MBE Advance Access originally published online on September 14, 2005
Molecular Biology and Evolution 2006 23(1):179-188; doi:10.1093/molbev/msj018
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Research Article |
Evidence for Recent Positive Selection at the Human AIM1 Locus in a European Population
* Department of Forensic Medicine and Human Genetics, Kurume University School of Medicine, Kurume, Japan; Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan; and Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan
E-mail: ykoda{at}med.kurume-u.ac.jp.
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Abstract |
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Two missense polymorphisms (E272K and L374F) of the AIM1 locus, encoding a melanocyte differentiation antigen, were shown to have a clear association with human ethnicities. These two nonpathogenic single nucleotide polymorphisms (SNPs) may be associated with human pigmentation variation. In this study, we investigated sequence variation in the coding region and exon-flanking sequence and found low genetic variation only in subjects of European descent. All four statistical tests applied to the 7.55-kb region surrounding the L374F polymorphism detected statistically significant deviations from selective neutrality in Europeans. In addition, haplotype analysis revealed that one haplotype carrying 374F was overrepresented in this population, and the low rate of variation, with some features of selective sweeps, was shown to be statistically significant. These results suggest that positive selection recently has been acting or has acted on at least this region of the melanogenic gene and that an advantageous haplotype spread rapidly in Europe.
Key Words: AIM1 • directional selection • pigmentation
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Introduction |
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Human (antigen in melanoma-1 (AIM-1) was first identified as a melanoma antigen (Harada et al. 2001
). The gene is located on chromosome 5p and consists of seven exons spanning a region of approximately 40 kb. The encoded protein is a 530-amino acid polypeptide and is predicted to span the lipid bilayer 12 times (Newton et al. 2001). This gene is expressed in human melanoma and shows homology to plant sucrose-proton symporters. Its homologue in medaka fish is responsible for the pigment phenotype of b mutants with different pigmentation phenotypes and encodes a transporter that mediates melanin synthesis (Fukamachi, Shimada, and Shima 2001). This medaka protein consists of 576 amino acids and is 55% identical to human AIM-1. The phenotypes of spliced or nonsense mutants exhibit fewer melanized melanophores than do the missense mutants. Newton et al. (2001) identified the human AIM1 locus, which they designated MATP (membrane-associated transporter protein), and a mouse gene located on chromosome 15 in a region containing the pigmentation locus, underwhite (uw). These proteins share 82% sequence identity. A series of mouse mutants have been described for this locus, and all were characterized by various degrees of pigment reduction in the eyes and fur. Recently, a study of mouse primary melanocytes carrying the underwhite (uw) mutation suggested that AIM1 is important for proper tyrosine processing and intracellular trafficking (Costin et al. 2003).
Albinism represents a group of genetically heterogeneous hereditary abnormalities of melanin pigment synthesis that result in a deficiency or complete absence of melanin in affected individuals. Four different types of oculocutaneous albinism (OCA) have been reported to date (OCA1, OCA2, OCA3, and OCA4). A homozygous G to A transition of the exon 2 splice-acceptor site of the AIM1 gene was identified in a Turkish patient with OCA as the fourth pathological OCA gene (Newton et al. 2001). In addition to this pathogenic mutation, Newton et al. identified two polymorphisms in this gene, L374F and T329T, in diverse populations from North America, Asia, Europe, and Africa. Reports about mutations in AIM1 of OCA4 patients in various populations have been accumulating (Inagaki et al. 2004; Rundshagen et al. 2004; Suzuki et al. 2005). Recently, we investigated sequence variation of the coding region of AIM1 in randomly selected individuals of European descent in South Africa, Ghanaians, Japanese, and New Guinea islanders (Nakayama et al. 2002) and identified two nonsynonymous polymorphisms. They are G814A and G1122C, resulting in E272K and L374F, respectively. The 272K allele was found in Japanese and New Guinea islander populations, and the 374F allele was found only in the South African Europeans with an allele frequency of 0.89. In addition to our results, Yuasa et al. (2004) showed that the 374F allele was present at a frequency as high as 0.96 in a German population, while it was completely absent in a Japanese population. These results suggest that the 374F allele is specific to Europeans. More recently, Graf, Hodgson, and van Daal (2005) reported that these two nonpathogenic nonsynonymous single nucleotide polymorphisms (SNPs) in the AIM1 gene were associated with normal human pigmentation variation, i.e., 374L is significantly associated with dark hair, skin, and eye color in Europeans. These results raise the possibility of a directional selection favoring the 374F allele in some environmental conditions, such as areas of low sunlight. To determine whether a selective force is acting on this locus, we analyzed the sequence variation in the coding region, exon-flanking region, and the 7.55-kb region surrounding the L374F polymorphism of the AIM1 gene.
