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Database: OMIM
Entry: 227220
LinkDB: 227220
MIM Entry: 227220
Title:
  #227220 SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 1; SHEP1
  ;;SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES;;
  SKIN/HAIR/EYE PIGMENTATION 1, BLUE/BROWN EYES;;
  SKIN/HAIR/EYE PIGMENTATION 1, BLOND/BROWN HAIR;;
  EYE COLOR, BROWN/BLUE;;
  EYE COLOR, BLUE/NONBLUE;;
  EYE COLOR 3; EYCL3;;
  BROWN EYE COLOR 2; BEY2;;
  HAIR COLOR 3; HCL3
Text:
  A number sign (#) is used with this entry because of evidence that
  variants of the OCA2 gene (611409) play a role in determining blue
  versus nonblue eye color, and blond versus brown hair. Noncoding
  variants in the HERC2 gene (605837) 200 kb downstream of OCA2 have also
  been associated that are thought to affect OCA2 expression.
  
  Multiple genes influence normal human skin, hair, and/or eye
  pigmentation. Pigmentation phenotypes influenced by variation in the
  OCA2 gene are termed SHEP1. The SHEP2 association (266300) is determined
  by variation at the MC1R locus (155555) and describes a phenotype
  predominantly characterized by red hair and fair skin. SHEP3 (601800)
  encompasses pigment variation influenced by the TYR gene (606933); SHEP4
  (113750), that influenced by the SLC24A5 gene (609802). Variation in the
  SLC45A2 (606202) and SLC24A4 (609840) genes result in the phenotypic
  associations SHEP5 (227240) and SHEP6 (210750), respectively. Sequence
  variation thought to affect expression of KITLG (184745) results in the
  SHEP7 (611664) phenotypic association, and SHEP8 (611724) has been
  associated with single-nucleotide polymorphisms (SNPs) at chromosome
  6p25.3. Polymorphism in the 3-prime-untranslated region of the ASIP gene
  (600201) influences the SHEP9 association (611742). The SHEP10
  association (612267) comprises variation in the TPCN2 gene (612163), and
  SHEP11 (612271) is associated with polymorphism near the TYRP1 gene
  (115501).
  
  DESCRIPTION
  
  Pigmentation of hair, eye, and skin is among the most visible examples
  of human phenotypic variation, with a broad normal range that is subject
  to substantial geographic stratification. Pigmentation in human tissues
  is attributable to the number, type, and cellular distribution of
  melanosomes (subcellular compartments produced by melanocytes that
  synthesize and store the light-absorbing polymer melanin) (Sulem et al.,
  2007). Variation in pigmentation among individuals is thought to be
  caused by biochemical differences that affect the number of melanosomes
  produced, the type of melanin synthesized (either black-brown eumelanin
  or red-yellow pheomelanin), and the size and shape of the melanosomes.
  The key physiologic role of skin pigmentation seems to be to absorb
  ultraviolet radiation (UVR). This protective role must be weighted
  against the reduced amount of UVR available for the synthesis of vitamin
  D3. It is generally believed that the geographic distribution of human
  skin pigmentation reflects a history of adaptation to latitude-dependent
  levels of UVR, with individuals tending to have lighter pigmentation
  with increasing distance from the equator (Relethford, 1997). The
  majority of variation in human eye and hair color is found among
  individuals of European ancestry, with most other human populations
  fixed for brown eyes and black hair (Sulem et al., 2007). Stokowski et
  al. (2007) cited studies suggesting that the genetic factors influencing
  lighter pigmentation in Europeans may be far different from the
  mechanism for lighter pigmentation in East Asians (Relethford, 1997;
  Norton et al., 2006; Myles et al., 2007). Given the direct correlation
  between skin pigmentation and incident UV exposure, it has long been
  postulated that it is a trait under intense selective pressure
  (Stokowski et al., 2007). Pigmentary mutants in model organisms and
  human disorders of pigmentation have been the main source for the
  discovery of genes involved in skin color. More than 100 pigmentation
  genes have been identified in mouse alone, most with identified human
  orthologs, and at least 18 genes had been implicated in human albinism.
  
