doi: 10.1111/j.1469-1809.2006.00261.x

Distribution of the F374 Allele of the SLC45A2 (MATP)
Gene and Founder-Haplotype Analysis
I. Yuasa1,∗ , K. Umetsu2 , S. Harihara3 , A. Kido4 , A. Miyoshi5 , N. Saitou6 , B. Dashnyam7 , F. Jin8 ,G. Lucotte9 , P. K. Chattopadhyay10 , L. Henke11 and J. Henke11
1
Division of Legal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan2
Department of Experimental and Forensic Pathology, Faculty of Medicine, Yamagata University, Yamagata, Japan3
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan
4
Department of Legal Medicine, Faculty of Medicine, University of Yamanashi, Nakakoma, Japan
5
Department of Forensic Medicine, Fukuoka University School of Medicine, Fukuoka, Japan
6
Division of Population Genetics, National Institute of Genetics, Mishima, Japan
7
Institute of Biological Sciences, Mongolian Academy of Sciences, Ulaan Baator, Mongolia
8Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
9Center of Molecular Neurogenetics, Paris, France
10
Amity Institute of Forensic Sciences, Defence Colony, New Delhi, India
11
Institut für Blutgruppenforschung, Cologne, Germany

Summary
The membrane-associated transporter protein (MATP) plays an important role in melanin synthesis. The L374F
mutation in the SLC45A2 gene encoding MATP has been suggested to be associated with skin colour in major
human populations. In this study more detailed distribution of the F374 allele was investigated in 1649 unrelated
subjects from 13 Eurasian populations and one African population. The highest allele frequency was observed inGermans (0.965); French and Italians showed somewhat lower frequencies; and Turks had an intermediate value(0.615). Indians and Bangladeshis from South Asia were characterized by low frequencies (0.147 and 0.059, respectively). We also found the F374 allele in some East and Southeast Asian populations, and explained this by admixture.
Haplotype analysis revealed that the haplotype diversity was much lower in Germans than in Japanese, and suggestthat the L374F mutation occurred only once in the ancestry of Caucasians. The large differences in distributionof the F374 allele and its haplotypes suggest that this allele may be an important factor in hypopigmentation in
Caucasian populations.
Keywords: haplotype, linkage disequilibrium, membrane-associated transporter protein, polymorphism, population study, SLC45A2

Introduction
Variation in skin colour is one of the most conspicuous and polymorphic traits of humans. Skin colour
is primarily due to a pigment called melanin, locatedin the epidermis, and is lighter in more northerly lat-

∗ Address for correspondence: Isao Yuasa, Division of Legal
Medicine, Faculty of Medicine, Tottori University, Yonago 6838503, Japan. Tel. +81-859-38-6123. Fax +81-859-38-6120.
E-mail: yuasai@grape.med.tottori-u.ac.jp
802

Annals of Human Genetics (2006) 70,802–811

itudes. The clinal distribution of skin colour observed
among indigenous peoples is correlated with ultraviolet
radiation levels. This variation in skin colour has beensuggested to reflect biological adaptation to such environments and is affected by natural selection. However,this view has not been universally accepted (Jablonski& Chaplin, 2000; Relethford, 2002; Jobling et al. 2004;
Diamond, 2005).
Currently 127 loci associated with mouse coat colour
have been identified, and 59 of the actual genes havebeen cloned and sequenced. Of these the mouse
C 2006 The Authors
C 2006 University College London
Journal compilation Genetic diversity in SLC45A2

