Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair
Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hairNeil F. Box1, Jason R. Wyeth1, Louise E. O'Gorman2, Nicholas G. Martin2 and Richard A. Sturm1,*
1Centre for Molecular and Cellular Biology, University of Queensland, Brisbane, Qld 4072 Australia and 2Queensland Institute of Medical Research, Brisbane, Qld 4029 Australia
Received May 30, 1997;Revised and Accepted July 25, 1997
The association between MSHR coding region variation and hair colour in humans has been examined by genotyping 25 red haired and 62 non-red Caucasians, all of whom were 12 years of age and members of a twin pair study.Twelve amino acid substitutions were seen at 11 different sites, nine of these being newly described MSHR variants.The previously reported Val92Met allele shows no association with hair colour, but the three alleles Arg151Cys, Arg160Trp and Asp294His were associated with red hair and one Val60Leu variant was most frequent in fair/blonde and light brown hair colours.Variant MSHR genotypes are associated with lighter skin types and red hair (P < 0.001).However, comparison of the MSHR genotypes in dizygotic twin pairs discordant for red hair colour indicates that the MSHR gene cannot be solely responsible for the red hair phenotype, since five of 13 pairs tested had both haplotypes identical by state (with three of the five having both identical by descent).Rather, it is likely that additional modifier genes exist, making variance in the MSHR gene necessary but not always sufficient, for red hair production.
Our understanding of the genetics of red hair in humans is incomplete, with the several reported attempts at gene linkage indecisive (1 ). However, the phenotype is generally considered to be recessive to dark hair and possibly dominant to fair/blonde. It has also been suggested that heterozygotes for this trait might have sandy-red hair, with the homozygous genotype associated with fair skin and freckling (2 ). Biochemical characterization and ultrastructural examination of the melanins synthesized and deposited within the hair follicle have shown that these compounds are the major determinant of the visible colour (3 ). Two broad classes of mammalian pigments may be synthesized by the follicular melanocytes and it is incorporation of eumelanin pigments, which are black or brown, that results in dark hair, while yellow or red hair results from incorporation of eu- and pheomelanins (4 ). It has also been shown that relatively minor differences in melanin quality or content can have dramatic effects on visible hair colour. Ultrastructurally, eumelanin synthesis is restricted to discrete organelles termed eumelanosomes, while the pheomelanins are synthesized in pheomelanosomes. In humans most hair types are the result of mixed melanogenesis, where different levels of both types of pigment are produced. It has been noted that the highest levels of pheomelanins in humans are present in Caucasian fiery red heads (3 ) and that this may be explained primarily by synthesis of pheomelanosomes within the follicular melanocytes. However, hair follicles from some types of human red hair have been found to contain not only pheomelanosomes but also eumelanosomes and an uncommon `mosaic' form of melanosome which exhibits features of both eumelanosomes and pheomelanosomes (3 ).
The physiological signals that control the production of the melanosome and melanin type are extrinsic to the melanocyte. In mice these include the [alpha]-melanocyte stimulating hormone (MSH) and the Agouti protein. However, intrinsic to the melanocyte is the ability to respond to these proteins through their interaction with the melanocyte stimulating hormone receptor (MSHR). Genetic studies on mouse coat colours have provided insight into the involvement of MSHR and Agouti in pigmentation (5 ), with mutations at either locus affecting melanogenesis and producing complementary phenotypes. The human MC1R gene has been cloned (6 -8 ), localized to chromosome 16q24.3 (9 ,10 ) and shown to encode the MSHR protein. MSHR is a seven transmembrane domain G protein-coupled receptor belonging to the melanocortin receptor subfamily homologous to the mouse extension locus (11 ).
Although it is presently unclear how MSHR directs the production of the different forms of melanosomes and, therefore, pigmentation phenotype in humans, there is little doubt that it has an important role. Recent research presented by Valverde et al. (12 ) has found polymorphisms within the MSHR coding region that are associated with red hair, reporting 82% of British or Irish individuals displaying different shades of red hair being either homozygous, heterozygous or compound heterozygous for nine different amino acid substitutions at the MC1R locus, compared with 22% of auburns, 33% of fair/blondes and <20% of brown or black haired individuals having one of these alleles. The relative likelihood for the red hair phenotype has been estimated to be 15-fold among individuals carrying one of the reported variant alleles and 170-fold among individuals who carry two variant alleles (5 ), although this may depend upon which allele is being considered. Additional evidence of MSHR involvement in pheomelanogenesis comes with the association of null or missense alleles of the MSHR gene in red Norwegian (13 ) and Holstein (14 ) cattle, chestnut coat colour in horses (15 ) and determination of the colour of chicken feathers (15 ).