  MAPPING
  
  Eiberg and Mohr (1996) sought the location of the BEY2 locus for brown
  eye color through an inquiry using data on eye color and hair color in
  832 families from the Copenhagen area. By exclusion mapping with 80
  markers in 120 segregating families and 290 markers in 5 segregating
  families, they obtained some indication of a locus BEY2 for brown eye
  color on chromosome 15. For possible confirmation, they selected a total
  of 45 families from their DNA bank segregating for BEY. All these were
  tested for chromosome 15 markers in the area between D15S11 and CYP19
  (107910). They found a strong indication of linkage with the DNA
  polymorphism D15S165 and with flanking markers D15S156 and D15S144. A
  multipoint lod score of 32.2 was obtained for location in this interval.
  These markers had been assigned to the 15q11-q21 region.
  
  Eiberg and Mohr (1996) obtained a lod score of 9.93 at theta (M = Z) =
  0.10 for linkage of a locus for brown hair color (HCL3) to a locus for
  brown eye color (BEY2) that they mapped to 15q11-q21. The studies were
  done in 45 families from the Copenhagen area segregating for brown eye
  color. They found 56 matings informative for brown eye color and hair
  color; in 51 of these families the 2 traits were inherited together (in
  cis), while in 5 families the 2 traits were separated when transmitted
  to the offspring (in trans). They analyzed 3 of the 'trans' families and
  found that BEY2 and HCL3 segregated with chromosome 15 markers. This
  supported the assumption of linkage disequilibrium between BEY2 and
  HCL3, due presumably to recent immigration of people with brown hair and
  brown eye color, as an explanation for the excess of the apparent phase
  cis. There was an association between brown eye color and brown hair
  color in the 45 selected families; among 46 parents with brown eye color
  44 had brown hair color, while among 44 spouses with blue eye color only
  26 had brown hair color. Eiberg and Mohr (1996) suggested the P gene
  (OCA2; 611409), which resides in the 15q11-q21 region and which is the
  site of mutations causing type II oculocutaneous albinism (203200), as a
  candidate gene for brown eye and hair color.
  
  MOLECULAR GENETICS
  
  Two OCA2 coding region variant alleles, arg305 to trp (R305W;
  611409.0011) and arg419 to gln (R419Q; 611409.0012), were shown to be
  associated with brown and green/hazel eye colors, respectively (Rebbeck
  et al., 2002; Jannot et al., 2005), and blue eye color was also shown to
  be linked to the OCA2 locus through use of microsatellite (Posthuma et
  al., 2006; Frudakis et al., 2003) and single-nucleotide polymorphism
  (SNP) (International HapMap Consortium, 2005) markers.
  
  Duffy et al. (2007) found that 3 SNPs in intron 1 of the OCA2 gene have
  the highest statistical association with blue eye color. Moreover, these
  are found in a tight linkage disequilibrium block, with the TGT
  haplotype 1 (611409.0013) representing 78.4% of alleles in their sample.
  Given that nonbrown eye colors are found at high frequency only in white
  populations, Duffy et al. (2007) considered it notable that haplotype 1
  was found at 82.5% in Europeans and at only minor frequencies (7.4% in
  those of African and 12.1% in those of East Asian descent) in others,
  suggesting strong positive selection for TGT in Europeans. The TGT/TGT
  diplotype of OCA2 was found in 62.2% of samples and was the major
  genotype seen to modify eye color, with a frequency of 0.905 in blue or
  green compared with only 0.095 in brown eye color. This genotype was
  also at highest frequency in subjects with light brown hair and was more
  frequent in fair and medium skin types, consistent with the TGT
  haplotype acting as a recessive modifier of lighter pigmentary
  phenotypes. Duffy et al. (2007) found only minor population impact of
  the R305W and R419Q associated with nonblue eyes, as contrasted with the
  tight linkage of the major TGT haplotype within intron 1 of OCA2 with
  blue eye color and lighter hair and skin tones, which suggested that
  differences within the 5-prime proximal regulatory control region of the
  OCA2 gene alter expression or mRNA transcript levels and may be
  responsible for these associations.
  