underwhite (uw) locus is a major determinant of pigmentation, and mutations at the uw locus also leadto hypopigmentation (Lehman et al. 2000; Bennett &Lamoreux, 2003). The SLC45A2 gene, originally called
the “antigen in melanoma (AIM-1)” gene, is expressedin most human melanoma cell lines and melanocytes,
but not in normal tissue, and has been cloned in medaka(a small fresh-water teleost), mouse and human. Mutations in this gene reduce the melanin content in medaka.
“AIM-1” was assigned to the uw locus and the encoded
protein referred to as membrane-associated transporter
protein (MATP). Thus, MATP takes part in melanin
synthesis in melanosomes and is suspected to function
as a membrane-transporter by directing the traffic ofmelanosomal proteins to the melanosome (Fukamachi
et al. 2001; Harada et al. 2001; Newton et al. 2001;
Kushimoto et al. 2003).
The human SLC45A2 gene (Entrez Gene ID:
51151; GenBank accession numbers: NM 016180 andNT 006576) spans 40 kb on chromosome 5p and consists of 7 exons, encoding the 530-amino acid MATP
polypeptide. The human SLC45A2 gene underlies oculocutaneous albinism type 4 (OCA4), for which several
mutations have been identified in Germans, Japanese,and an individual of Turkish descent, (Newton et al.
2001; Inagaki et al. 2004; Rundshagen et al. 2004). Onlya few polymorphisms have been identified in exons of
this gene. Of these the L374F mutation, resulting froma G-to-C transversion in exon 5, has been found tohave a unique distribution: the F374 allele was observed
at high frequencies of 0.89 and 0.96 in white South
Africans and Germans, respectively, while it has notbeen observed in Ghanaians, Japanese and New Guinea
Islanders. The F374 allele is likely to be associated withskin pigmentation in the major human populations. The
striking difference in distribution of the F374 allele may
be a consequence of natural selection, i.e. adaptation tolower amounts of ultraviolet radiation (Nakayama et al.
2002; Yuasa et al. 2004). However, knowledge of theallele frequency and haplotype diversity in the gene encoding MATP is very limited. Elucidation of its genetic
polymorphisms and haplotypes would serve as a starting point for molecular approaches to its anthropologicalgenetics. In this study, we investigated i) the distributionof the F374 allele in several populations, ii) 13 additional
SNPs in SLC45A2 and its immediately adjacent genes,C 2006 The Authors
C 2006 University College London
Journal compilation 

AMACR (alpha-methylacyl-CoA racemase; Gene ID
23600) and RLN3R1 (relaxin 3 receptor 1, also known
as SALPR; Gene ID 51289) in Africans, Japanese andGermans, and iii) founder haplotype(s) with the F374
allele in a German population.

Materials and Methods
DNA Samples
DNA samples were obtained from a total of 1649
unrelated individuals, mostly living in various regionsof Eurasia (Fig. 1 & Table 1). The donors wereselected at random, irrespective of skin colour, andtheir phenotypic data were unavailable. German
samples were obtained from Germans living inNorthrhine-Westphalia. French and Italians samples
were from Rheims and Genoa, respectively. Turkish
samples were collected from Turks living in West
Germany as immigrants, and all subjects were bornin various regions of Turkey. The DNA samples
from Bangladeshis and Indonesians were described
previously (Dobashi et al. 2003); Bangladeshis andIndians investigated in this study were Indo-Europeanspeaking. Khalhas and Buryats are major and minor
ethnic groups in Mongolia, respectively. Chinese
samples came from three Han populations from
Shenyang, Wuxi and Huizhou. Japanese from Okinawa
were also studied. African samples were obtained
from various Sub-Saharan Africans immigrating into
Germany or Japan: 10 Africans were from Ghana andthe others were from the Congo, Nigeria, Zambia,
Ivory Coast, Uganda, Kenya and Zimbabwe. The
samples from Munich and Tottori used for haplotype
analysis are the same set as used in our previous study(Yuasa et al. 2004). The data on average pigmentation
for the selected populations have been summarized in
the references (Jablonski & Chaplin, 2000; Jobling et al.
2004). This study was approved by the Ethical Committee at the Faculty of Medicine, Tottori University.

Population Study of the F374 Allele
DNA samples were typed for the L374F polymorphism by the amplified product length polymorphism(APLP) method as described previously (Yuasa et al.
2004).
Annals of Human Genetics (2006) 70,802–811

803

I. Yuasa et al.

Figure 1 Location of Eurasian populations analyzed in the present study.
Table 1 Distribution of L374F genotypes and the F374 allele in various populations
Genotypes of L374F
No

Population

Collection place

n

L

L/F

F

Frequency of F374

References

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

GermanGermanFrenchItalian
Turk
IndianBangladeshi
KhalhaBuryatHan
Han
Han
JapaneseJapanese
Indonesian
AfricanWhite South African
Ghanaian
New Guinea Islander
Japanese

Northrhine-Westphalia
MunichRheimsGenoa
West Germany
New Delhi
Dhaka
Ulaan Baator
Dashbalbar
Shenyang
Wuxi
Huizhou
Tottori
Okinawa
Surabaya
Germany/Japan

241
93
98
97
200
51
118
173
143
89
119
111
103
87
105
17
54
50
52
49

0
0
1
5
41
37
104
135
111
84
119
110
103
87
104
17

17
7
19
19
72
13
14
37
31
5
0
1
0
0
1
0

224
86
78
73
87
1
0
1
1
0
0
0
0
0
0
0

0.965
0.962
0.893
0.851
0.615
0.147
0.059
0.113
0.115
0.028
0.000
0.005
0.000
0.000
0.005
0.000
0.89
0.00
0.00
0.00