To further substantiate the reported association between the status of the human MC1R locus and the Caucasian red hair genotype, we have analysed the MSHR coding sequence alleles in a sample of young twins of red and non-red hair colour. We also describe variants that segregate with the red phenotype observed in four families.
Of the three reported MC1R sequences which are of unknown racial origin, two are identical (7 ,8 ), with the third (6 ) differing by three MSHR amino acid changes: Thr90Ser, Pro162Arg and Ala164Arg. In our initial PCR experiments on Caucasian DNA samples we found a composite of amino acids at each of these positions, with consistent observation of Ser90, Arg162 and Ala164 (Fig. 1 ). Uncertain of which of these published sequences to define as a non-variant consensus, we decided to determine the MSHR protein sequence from a more heavily pigmented population that does not manifest any red hair phenotypes. The MC1R coding region was amplified using nested PCR from DNA isolated from 10 Chinese individuals from Jiangsu Province and subjected to direct automated sequence analysis. The derived sequences were in each case homozygous and consistent for Ser90, Arg162 and Ala164, suggesting that these amino acids probably do not contribute to red pigmentation in Caucasians.
As nine of the 12 MSHR polymorphisms detected in the red haired twin samples had not previously been reported, in addition to the 25 red heads we also determined the frequency of each of the variants in one member of twin pairs with fair/blonde (19 ), light brown (20 ) or dark brown (20 ) hair colour, to secure independence of the haplotypes. The genotypes of all 87 individuals are tabulated according to hair colour and skin type (Table 1 ).
The sample size was insufficient to statistically test the association of all of the variants with hair or skin type. The single Lys65Asn, Arg142His, Ile155Thr and Ala299Thr polymorphisms were only detected in the red haired samples; the Asp84Glu, Val92Leu and Arg163Gln variants were detected once each in red and non-red hair colours. The Val92Met polymorphism was found to be present in all hair colour divisions and shows no association with any hair or skin classification, the two individuals homozygous for the Val92Met variant having dark brown hair colour and medium skin type.
Four of the variant alleles were found to have statistically significant associations with hair colour, but no variant by itself was associated with any skin type. The Val60Leu variant was the most frequent variant haplotype in both fair/blonde and light brown hair, but was found only once in the red and dark brown groups. The Arg151Cys, Arg160Trp and Asp294His variants are all associated with red hair, with homozygosity of Arg151Cys and Arg160Trp found in five and two cases respectively.
When the frequency of the consensus MSHR haplotype alone is examined even stronger associations with hair colour and skin type are found (P < 0.001, Table 2 ). No red haired individual was found to have a normal MSHR genotype and all four individuals with olive/dark skin were found to have a wild-type genotype, suggesting that variation in the MSHR protein is a strong determinant of red hair colour and is associated with lighter skin types. As the Val92Met variant was apparently unrelated to hair colour or skin type (Table 1 ), we redefined the consensus haplotype frequencies without regard to Val92Met as consensus/Val92Met (Table 2 ). Using this definition, no individual with dark brown hair was found to have a double variant haplotype and the associations with hair colour and skin type were even stronger.
In addition to their inclusion in the analysis of the frequencies of variant MSHR alleles in relation to hair and skin colour, the genotypes of 16 of the 17 dizygotic twin partners were available to test segregation of MSHR variants, with three twin pairs concordant and 13 discordant for the red hair phenotype. If red hair is a monogenic recessive trait the genotype of the red twin would be anticipated to contain two variant MSHR alleles and the genotype of the non-red partner should contain either two normal MSHR alleles or possibly one normal and one variant. Thus a discordant pair should share either zero or one alleles identical by state (IBS0 or IBS1). Given the selection for a red haired co-twin it is not surprising that none of the 13 non-red haired twins were found to have two normal MSHR alleles, but neither was any non-red twin found to have a homozygous variant genotype.