  Among 2,986 Icelanders, Sulem et al. (2007) carried out a genomewide
  association scan for variants associated with hair and eye pigmentation,
  skin sensitivity to sun, and freckling. The most closely associated SNPs
  from 6 regions were then tested for replication in a second sample of
  2,718 Icelanders and a sample of 1,214 Dutch. A 1-Mb region on
  chromosome 15 overlapping the OCA2 gene and containing 16 SNPs showed
  association with blue versus brown eyes, blue versus green eyes, blond
  versus brown hair, or some combination of these traits in the Icelandic
  sample that reached genomewide significance. The 3 common variants in
  intron 1 of OCA2, dbSNP rs7495174, dbSNP rs4778241, and dbSNP rs4778138,
  reported by Duffy et al. (2007) as strongly associated with skin, hair,
  and eye pigmentation in populations of European ancestry, were among the
  16 detected in the genomewide scan. However, the SNP that showed the
  strongest association was dbSNP 1667394 (OR = 35.42, P = 1.4 x 10(-124)
  for blue versus brown eyes; OR = 7.02, P = 5.1 x 10(-25) for blue versus
  green eyes; OR = 5.62, P = 4.4 x 10(-16) for blond versus brown hair).
  This SNP is located 200 kb downstream of OCA2, within intron 4 of the
  HERC2 gene (605837.0001). Given the established relationship between
  OCA2 and pigmentation, Sulem et al. (2007) considered it unlikely that
  the association signal provided by this SNP was due to a functional
  effect on HERC2. Rather, they suggested that perhaps sequence variation
  in the introns of HERC2 affects the expression of OCA2, or that
  functional variants exist within OCA2 that correlate with dbSNP 1667394.
  
  In European populations, Kayser et al. (2008) and Sturm et al. (2008)
  identified variants in introns of the HERC2 gene (605837.0002,
  605837.0003) that were better predictors of blue eye color than were the
  variants found by Duffy et al. (2007) in intron 1 of OCA2 (611409.0013).
  Sturm et al. (2008) identified the R419Q variant of OCA2 (611409.0012)
  as a penetrance modifier of the HERC2 variant dbSNP rs12913832
  (605837.0003) and of the risk of malignant melanoma.
  
  In a 3-generation Danish family segregating blue and brown eye color,
  Eiberg et al. (2008) used fine mapping to identify a 166-kb candidate
  region within the HERC2 gene. Further studies of SNPs within this region
  among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs,
  dbSNP rs1129038 and the strongly conserved dbSNP rs12913832, that showed
  significant associations with the blue-eyed phenotype (p = 6.2 x
  10(-46)). A common founder haplotype containing these SNPs was
  identified among blue-eyed persons from Denmark, Turkey, and Jordan.
  
  HISTORY
  
  Iris color was one of the first human traits used in investigating
  mendelian inheritance in humans. Davenport and Davenport (1907) outlined
  what was long taught in schools as a beginner's guide to genetics, that
  brown eye color is always dominant to blue, with 2 blue-eyed parents
  always producing a blue-eyed child, never one with brown eyes. As with
  many physical traits, the simplistic model does not convey the fact that
  eye color is inherited as a polygenic, not as a monogenic, trait (Sturm
  and Frudakis, 2004). The early view that blue is a simple recessive has
  been repeatedly shown to be wrong by observation of brown-eyed offspring
  of 2 blue-eyed parents. My monozygotic twin brother and I, brown-eyed,
  had blue-eyed parents and blue-eyed sibs (VAM). Blue-eyed offspring from
  2 brown-eyed parents is a more frequent finding.
  
  In some Norwegian families, Gedde-Dahl (1981) found diffusely brown eyes
  or centrally brown eyes segregating as simple dominant traits,
  symbolized BEY1. Possible linkage to Km (Inv) and to Co was found,
  suggesting the order Jk--Km--BEY1--Co. (Co and Km are not measurably
  linked.)
  
  Gedde-Dahl et al. (1982) found positive lod scores between brown eye
  color BEY1 (later described as central brown eye color) and the blood
  groups Colton (CO; 110450, which maps to chromosome 7) and Kidd (JK;
  111000, which maps to chromosome 18, Eiberg (1997)). Another phenotype,
  green eye color (GEY; see 601800), mapped to chromosome 19 by linkage to
  secretor (SE; 182100) and Lutheran (LU; 111150). A gene for brown hair
  color segregated with GEY (maximum lod = 5.6 at theta = 0.010) in the
  data of Eiberg and Mohr (1987).
  