This study
Yuasa et al. (2004)
This study
This study
This study
This study
This study
This study
This study
This study
This study
This study
Yuasa et al. (2004)
This study
This study
This study
Nakayama et al. (2002)
Nakayama et al. (2002)
Nakayama et al. (2002)
Nakayama et al. (2002)

Genotyping of SNPs
Many SNPs at the loci AMACR, SLC45A2 and
RLN3R1 have been reported in the GenBank SNP
database. In this study several SNPs which could be804

Annals of Human Genetics (2006) 70,802–811

genotyped with restriction enzymes were arbitrarily selected (Fig. 2). DNA from 17 Africans, 103 Japanesefrom Tottori and 92 Germans from Munich were subjected to polymerase chain reaction (PCR) followedby restriction fragment length polymorphism (RFLP)
C 2006 The Authors
C 2006 University College London
Journal compilation Genetic diversity in SLC45A2

Figure 2 Schematic diagram of the AMACR, SLC45A2 and RLN3R1 genes, showing locations ofexons and 17 SNPs. Arrows below each gene name show the direction of transcription.

Table 2 Oligonucleotide sequence for SNP genotyping in human AMACR, SLC45A2 and RLN3R1
SNP

Marker Position on NT 006576

PrimerSequence (5 → 3 ) enzyme

Restriction

116459765
16458616

316450989

416447049

516435295

616434674

716430294

8

16426848

9164221121216404484

14

16402809

15

16400425

17

16388182

CTTGGGTTCTGAGATACTGCTGTT
CAGGAAGGGAATCCTATGGCTTT
TGGTTACCTGGGGTTTGTGCTGCCTAGCATCAGTACCTTCACGAATGCTTTGACACTTGAGTTATCTGG
CATCTGCTGTCCTGTAAGTCGTCATATCCACACTTCACCTCAAACTCAGCAGAAGAATACCCGTTCAAAGATGTGGCCTCTGAC
GTAGTCAAACGCAGTGCTTCTCTTGTGTTTTCTGGACATTCGCT
CTTCCTCCTTGGGTTAGCAATCTATGTCCAACACCTCCCTTCTCTCTAAGGCCTCCAACTGACTG
ACTGTGGTATCCTCACTCTG
TGCTTCAAGTGGAATGCTG
AAACGCTTCACGGTGTGCTGA
ATTTCCTGGTCAGACCCCATGGAAGCAATCATGGCAGGCTTCA
AGTCATAGGTCACCGCATCCTACCATTCTCAGGAGGACTCAGTGCTATGGCTAGGTAAAGGG
AGCCAAGTTGACCTGCTAGATGAAATCACCCAGCTTAATGCC
ACGTCAAAGCCGACTTTCTCCGAGAGTTGAGCTGCAGGCAA

MspI

2

AMACR-Y1F1
AMACR-Y1R1
AMACR-Y1F2
AMACR-Y1R2
AMACR-E4F2
AMACR-E4R2
AMACR-Y4F1
AMACR-Y4R1
MATP-Y1F2
MATP-Y1R2
MATP-Y1F
MATP-Y1R
MATP-Y2F6
MATP-Y2R6
MATP-Y2F2
MATP-Y2R2
MATP-Y2F3
MATP-Y2R3
MATP-Y4F
MATP-Y4R
MATP-Y5F
MATP-Y5R
MATP-Y5F2
MATP-Y5R2SALPR-F
SALPR-R

RsaI
Tsp509I
TaqI
MspI
Bsh1236I
Eco130I
Hsp92II
VspI
Hsp92II
Mph1103I
MspI
PvuII

The primers for the SNPs 10, 11, 13 and 16 were described previously (Yuasa et al. 2004).

analysis. In the African samples prior to PCR the wholegenome was amplified using REPLI-g (Qiagen, Hilden,
Germany) because of their small DNA volumes. Primers(Table 2) for the specific amplification of fragments encompassing mutation sites were designed on the basis of the genomic sequence (NT 006576). PCR was
performed in a volume of 12 µl containing 20 ng
genomic DNA, 2.5 pmol of each primer, 200 µM
of each dNTP and 0.3 U HotStarTaq polymerase
C 2006 The Authors
C 2006 University College London
Journal compilation (Qiagen). Cycle conditions were 95◦ C for 15 min, then30-35 cycles of 94◦ C for 30 sec, 55-56◦ C for 30 sec,
72◦ C for 40 sec, and a final extension step of 10 min
at 72◦ C, in a GeneAmp PCR System 9700 (Applied
Biosystems, Foster City, CA). Products were digested
with restriction enzymes (Table 2). The digested fragments were separated by 6% or 7.5% polyacrylamide gelelectrophoresis and then visualized by ethidium bromide
staining.
Annals of Human Genetics (2006) 70,802–811