Association of the consensus MSHR haplotype with hair and skin type
Variant allele
Genotype
Hair colour
Skin type
Fair/blonde
Light brown
Dark brown
Red
[chi]62
Fair/pale
Medium
Olive/dark
[chi]42
Consensus
0
5
5
6
0
38.90***
5
7
4
22.23***
1
7
13
13
3
20
16
0
2
8
3
2
22
25
10
0
Consensus/
0
7
6
12
0
46.04***
8
13
4
16.23**
V92M
1
6
13
9
5
21
12
0
2
7
2
0
20
21
8
0
The consensus haplotype is wild-type for all 12 possible variants; 0 = homozygous consensus, 1 = variant heterozygote, 2 = homozygous variant (all but five in trans; see text). For the consensus/V92M haplotype the same applies but the V92M variant is ignored and considered equivalent to wild-type. **0.001 < P < 0.01; ***P < 0.001.
. Allele sharing by state in dizygotic twin pairs concordant and discordant for red hair
Alleles shared by state
Concordant red/red twins
Discordant red/non-red twins
0
0
2
1
1
6a
2
2
5b
Total
3
13
aExcludes Val92Met.
bOf these three are IBD2, one is probably IBD2 and one is either IBD1 or IBD2 (P = 0.5 in each case).
Of the discordant twins, two pairs shared neither haplotype, six pairs shared one haplotype in common and, contrary to the recessive hypothesis, shared haplotypes (IBS2) were found in five of the 13 twin discordant pairs (Table 3 ). Sequencing of parental MSHR alleles in these cases showed that three of the five share both parental alleles (IBD2) and the other two pairs probably do, excluding the possibility that the MSHR variants analysed in these individuals are the sole determinants of red hair.
If the variant MSHR alleles that we have described are associated with recessive expression of the red hair phenotype, it is of interest to determine how they segregate with hair colour in families. Of the 13 discordant dizygotic twin pairs, there were three families in which one parent was red and one non-red; an additional non-twin family (1000110) is also included (Fig. 3 ). In all four families both the red haired child and parent is a compound heterozygote or homozygous variant. However, there are four other individuals who are compound heterozygotes who are non-red, but three of these have Val92Met, which we have argued is phenotypically equivalent to wild-type. That more genes than MC1R determine red hair colour is seen from individual 80066301, who is red haired but has the same Arg151Cys/Arg160Trp genotype as his red haired sib. Since they are of opposite sex, it is possible that sex-related factors may be important.
Of the nine MSHR amino acid replacement variants that were described in the British and Irish populations (12 ) only three of these have been identified in our southeast Queensland twin collection. These are Asp84Glu, Val92Met and Asp294His. However, the Val92Met change is commonly seen in the Chinese population and is found in our four categories of hair colour without apparent association (Table 1 ), indicating that it represents a polymorphism of the MSHR receptor neutral with respect to red hair phenotype, contrary to its first description (12 ). The neutrality of this polymorphism was also suggested in a later study which investigated the frequency of the British/Irish MSHR mutations in melanoma patients (21 ). Functional testing of the Val92Met variant has suggested that it may display an altered affinity for the MSH ligand (19 ), but if this is the case any loss of binding potency is not seen when testing the ability of the receptor to activate adenylyl cyclase (20 ), predicting its functional equivalence to the wild-type state.
An additional nine variant MSHR alleles (Fig. 1 ) are described for the first time in this report, the most common being Arg151Cys and Arg160Trp (Table 1 ). Given the high frequency of these two alleles in our population it is perhaps surprising that they were not observed in the British and Irish population, which were the main contributors to the population of southeast Queensland. The latter also accounts for the incidence of red hair in our group, with the 6% frequency of red hair in our twin collection similar to the reported UK frequency of between 5.3 and 7.7% (22 ). Four of the variants were found to be associated with hair colour but none was by itself associated with skin type. The Val60Leu change may well be associated with fair/blonde and light brown hair colours whereas Arg151Cys, Arg160Trp and Asp294His variants are now shown to be associated with red hair colour. Considering all variants together, an association of the consensus wild-type haplotype with darker skin types is apparent and the association of total variant haplotypes with hair colour is highly significant (P < 0.001).
Although it is clear from these results and those of Valverde et al. (12 ) that human red hair colour is associated with variant MSHR alleles, our study has also shown that polymorphisms in the MC1R locus encoding MSHR are necessary but not sufficient for expression of the red hair phenotype. This conclusion is drawn from the observation that some dizygotic twins who share both MSHR haplotypes by state can be discordant for red hair colour (Table 3 ). Of the five red/non-red IBS2 twin pairs three are definitely identical by descent (IBD2) and one is probably IBD2, with the remaining pair sharing either one or both haplotypes by descent (IBD1 or IBD2), discounting the possibility that other polymorphisms not detectable in the MSHR coding region are responsible for the hair colour difference. It may be of interest that four of these five twin pairs are of opposite sex, with the female being red, suggesting that sex differences may play a role in expression of the red hair phenotype. The lack of absolute correlation between MSHR genotype and red hair phenotype is perhaps not unexpected given the polygenic nature of the pigmentary trait in other animal species. The chemical characteristics of the melanin polymer are formed in a complex biochemical pathway dependent on a number of enzymes and intermediates (23 ), allowing genetic interaction and modification to determine the final phenotype (24 ).
