AD, Stratigos AJ (February 2009). "A study of a single variant allele (rs1426654) of the pigmentation-related gene SLC24A5 in Greek subjects". Experimental Dermatology. 18 (2): 175–7. doi:10.1111/j.1600-0625.2008.00758.x. PMID 18637132.
External links
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Wikimedia Commons has media related to SLC24A5. |
- SLC24A5+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)