805

I. Yuasa et al.

Statistical Analysis

SNP Genotyping

Allele frequencies were estimated by direct counting, and conformity to Hardy-Weinberg equilibrium
was tested using the χ 2 test with 1 df. Wright’s F ST
statistic was used to estimate the proportion of variation attributable to differences in the L374F mutation among 17 populations, and in each SNP among
the African, Japanese and German populations (Hartl& Clark, 1997). Linkage disequilibrium (LD) between
pairs of polymorphic sites was measured using the statistics D (Lewontin, 1964) and r 2 (Hill & Robertson,1968). Haplotype diversity and frequency for multipleloci were estimated by the expectation-maximization(EM) method using the Alrequin program (Schneider
et al. 2000).

A total of 17 SNPs, which are scattered throughout
an 80 kb genomic region containing the complete
AMACR, SLC45A2 and RLN3R1 genes (Fig. 2), were
investigated in three populations. Table 3 shows the frequencies of mutant alleles, which were defined in thisstudy as minor alleles found in the African and thenJapanese populations. Striking differences were observedin allele frequency among the three populations. The
German population was characterized by the lowest average heterozygosity for 12 SNPs in the SLC45A2 gene.
Interestingly, the heterozygosity of 4 out of 5 SNPs in
the two adjacent genes, AMACR and RLN3R1, wasrather higher in Germans than in Japanese. Of all the
17 SNPs the L374F mutation revealed the highest F ST
value (0.94). The SNPs near the L374F mutation site
also revealed relatively high values in comparison with
the SNPs in the 5 -flanking region of the SLC45A2
gene. Low F ST values were generally observed in the
two adjacent genes.

Results
Distribution of F374 Allele in SLC45A2
Table 1 summarizes the distribution of L374F genotypes
and frequencies of the F374 allele in a total of 2050 unrelated individuals from 20 populations, including previously reported data (Nakayama et al. 2002; Yuasa et al.
2004). A significant deviation from Hardy-Weinberg
equilibrium was observed in the Italian and Turkish
populations due to an excess of homozygotes and a deficiency of heterozygotes. Although the reasons for thisare not known, this deviation may be affected by assortative mating and/or Wahlund’s principle (Hartl & Clark,
1997). The results showed a marked difference in the distribution of the F374 allele among various populations.
Germans had the highest estimated frequency. French
and Italians showed a significantly lower frequency than
Germans. Turks were characterized by an intermediate
value. Indians and Bangladeshis showed a much lower
frequency than Europeans and Turks. Khalhas and Buryats from Mongolia revealed similar values to each other,and were somewhat higher than Bangladeshis. In contrast, the F374 allele was much less common in Han
Chinese and Indonesian populations, and completely
absent in Africans and Japanese (Nakayama et al. 2002).
F ST was estimated to be 0.74 among the 20 populations(see Table 1).
806

Annals of Human Genetics (2006) 70,802–811

Pairwise LD in MATP
Pairwise LD values in the Japanese and German populations were evaluated between major SNPs in SLC45A2
by D and r 2 . Fig. 3 illustrates substantial differences between D and r 2 . The D values were generally muchhigher than the r 2 values, as D values equal to 1.0 arecaused by the presence of only three out of four possible haplotypes for a pair of loci. Although rare alleles
with frequencies <5% do not have sufficient statisticalpower for LD detection (Lewontin, 1995; Goddard et al.
2000), the pairwise values between SNPs 10–15 wererelatively high in both populations, suggesting that this
15-kb region forms a haplotype block.

Haplotype Analysis
Haplotypes were constructed on the basis of the
genotype data from 12 SNPs in SLC45A2. Table 4 lists
the 32 haplotypes and their frequencies, as estimated by
the EM algorithm, with phase-unknown samples. This
procedure has been shown to estimate common haplotype frequencies accurately when the Hardy-Weinberg
assumption is fulfilled (Fallin & Schork, 2000; TishkoffC 2006 The Authors
C 2006 University College London
Journal compilation C 2006 The Authors
C 2006 University College London
Journal compilation 

16459765
16458616
16450989
16447049
Average heterozygosity

SNP position on NT 006576

∗

t>c
c>t
t>c
g>a
t>c
G > A (E272K)
G > A (T329T)
g>c
G > C (L374F)
t>ca>g
G > C (V507L)
c>g5 -flanking

rs42868c>t
g>a
C > T (S201L)
c>g

Mutation

intron 1
intron 1
intron 2
intron 2
intron 2
exon 3exon 4
intron 4
exon 5
intron 5
intron 5
exon 7

intron 1
intron 1
exon 4
intron 4

Regionrs732740
rs250413
rs181832
rs3776549
rs3756462
rs26722
rs2287949
rs250417
rs16891982
rs40132
rs35394
rs3733808

rs34688
rs34687
rs2287939
rs840409

GenBank SNP number

Mutant alleles are defined as minor alleles found in Africans in this study.