It is notable that two of the variant alleles found in the segregating families, Arg151Cys and Ile155Thr, occur close together in the second intracellular domain. This region contains two consensus sequences for cAMP-dependent protein kinase recognition between amino acids 142-145 and 151-154 (6 ,17 ). These changes in or immediately adjacent to the second kinase site may block phosphorylation and hence receptor signalling, with a similar situation likely to occur with the Arg142His change in the first kinase site. This would give a biochemical explanation for the apparent recessive nature of these variants. Statistical evidence for association of the remaining amino acid variants we describe with either hair colour or skin type and association with epistatically interacting genes will require a larger sample to be studied.
The subjects studied were adolescent twins and their parents obtained through southeast Queensland schools with the aim of identifying major genes affecting mole frequency, pigmentation and other risk factors for melanoma. Twins were examined at age 12, with number of naevi counted and pigmentation characteristics, including hair colour, recorded. A 10 ml blood sample was collected to prepare genomic DNA (25 ) for zygosity diagnosis and DNA typing. A longitudinal study on mole formation in the twins is being performed with follow-up examination at ages 14 and 16. Parental blood samples were also collected and DNA prepared using the same technique. From the available collection of >300 twin pairs, 25 pairs where one or both had red/auburn hair were selected for study, as well as samples of approximately equal size in the three broad hair colour categories of fair/blonde, light brown and dark brown. Hair colour was assigned to one of these categories by the research nurse coordinating the study, who also classified untanned skin type as fair/pale, medium or olive/dark. Hair samples and colour photographs were also taken for validation.
A nested primer strategy was used to obtain sufficient DNA from the MSHR locus for direct sequence analysis and to allow molecular cloning of alleles and identification of haplotypes. The primers for amplification of the MSHR coding region exon were based on the nucleotide sequence reported by Mountjoy et al. (7 ) (accession number X65634). The first primer set, hMSHR N-outer (5'-AGATGGAAGGAGGCAGGCAT-3') and C-outer (5'-CCGCGCTTCAACACTTTCAGAGATCA-3') (12 ), was used in a 25 [mu]l Pfu DNA polymerase amplification reaction (according to the conditions recommended by Stratagene) containing 25 ng genomic DNA, 10% DMSO (26 ), initially denatured for 3 min at 94oC, followed by 30 cycles of 1 min 94oC, 1 min 55oC and 3 min 72oC, ending with a 7 min 72oC extension. Internal primers hMSHR N-inner (5'-CCCCTGGCAGCACCATGAACT-3') and C-inner (5'-TGCCCAGGGTCACACAGGAAC-3') were used in a second 25-50 [mu]l reaction seeded using 5 [mu]l of the first round reaction as template. Amplification conditions were identical to the first round; however, Pfu was used for cloning of amplification products while Taq DNA polymerase was utilized for preparing template for direct sequencing.
DNA products from the Taq DNA polymerase amplification reactions were purified by agarose gel electrophoresis, isolated by Bandpure (Progen) and eluted in a 20 [mu]l volume. Automated sequencing reactions were performed by addition of 4 [mu]l template DNA to 8 [mu]l ABI Prism dye terminator premix/AmpliTaq DNA polymerase FS (Perkin Elmer), 3.2 pmol primer and made up to 20 [mu]l with water. Standard cycle conditions were used for a Thermal Cycler Model 480 (Perkin Elmer), with reaction products ethanol precipitated, dried and applied to an ABI 373 automated sequencer. Sequencing oligonucleotides spaced intermittently and in both directions throughout the coding region included forward hMSHR N-inner, Seq1 (5'-TCTGACGGGCTCTTCCTC-3'), Seq3 (5'-TCCAGCCTCTGCTTCCTG-3') and Seq4 (5'-GCCCGGCTCCACAAGAGG-3') and reverse hMSHR C-inner, Seq5 (5'-GCGCTGCCTCTTGTGGAG-3') and Seq2 (5'-ATGGAGCTGCAGGTGATC-3').