  Eiberg and Mohr (1987) found a lod score of 5.06 for linkage of GEY to
  brown hair color (BRHC, HCL1). Of interest is the fact that 6 loci on
  chromosome 19 in man have their homologs on chromosome 7 in the mouse.
  Chromosome 7 carries at least 3 'pigment loci,' namely, ruby-2 (ru-2),
  pink-eyed dilution (p; see 611409), and albino (c).
  
  Eiberg (1997) stated that they found both cis and trans segregations of
  green eye color and brown hair color in families chosen primarily for
  segregation for green eye color.
  
See Also:
  Rufer et al. (1970)
References:
  1. Davenport, G. C.; Davenport, C. B.: Heredity of eye color in man. Science 26:  
  589-592, 1907.
  
  2. Duffy, D. L.; Montgomery, G. W.; Chen, W.; Zhao, Z. Z.; Le, L.;
  James, M. R.; Hayward, N. K.; Martin, N. G.; Sturm, R. A.: A three-single-nucleo  tide
  polymorphism haplotype in intron 1 of OCA2 explains most human eye-color
  variation. Am. J. Hum. Genet. 80: 241-252, 2007.
  
  3. Eiberg, H.: Personal Communication. Copenhagen, Denmark  5/9/1997.
  
  4. Eiberg, H.: Personal Communication. Copenhagen, Denmark  3/25/1997.
  
  5. Eiberg, H.; Mohr, J.: Assignment of genes coding for brown eye
  colour (BEY2) and brown hair colour (HCL3) on chromosome 15q. Europ.
  J. Hum. Genet. 4: 237-241, 1996.
  
  6. Eiberg, H.; Mohr, J.: Major genes of eye color and hair color
  linked to LU and SE. Clin. Genet. 31: 186-191, 1987.
  
  7. Eiberg, H.; Troelsen, J.; Nielsen, M.; Mikkelsen, A.; Mengel-From,
  J.; Kjaer, K. W.; Hansen, L.: Blue eye color in humans may be caused
  by a perfectly associated founder mutation in a regulatory element
  located within the HERC2 gene inhibiting OCA2 expression. Hum. Genet. 123:
  177-187, 2008.
  
  8. Frudakis, T.; Thomas, M.; Gaskin, Z.; Venkateswarlu, K.; Chandra,
  K. S.; Ginjupalli, S.; Gunturi, S.; Natrajan, S.; Ponnuswamy, V. K.;
  Ponnuswamy, K. N.: Sequences associated with human iris pigmentation. Genetics 1  65:
  2071-2083, 2003.
  
  9. Gedde-Dahl, T., Jr.: Personal Communication. Oslo, Norway  6/1981.
  
  10. Gedde-Dahl, T., Jr.; Olaisen, B.; Siverts, A.; Wilhelmy, M.:
  Support for synteny of PTC-K with Jk-IGK-BEY1-Co? (Abstract) Cytogenet.
  Cell Genet. 32: 278 only, 1982.
  
  11. International HapMap Consortium: A haplotype map of the human
  genome. Nature 437: 1299-1320, 2005.
  
  12. Jannot, A.-S.; Meziani, R.; Bertrand, G.; Gerard, B.; Descamps,
  V.; Archimbaud, A.; Picard, C.; Ollivaud, L.; Basset-Seguin, N.; Kerob,
  D.; Lanternier, G.; Lebbe, C.; Saiag, P.; Crickx, B.; Clerget-Darpoux,
  F.; Grandchamp, B.; Soufir, N.; Melan-Cohort: Allele variations
  in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic
  susceptibility to melanoma. Europ. J. Hum. Genet. 13: 913-920, 2005.
  
  13. Kayser, M.; Liu, F.; Janssens, A. C. J. W.; Rivadeneira, F.; Lao,
  O.; van Duijn, K.; Vermeulen, M.; Arp, P.; Jhamai, M. M.; van IJcken,
  W. F. J.; den Dunnen, J. T.; Heath, S.; and 10 others: Three genome-wide
  association studies and a linkage analysis identify HERC2 as a human
  iris color gene. Am. J. Hum. Genet. 82: 411-423, 2008.
  
  14. Myles, S.; Somel, M.; Tang, K.; Kelso, J.; Stoneking, M.: Identifying
  genes underlying skin pigmentation differences among human populations. Hum.
  Genet. 120: 613-621, 2007.
  