SLC45A2
516435295
616434674
716430294
8
16426848
916422112
1016415976
11
16406617
12
16404484
13
16403799
1416402809
15
16400425
16
16396933
Average heterozygosity
RLN3R1
17
16388182
Average heterozygosity in three loci

AMACR
1
2
3
4

SNP No0.35290.00000.00000.32350.26470.00000.05880.08820.20590.00000.02940.02940.00000.50000.4706
0.11760.00000.04370.00000.16500.16500.20870.20870.38350.23790.64080.00000.40780.40290.00490.08740.08740.14080.08740.18480.00540.01090.02170.04890.04890.03260.00540.0326
0.96200.02720.02720.00000.11960.1196
0.29890.0761

0.471
0.194

0.000
0.000
0.451
0.401
0.000
0.110
0.166
0.337
0.000
0.059
0.059
0.000
0.132

0.515
0.513
0.214
0.000
0.311

0.084
0.253

0.000
0.277
0.277
0.332
0.332
0.475
0.364
0.463
0.000
0.485
0.483
0.010
0.292

0.160
0.160
0.243
0.160
0.181

Japanesen = 103

Africann = 17

Germann = 92Africann = 17

Japanesen = 103

Heterozygosity

Frequency of mutant∗

Table 3 Frequency, heterozygosity and F ST of SNPs in Africans, Japanese (Tottori) and Germans (Munich)

0.303
0.110

0.011
0.022
0.043
0.094
0.094
0.063
0.011
0.063
0.074
0.053
0.053
0.000
0.048

0.212
0.212
0.421
0.141
0.247

Germann = 92

0.102

0.004
0.103
0.108
0.058
0.101
0.191
0.094
0.316
0.944
0.245
0.240
0.003

0.195
0.172
0.043
0.029

F ST

Genetic diversity in SLC45A2

Annals of Human Genetics (2006) 70,802–811

807

I. Yuasa et al.
A

r^2

B

15

15

14

14

12

13

11

12

10

10

9

9

8

8

7

7

6

r^2

6
6 7 8 9 10 11 12 14 15

6 7 8 9 10 12 13 14 15

D'

D'

>0.9

>0.75

>0.5

>0.25

>0.1

Figure 3 Pairwise LD analysis of the SLC45A2 gene region in
Japanese (A) and Germans (B), evaluated by r 2 and D (aboveand below the diagonal, respectively). Number shows the SNPs.

et al. 2000). Although SNPs 8 and 9 investigated in theJapanese samples showed a slight deviation from HardyWeinberg equilibrium (χ 2 = 4.33; 0.05 > p > 0.02),
data from these SNPs were included in the estimationof haplotypes. A total of 32 haplotypes were observedand classified into 4 groups based on SNPs 10-15. In
the Japanese population 17 haplotypes were observed
belonging to the 3 groups, and all major haplotypes ineach group (hp1, hp15 and hp25) shared a nucleotide
sequence of TCTGT for SNPs 5-9. Group 2, consistingof the F374-containing haplotypes, accounted for mostof the haplotypes in Germans. The L374-containing
haplotypes found in Germans were a subset of those in
the Japanese. These findings indicate less allelic complexity in Germans than in Japanese. Haplotype diversity was estimated as 0.815 ± 0.051 for Africans,Frequency
Group

Haplotype

Sequence of the SNPs 5-16

AfricanJapanese

1

hp1
hp2
hp3
hp4
hp5
hp6
hp7
hp8
hp9
hp10
hp11
hp12
hp13
hp14
hp15
hp16
hp17
hp18
hp19
hp20
hp21
hp22
hp23
hp24
hp25
hp26
hp27
hp28
hp29
hp30
hp31
hp32