Fragments obtained by Pfu DNA polymerase amplification were purified by agarose gel electrophoresis, isolated by Bandpure (Progen) and eluted in a 20 [mu]l volume. An aliquot of 10 [mu]l product was 5'-phosphorylated using ATP/polynucleotide kinase with half of this insert then ligated to HincII-digested/dephosphorylated pBS vector. Single-stranded DNA prepared from recombinant clones was used as template for manual sequencing reactions (Pharmacia T7 kit) using the primers listed above, with results compiled from at least four clones or until both haplotypes were obtained and confirmed by restriction digestion (27 ).
We wish to thank Robert Slade for preliminary statistical analysis and Angela Salden for technical assistance. This work was supported by an Australian NHMRC grant to R.A.S. and Queensland Cancer Fund and NHMRC grants to L.E.O'G., N.G.M. and Adèle Green. The CMCB is a Special Research Centre of the Australian Research Council. N.F.B. was supported by a Queensland Cancer Fund Postgraduate Research Award. We thank Don McManus for provision of the Chinese DNA samples, Ann Eldridge and Marleen Grace for collection of photographic data and blood samples and the twins and their parents for their cooperation.
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*To whom correspondence should be addressed. Tel: +61 7 3365 1831; Fax: +61 7 3365 4388; Email: r.sturm@mailbox.uq.edu.au
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T. Frudakis, M. Thomas, Z. Gaskin, K. Venkateswarlu, K. S. Chandra, S. Ginjupalli, S. Gunturi, S. Natrajan, V. K. Ponnuswamy, and K. N. Ponnuswamy Sequences Associated With Human Iris Pigmentation
Genetics,
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[Abstract][Full Text][PDF]
E. A. Hurst, J. W. Harbour, and L. A. Cornelius Ocular Melanoma: A Review and the Relationship to Cutaneous Melanoma
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S. J. Getting, H. C. Christian, C. W. Lam, F. N. E. Gavins, R. J. Flower, H. B. Schioth, and M. Perretti Redundancy of a Functional Melanocortin 1 Receptor in the Anti-inflammatory Actions of Melanocortin Peptides: Studies in the Recessive Yellow (e/e) Mouse Suggest an Important Role for Melanocortin 3 Receptor
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K. Diefenbach, P. M. Mrozikiewicz, B. Brien, O. Landt, and I. Roots Rapid Genotyping of Melanocortin-1 Receptor with Use of Fluorescence-labeled Oligonucleotides
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M. C. Scott, K. Wakamatsu, S. Ito, A. L. Kadekaro, N. Kobayashi, J. Groden, R. Kavanagh, T. Takakuwa, V. Virador, V. J. Hearing, et al. Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation
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J. V. Schaffer and J. L. Bolognia The Melanocortin-1 Receptor: Red Hair and Beyond
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E. Healy, S. A. Jordan, P. S. Budd, R. Suffolk, J. L. Rees, and I. J. Jackson Functional variation of MC1R alleles from red-haired individuals
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M. Bastiaens, J. ter Huurne, N. Gruis, W. Bergman, R. Westendorp, B.-J. Vermeer, and J.-N. B. Bavinck The melanocortin-1-receptor gene is the major freckle gene
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J. A. W. Metzelaar-Blok, J. A. C. ter Huurne, H. M. H. Hurks, J. E. E. Keunen, M. J. Jager, and N. A. Gruis Characterization of Melanocortin-1 Receptor Gene Variants in Uveal Melanoma Patients
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N. Flanagan, E. Healy, A. Ray, S. Philips, C. Todd, I. J. Jackson, M. A. Birch-Machin, and J. L. Rees Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation
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V. Bataille, H. Snieder, A. J. MacGregor, P. Sasieni, and T. D. Spector Genetics of Risk Factors for Melanoma: an Adult Twin Study of Nevi and Freckles
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A. Clairmont, H. Sies, S. Ramachandran, J. T. Lear, A. G. Smith, B. Bowers, P. W. Jones, A. A. Fryer, and R. C. Strange Association of NAD(P)H:quinone oxidoreductase (NQO1) null with numbers of basal cell carcinomas: use of a multivariate model to rank the relative importance of this polymorphism and those at other relevant loci
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J. Aitken, J. Welch, D. Duffy, A. Milligan, A. Green, N. Martin, and N. Hayward CDKN2A Variants in a Population-Based Sample of Queensland Families With Melanoma
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J.L. Rees and N. Flanagan Pigmentation, melanocortins and red hair
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