  15. Norton, H. L.; Kittles, R. A.; Parra, E.; McKeigue, P.; Mao, X.;
  Cheng, K.; Canfield, V. A.; Bradley, D. G.; McEvoy, B.; Shriver, M.
  D.: Genetic evidence for the convergent evolution of light skin in
  Europeans and East Asians. Molec. Biol. Evol. 24: 710-722, 2006.
  
  16. Posthuma, D.; Visscher, P. M.; Willemsen, G.; Zhu, G.; Martin,
  N. G.; Slagboom, P. E.; de Geus, E. J.; Boomsma, D. I.: Replicated
  linkage for eye color on 15q using comparative ratings of sibling
  pairs. Behav. Genet. 36: 12-17, 2006.
  
  17. Rebbeck, T. R.; Kanetsky, P. A.; Walker, A. H.; Holmes, R.; Halpern,
  A. C.; Schuchter, L. M.; Elder, D. E.; Guerry, D.: P gene as an inherited
  biomarker of human eye color. Cancer Epidemiol. Biomarkers Prev. 11:
  782-784, 2002.
  
  18. Relethford, J. H.: Hemispheric difference in human skin color. Am.
  J. Phys. Anthrop. 104: 449-457, 1997.
  
  19. Rufer, V.; Bauer, J.; Soukup, F.: On the heredity of eye colour. Acta
  Univ. Carol. Med. 16: 429-434, 1970.
  
  20. Stokowski, R. P.; Pant, P. V. K.; Dadd, T.; Fereday, A.; Hinds,
  D. A.; Jarman, C.; Filsell, W.; Ginger, R. S.; Green, M. R.; van der
  Ouderaa, F. J.; Cox, D. R.: A genomewide association study of skin
  pigmentation in a South Asian population. Am. J. Hum. Genet. 81:
  1119-1132, 2007.
  
  21. Sturm, R. A.; Duffy, D. L.; Zhao, Z. Z.; Leite, F. P. N.; Stark,
  M. S.; Hayward, N. K.; Martin, N. G.; Montgomery, G. W.: A single
  SNP in an evolutionary conserved region within intron 86 of the HERC2
  gene determines human blue-brown eye color. Am. J. Hum. Genet. 82:
  424-431, 2008.
  
  22. Sturm, R. A.; Frudakis, T. N.: Eye color: portals into pigmentation
  genes and ancestry. Trends Genet. 20: 327-332, 2004.
  
  23. Sulem, P.; Gudbjartsson, D. F.; Stacey, S. N.; Helgason, A.; Rafnar,
  T.; Magnusson, K. P.; Manolescu, A.; Karason, A.; Palsson, A.; Thorleifsson,
  G.; Jakobsdottir, M.; Steinberg, S.; and 13 others: Genetic determinants
  of hair, eye and skin pigmentation in Europeans. Nature Genet. 39:
  1443-1452, 2007.
  
Clinical Synopsis:
  
  Eyes:
     Blue color recessive to brown
  
  Inheritance:
     Autosomal recessive at BEY locus;
     Eye color probably polygenic
  
Contributors: 
  Cassandra L. Kniffin - updated: 4/11/2008
  Anne M. Stumpf - reorganized: 1/10/2008
  Victor A. McKusick - updated: 2/8/2007
  Victor A. McKusick - updated: 5/15/1997
  
Creation Date: 
  Victor A. McKusick: 12/16/1986
  
Edit Dates: 
  alopez: 09/04/2008
  terry: 6/6/2008
  wwang: 4/18/2008
  ckniffin: 4/11/2008
  alopez: 4/4/2008
  alopez: 4/3/2008
  alopez: 2/18/2008
  alopez: 1/18/2008
  alopez: 1/17/2008
  alopez: 1/16/2008
  alopez: 1/10/2008
  carol: 9/12/2007
  terry: 8/9/2007
  alopez: 2/9/2007
  terry: 2/8/2007
  alopez: 3/18/2004
  carol: 6/15/1999
  dkim: 7/21/1998
  mark: 5/15/1997
  alopez: 5/13/1997
  terry: 5/6/1997
  mimadm: 2/19/1994
  supermim: 3/16/1992
  supermim: 3/20/1990
  ddp: 10/26/1989
  marie: 3/25/1988
  marie: 12/16/1986
  
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