TCTGTGGGGTAG
TCCGTGGGGTAG
TCCATGGGGTAG
TCTATGGGGTAG
TCCGTAGGGTAG
TTCGTGGGGTAG
TCTACGGGGTAG
TCTGTGAGGTAG
TCTGTGGGCTAG
TCTACGGGCTAG
TTCGTGGGCTAG
TCCGTGGGCTAG
CCCGTGGGCTAG
TCTGTAGGCTAG
TCTGTGACGTAG
TCTATGACGTAG
TCCATGACGTAG
TCTACGACGTAG
TTCGTGACGTAG
TCTGTGACGTACTTCACGACGTAG
TTCGTAACGTAG
TCTGTGGCGTAG
TCCGTAGCGTAG
TCTGTAGCGCGG
TCTACAGCGCGG
TTCGTAGCGCGG
TCCATGGCGCGG
TCTGTGGCGCGG
TCTACGGCGCGG
TCTGTGGCGCAG
TTCACGGCGCGG

0.449
0.116
0.109
0.085
0.034

0.245

2

3

4

Total
808

Annals of Human Genetics (2006) 70,802–811

0.056
0.053
0.005

0.048
0.031
0.010

0.102

German

0.005
0.896
0.039
0.011
0.005
0.005
0.005
0.005

Table 4 Haplotypes and their frequencies in African, Japanese and German

0.059
0.055
0.005
0.003
0.010
0.064
0.025
0.256
0.078
0.039

0.023
0.004

0.029

1.000

0.014
0.013
0.005
0.003
1.000

1.000

C 2006 The Authors
C 2006 University College London
Journal compilation Genetic diversity in SLC45A2

0.881 ± 0.017 for Japanese and 0.261 ± 0.043 for Germans, and the mean number of pairwise differences was
1.586 ± 0.090 for Africans, 3.50 ± 1.79 for Japaneseand 0.58 ± 0.47 for Germans. One major haplotype(hp9) differed by one nucleotide in SNP 13 from hp1;
hp9 must have arisen following a G-to-C transversion
in hp1. Minor alleles in each group occurred due to recombination events, as revealed by the presence of thesame sequences in SNPs 5-9. In the German populations recombination between both F374-containing andL374-containing haplotypes must have occurred prior
to the disappearance of the L374-carrying haplotypes.

Discussion
In this study the distribution of the F374 allele of the human SLC45A2 gene, encoding MATP, was confirmed
to differ greatly among three major human populations.
No other alleles like the F374 allele have been identified from many Caucasian-specific alleles observed todate. The F374 allele shows near-fixation in Germans.
White South Africans showed a frequency of 0.89 due toadmixture of several European ethnic groups, and contained 7% non-European genes (Nakayama et al. 2002).
It is possible to estimate the allele frequency in their ancestors (p) using the model of one-way migration (Hartl& Clark, 1997):p = (1 − m)p + mp∗ ,(1)

where p is the frequency in white South Africans (0.89),p∗ is the frequency in non-Europeans (0), and m is thepresent proportion of copies of SLC45A2 that were derived from non-Europeans (0.07). The allele frequency
in ancestors of white South Africans (p) was calculated
to be 0.957; this value is comparable to that foundin Germans, suggesting that northern Europeans, orGermanic-speaking people, share high frequencies of
the F374 allele. In comparison with Europeans Turks,
Indians and Bangladeshis showed significantly low frequencies of the F374 allele, which gradually declined
from Germany to Bangladesh. It seems that these frequencies are associated with latitude, ultraviolet radiation levels and skin colour. The F374 allele was also
found in East and Southeast Asia, excluding Japanese
populations and a Han-Chinese population from Wuxi.
It is likely that there was gene flow from Europe and theC 2006 The Authors
C 2006 University College London
Journal compilation 