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Materials and Methods |
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DNA Samples
This study protocol was approved by the ethical committee of Kurume University School of Medicine. Randomly selected individuals from populations sampled were 80 Chinese from Guangzhou (south China), 121 Ghanaians from Accra, 102 Xhosans (Africans) and 101 European-Africans from Cape Town, and 54 Sinhalese and 58 Tamils from Sri Lanka. In addition, genomic DNA of one chimpanzee and one orangutan were also sampled.
Direct Sequencing Analysis
The primers used and the temperature profile for amplification of the coding region, exon-flanking sequence, and flanking sequence of L374F polymorphism of AIM1 are available at http://www.med.kurume-u.ac.jp/med/foren/AIM1supp1.htm. All amplifications were performed in 20 µl of 1x buffer containing 1 U of Takara Ex Taq polymerase (Takara, Tokyo, Japan). Resultant polymerase chain reaction (PCR) products were purified using Microcon PCR (Millipore, Bedford, Mass.), and the DNA sequence was determined as described previously (Koda et al. 2004). The PCR primers and several sequence-specific internal primers (not shown) were used for DNA sequencing.
Denaturing High Performance Liquid Chromatography Analysis
To identify the L374F polymorphism in various populations, denaturing high performance liquid chromatography (DHPLC) analysis was performed. Amplification was done in 25 µl of a mixture of 1x buffer and 0.75 U of Optimase polymerase (Transgenomic, Courtaboeuf, France). The primers used, temperature profile for PCR, and analysis condition are available at http://www.med.kurume-u.ac.jp/med/foren/AIM1supp2.htm. Resultant PCR products were denatured for 5 min at 95°C, then gradually reannealed over 40 min by decreasing the sample temperature from 95°C to 25°C, and 5 µl of the annealed sample was injected into a WAVE-MD system (Transgenomic). Two microliters of the samples that had an unexpected peak profile was treated with 1 U of Exonuclease I (New England Biolabs, Beverly, Mass.) and 1 U of shrimp alkaline phosphatase (Roche Diagnostics, Mannheim, Germany) for 1 h at 37°C and then heat denatured for 15 min at 72°C.
PCR–Restriction Fragment Length Polymorphism Analysis to Identify E272K Polymorphism
The region containing E272K was amplified in 20 µl of 1x buffer containing 1 U of Takara Ex Taq polymerase. The temperature profile was denaturation at 96°C for 3 min, followed by 35 cycles of denaturation at 96°C for 15 s, annealing at 55°C for 30 s, and extension at 72°C for 30 s. The resultant PCR products were digested with TaqI (Toyobo, Osaka, Japan), which digested the restriction site in alleles containing 272K, and then were electrophoresed.
Data Analysis
To measure the diversity within a population, the number of segregating sites S for sample size 
and the average pairwise sequence difference (k) were calculated. Under the equilibrium neutral model, 
w and k provide alternative estimators of = 4Neµ, where Ne is the effective population size and µ is the mutation rate per sequence per generation (Watterson 1975; Nei and Tajima 1981). From the two estimates of , the test statistic D proposed by Tajima (1989) was computed. In addition, test statistics D and F proposed by Fu and Li (1993) were computed with the number of mutations in external branches 
e, using a chimpanzee sequence as the outgroup. In these tests, departures from neutrality are detected as differences between estimates of derived from the number of mutations in external branches of the genealogy and from w (giving the index D) or k (giving the index F). Fay and Wu's (2000) H statistic, which is based on the differences between two estimators of : 
(or k) and H, an estimator based on the frequency of the derived variants, was computed. For Fu and Li's D and F tests and Fay and Wu's H test, a 1,785-bp segment in intron 4, which is thought to have been inserted into the human sequence after divergence from the human-chimpanzee common ancestor, was excluded. Nucleotide diversity () was estimated by dividing k by the number of sites. We used the McDonald-Kreitman test (1991) to determine if the ratio of intra- and interspecific variation is homogenous between synonymous and nonsynonymous substitutions. All analyses were carried out using DnaSP ver. 4.10 (http://www.ub.es/dnasp/) (J. Rozas and R. Rozas 1999).
