MIM Entry: 227220
#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
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
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.
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.
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.
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
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.
Rufer et al. (1970)
1. Davenport, G. C.; Davenport, C. B.: Heredity of eye color in man. Science 26:
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:
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:
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:
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:
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:
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:
Blue color recessive to brown
Autosomal recessive at BEY locus;
Eye color probably polygenic
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
Victor A. McKusick: 12/16/1986