Middle East to East Asia along the Silk Road and/or
its northern and southern regions. Western Eurasianspecific haplogroups of mitochondrial DNA were observed at a frequency of 14.3% in Mongolians from Xinjiang Province, China (Yao et al. 2004). Khalhas from
Mongolia and Buryats from Siberia have a fairly highfrequency of mitochondrial DNA haplotypes of European origin (Pakendorf et al. 2003). Thus, extensive
gene admixture has occurred between Asians and Europeans, and we suggest that the F374 allele is substantially
specific to so-called Caucasoid populations, including
Europeans, west and south Asians and north Africans.
The large differences in distribution of the F374 allele
are comparable to that of the FY ∗ O allele (the null allele at the Duffy blood group locus), with an F ST valueof 0.78 found in Sub-Saharan Africans (Cavalli-Sforza
et al. 1994). Exceptionally high F ST values are a potential
indicator of the effects of directional selection (Lewontin & Krakauer, 1973; Bowcock et al. 1991). Because
MATP plays an important role in melanin synthesis thehigh frequency of the F374 allele among Europeans may
be a response to selection for the lower amount of solar ultraviolet radiation, and associated with depigmentation. The highest frequencies of the F374 allele innorthern parts of Europe do not necessarily indicate its
origin and spread. European ancestors, after expanding
toward the higher latitudes, may have acquired higher
frequencies of this allele to adapt to lower levels of solar
ultraviolet radiation. Most of the L374-carrying haplotypes were lost during expansion. Haplotype analysis
has also revealed a large difference in haplotype diversity
between the Japanese and Germans. The F374-bearing
haplotypes found in Germans shared the same basic sequence in SNPs 10-15 in a 15-kb region, which formeda haplotype block characterized by low haplotype diversity, strong associations between alleles, and rare recombination. These findings suggest that the L374F mutation occurred only once in the ancestry of the Caucasiangroup. The hp9 is probably a founder haplotype, constituting 93% of the F374-carrying haplotypes.
Relatively little is understood about the genes responsible for differences in skin, hair and eye colour
among individuals within or between populations. Of
several human pigmentation-related genes, the MC1R
(melanocortin 1 receptor) gene also plays very importantroles. Some mutations in MC1R are associated with red
Annals of Human Genetics (2006) 70,802–811

809

I. Yuasa et al.

hair, fair skin and freckles. Low diversity in MC1R was
observed in Africans, whereas the diversity increases in
Europeans and, to a lesser degree, in Asians (Rees, 2004;
Sturm & Frudakis, 2004). In contrast, genetic diversity
in SLC45A2 was very low in Europeans in comparison
to Africans and Japanese. Because the SLC45A2 geneis known to be responsible for OCA4, some mutations
would be expected to generate hypopigmentation. Although no direct experimental data has been obtained
to date on the effect of the F374 allele on the activityof MATP in pigmentation, the large difference in distribution of the F374 allele and its haplotypes suggeststhat this allele may be an important factor in hypopigmentation in Caucasian populations.

Acknowledgements
We would like to thank the late Prof. Satoshi Horai for providing us with some African DNA samples. This study was
supported in part by Grants-in-Aid for Scientific Research (toI.Y. and K.U.) from the Japan Society for the Promotion of
Science.

References
Bennett, D. C. & Lamoreux, M. L. (2003) The color loci ofmice - a genetic century. Pigment Cell Res 16, 333–344.
Bowcock, A. M., Kidd, J. R., Mountain, J. L., Hebert, J. M.,
Carotenutos, L., Kidd, K.K. & Cavalli-Sforza, L.L. (1991)
Drift, admixture, and selection in human evolution: a study
with DNA polymorphisms. Proc Natl Acad Sci USA 88,
839–843.
Cavalli-Sforza, L. L., Menozzi, P. & Piazza, A. (1994) The
history and geography of human genes. Princeton University
Press, Princeton, NJ.
Diamond, J. (2005) Geography and skin colour. Nature 435,
283–284.
Dobashi, Y., Kido, A., Fujitani N., Susukida, R. & Oya,M. (2003) Population data of nine STR loci, D3S1358,
vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317
and D7S820, in Bangladeshis and Indonesians. Forens Sci Int
135, 72–74.
Fallin, D. & Schork, N.J. (2000) Accuracy of haplotype frequency estimation for bialleic loci, via the expectationmaximization algorithm for unphased diploid genotype
data. Am J Hum Genet 67, 947–959.
Fukamachi, S., Shimada, A. & Shima, A. (2001) Mutations in
the gene encoding B, a novel transporter protein, reducemelanin content in medaka. Nature Genet 28, 381–385.