Haplotype frequencies were inferred using PHASE (version 2.02) (Stephens, Smith, and Donnelly 2001; Stephens and Donnelly 2003). To simplify inference, we ignored less frequent polymorphisms, those less than 5% in the total population samples. The Network 4.1 package (http://www.fluxus-technology.com/sharenet.htm) was used to construct the median-joining network using the method of Bandelt, Forster, and Rohl (1999), which reflects the mutational relationships among the inferred haplotypes and the evolutionary history of genetic changes at the AIM1 locus with the common chimpanzee as an outgroup species. The insertion/deletion polymorphisms were not included in any of the data analyses.
The haplotype test of Hudson et al. (1994) was used on the Europeans and Chinese. Data sets expected under the neutrality assumption and conditioned on the observed number of segregating sites were generated by a coalescent simulation program, ms (Hudson 2002). We assumed a model with no recombination.
To detect a selective sweep, we used the composite-likelihood ratio (CLR) test proposed by Kim and Stephan (2002) and also used a modified method of it to allow incomplete sweeps like those obtained by Meiklejohn et al. (2004). In this test, the different hypotheses are tested using the likelihood ratios LR1 = log(L1/L0) and LR2 = log(L2/L1) of the maximum composite likelihoods under the neutral model (L0), the complete sweep model (L1), and incomplete sweep model (L2). In addition, the CLR test that does not distinguish ancestral/derived alleles (Kim and Stephan 2002) and a goodness-of-fit (GOF) test, which aims to distinguish between selective sweep and demography (Jensen et al. 2005), were also performed. All these CLR and GOF test statistics and the estimates of the strength of selection 
= 2Nes, where Ne is the effective population size and s is the selection coefficient, were calculated using programs kindly provided by Y. Kim. The time since the fixation and the strength of selection at the AIM1 locus in a European population were estimated by using the maximum-likelihood method proposed by Meiklejohn et al. (2004).
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Sequence Variation in Coding Region, Intronic Region, 3' Untranslated Region, and 7,551-bp Region
All seven exons, the exon-flanking sequences, and the continuous 7,551 bp surrounding the L374F polymorphism of the AIM1 locus (fig. 1) were sequenced from 17 randomly selected Europeans in South Africa and 10 each of Chinese, Sinhalese in Sri Lanka, and Ghanaians and Xhosans in South Africa. In total, we identified five SNPs in a 1,593-bp coding region, two of them synonymous and three nonsynonymous, and 55 polymorphisms in an 8,558-bp intron sequence, seven indel polymorphisms, and 48 SNPs (table 1).
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One chimpanzee sequence and one orangutan partial sequence were also obtained to infer the ancestral and derived states of each human polymorphism and haplotype. Because comparison of the human sequence with the chimpanzee and the orangutan sequences revealed that 1,785 bp in intron 4 (from 30,437 to 32,222 bp) had been inserted into the human sequence after divergence from the human-chimpanzee common ancestor, we could not estimate the ancestral states of 13 intronic SNPs. There were five synonymous and six nonsynonymous fixed differences in the coding region. We applied the McDonald-Kreitman test to the AIM1 coding sequence, but there was no significant excess of nonsynonymous substitutions between human and chimpanzee sequences as compared to nonsynonymous polymorphisms in humans (P = 1). In the intronic sequence, 79 fixed differences were encountered: they were 69 dinucleotide and 10 indel differences. The chimpanzee sequence was monomorphic at all the positions that were polymorphic in humans. Human-chimpanzee divergence was 0.95% (80 sites), that is, 0.69% for the coding and 1.0% for the noncoding regions.
Nucleotide diversities were calculated for the total sequenced region, nonsynonymous sites, noncoding region + synonymous sites, and the chosen 7,551-bp region encompassing a part of intron 3, exon 4, intron 4, exon 5, intron 5, exon 6, and a part of intron 6 (table 2) because this partition could reveal a contrasting pattern of population-specific variation. In addition, summary statistics for the 7,551-bp region are also presented. The values for each population except Europeans and for the pooled sample at the total sequenced region, noncoding region + synonymous sites, and 7,551-bp region were similar to the average (0.0011) for a fourfold degenerate site in humans (Li and Sadler 1991), but the values for Europeans were quite low (table 2). Because of low-frequency SNPs and high frequency–derived SNPs (five sites), all four statistical tests in the 7,551-bp region detected statistically significant deviations from selective neutrality for Europeans (table 2).