810

Annals of Human Genetics (2006) 70,802–811

Goddard, K. A. B., Hopkins, P. J., Hall, J. M. & Witte, J.S.
(2000) Linkage disequilibrium and allele-frequency distributions for 114 single-nucleotide polymorphisms in five
populations. Am J Hum Genet 66, 216–234.
Harada, M., Li, Y. F., El-Gamil, M., Rosenburg, S. A. &Robbins, P.F. (2001) Use of an in vitro immunoselected tumor line to identify shared melanoma antigens recognized∗by HLA-A 0201-restricted T cells. Cancer Res 61, 1089–
1094.
Hartl, D. L. & Clark, A.G. (1997) Principles of population genetics, 3rd editions. Sinauer Associates, Sunderland.
Hill, W. G. & Robertson, A. (1968) Linkage disequilibrium
in finite populations. Theor Appl Genet 38, 226–231.
Inagaki, K., Suzuki, T., Shimizu, H., Ishii, N., Umezawa, Y.,
Tada, J., Kikuchi, N., Takata, M., Takamori, K., Kishibe,M., Tanaka, M., Miyamura, Y., Ito, S. & Tomita, Y. (2004)
Oculocutaneous albinism type 4 is one of the most common
types of albinism in Japan. Am J Hum Genet 74, 466–471.
Jablonski, N. G. & Chaplin, G. (2000) The evolution of skincoloration. J Hum Evol 39, 57–106.
Jobling, M. A., Hurles, M. E. & Tyler-Smith C. (2004) Human
evolutionary genetics-Origins, peoples & disease. Garland, NewYork.
Kushimoto, T., Valencia, J. C., Costin, G. E., Toyofuku, K.,
Watanabe, H., Yasumoto, K., Rouzaud, F., Vieira, W. D. &Hearing, V. J. (2003) The melanosome: an ideal model tostudy cellular differentiation. Pigment Cell Res 16, 237–244.
Lehman, A. L., Silvers, W. K., Puri, N., Wakamatsu, K., Ito, S.
& Brilliant, M. H. (2000) The underwhite (uw) locus acts
autonoumously and reduces the production of melanin. J
Invest Dermatol 115, 601–606.
Lewontin, R. C. (1964) Interaction of selection and linkage. I.
General considerations; heterotic models. Genetics 49, 49–
67.
Lewontin, R. C. (1995) The detection of linkage disequilibrium in molecular sequence data. Genetics 140, 377–388.
Lewontin, R. C. & Krakauer, J. (1973) Distribution of genefrequency as a test of the theory of the selective neutralityof polymorphisms. Genetics 74, 175–195.
Nakayama, K., Fukamachi, S., Kimura, H., Koda, Y., Soemantri, A. & Ishida, T. (2002) Distinctive distribution of
AIM1 polymorphism among major human populations
with different skin color. J Hum Genet 47, 92–94.
Newton, J. M., Cohen-Barak, O., Hagiwara, N., Gardner, J.
M., Davisson, M. T., King, R. A. & Brilliant, M.H. (2001)
Mutations in the human orthologue of the mouse underwhitegene (uw) underlie a new form of oculocutaneous albinism,
OCA4. Am J Hum Genet 69, 981–988.
Pakendorf, B., Wiebe, V., Tarskaia, L. A., Spitsyn, V. A.,
Soodyall, H., Rodewald, A. & Stoneking, M. (2003) Mitochondrial DNA evidence for admixed origins of Central
Siberian populations. Am J Phys Anthropol 120, 211–224.

C 2006 The Authors
C 2006 University College London
Journal compilation Genetic diversity in SLC45A2

Rees, J. L. (2004) The genetics of sun sensitivity in humans.
Am J Hum Genet 75, 739–751.
Relethford, J. H. (2002) Apportionment of global human genetic diversity based on craniometrics and skin color. Am J
Phys Anthropol 118, 393–398.
Rundshagen, U., Zühlke, C., Opitz, S., Schwinger, E. &Käsmann-Kellner, B. (2004) Mutations in the MATP genein five German patients affected by oculocutaneous albinism type 4. Hum Mutat 23, 106–110.
Schneider, S., Roessli, D. & Excoffier, L. (2000) Arlequin: A
software for population genetics data analysis. Ver 2.000. Genetics and Biometry Lab, Dept of Anthropology, University ofGeneva.
Sturm, R. A. & Frudakis, T.N. (2004) Eye colour: portals into
pigmentation genes and ancestry. Trends Genet 20, 327–332.
Tishkoff, S. A., Pakstis, A. J., Ruano, G. & Kidd, K. K. (2000)
The accuracy of statistical methods for estimation of hap-C 2006 The Authors
C 2006 University College London
Journal compilation 

lotype frequencies: an example from the CD4 locus. Am J
Hum Genet 67, 518–522.
Yao, Y. G., Kong, Q. P., Wang, C. Y., Zhu, C. L. & Zhang, Y. P.
(2004) Different matrilineal contributions to genetic structures of ethnic groups in the Silk Road region in China.
Mol Biol Evol 21, 2265–2280.
Yuasa, I., Umetsu, K., Watanabe, G., Nakamura, H., Endoh,
M. & Irizawa, Y. (2004) MATP polymorphisms in Germans
and Japanese: L374F mutation as a population marker for
Caucasoids. Int J Legal Med 118, 364–366.

Received: 26 April 2005
Accepted: 21 October 2005

Annals of Human Genetics (2006) 70,802–811

811