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As reported previously (Nakayama et al. 2002
; Yuasa et al. 2004; Graf, Hodgson, and van Daal 2005), two nonsynonymous polymorphisms (E272K and L374F) show a population-specific pattern. However, because our sample size for the sequence analysis was small, we then checked the frequencies of E272K and L374F polymorphisms in a larger sample of the same populations (101 Europeans, 80 Chinese, 54 Sinhalese, 121 Ghanaians, 102 Xhosans) and 58 Tamils in Sri Lanka by PCR–restriction fragment length polymorphism and DHPLC. These sites show distinctive frequency distributions among different population groups; that is, 272K is the common allele of Asian populations, such as Chinese (43.4%), Sinhalese (20.4%), and Tamils (12.1%), but is rare in Europeans (2.5%), Xhosans (3.4%), and Ghanaians (4.1%). The 374F is exclusively found in Europeans (91.6%) but not in the other five populations (0%–1.9%). The fact that this derived SNP, 374F, is dominant in only a single population also raises the possibility that a kind of population-specific selection has been acting on it or its surrounding region.
Haplotype Variation
To elucidate the history of the generation of variations and recombinations of this locus, we next inferred haplotypes on the basis of genotype data from 23 of 53 SNPs, whose frequencies were more than 5% in the total sample of the five populations by using PHASE software version 2.1.1. As shown in table 3, 31 haplotypes were estimated in the five populations. A total of 7, 6, 3 16, and 10 haplotypes were observed in the Chinese, Sinhalese, European, Xhosan, and Ghanaian populations, respectively (table 4). Only one haplotype in the Europeans contained 374F (haplotype 12).
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To determine the relationships among inferred haplotypes, we constructed a median-joining network by using Network software v.4.1 (fig. 2). It is clear that haplotype 12 is European specific and has no derived haplotypes.
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Signature of Directional Selection
Positive selection can play an important role by sweeping out nucleotide variation around selected sites (Maynard Smith and Haigh 1974
). The haplotype test can address whether it is likely that a kind of haplotype structure will occur under neutrality. In Europeans, PHASE analysis inferred that 32 of the 34 chromosomes share the same haplotype (haplotype 12) when we considered polymorphic sites whose frequencies were more than 5% in the total sample of the five populations, whereas at least 28 chromosomes share the same haplotype carrying 374F when we considered all polymorphic sites; of the 17 individuals, 13 and 2 were homozygous and heterozygous for only one site, respectively. The estimated P value from 10,000 random coalescent simulations of observing 28 or more of the same haplotype is 0.0009. Coalescent simulations were conditioned on the number of segregating sites observed. Also, the three haplotypes that bear the K allele at the E272K polymorphic site (i.e., haplotypes 24, 25, and 26, but particularly 24) are overrepresented in the samples, especially in Chinese. This raises the possibility that the 272K allele also might be under selection in some populations. We used the haplotype test to address this possibility as well. There are 10 with the same haplotype in 20 chromosomes in Chinese, and the test did not yield a significant result.
The CLR test (Kim and Stephan 2002; Meiklejohn et al. 2004) was also conducted to detect positive selection in this region by examining a local reduction of variation and a skew of the frequency spectrum caused by a hitchhiking event. For both simulation and composite-likelihood analyses, the sequence was divided into noncoding and coding regions, and the per-nucleotide mutation rate for each region was given as , where is Watterson's estimator of the population mutation parameter calculated from the data (Watterson 1975). The scaled per-nucleotide recombination parameter (Rn = 4Ner) was estimated to be 4 x 10–4 by the assumption of effective population size (Ne) as 10,000 (Takahata 1993) and recombination rates (r) as 1 x 10–8 that was calculated to be the average for humans (Kong et al. 2002). Because we could not determine the ancestral status of the 1,785-bp region, we tentatively treated high-frequency alleles in the 1,785-bp region as ancestral alleles (0) and low-frequency alleles as derived alleles (1). Then, the CLRs were obtained for both situations, one for distinguishing ancestral/derived alleles (LRoption1) and the other for not distinguishing them (LRoption2). We compared the LR1 values obtained by polymorphism data of Europeans with those obtained by 1,000 simulated data sets for a neutral model for Europeans. As shown in table 5, the AIM1 data sets in Europeans yielded significantly large ratios (LRs) regardless of the states of alleles, and the strength of selection ( = 2Nes) is 220–240. However, this test is not robust enough to reveal an undetected population structure or a recent bottleneck.
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To distinguish between selective sweep and demography, we also used the GOF test (Jensen et al. 2005
). We conducted 1,000 simulations to obtain data sets for the complete sweep model for Europeans. We compared GOF statistics obtained by polymorphism data with those obtained by simulation data for the complete sweep model in Europeans. The GOF values with both option1 and option2 in Europeans were not significant. These results suggested that the original rejection of neutrality in Europeans by the CLR test is more likely to be due to a selective sweep than demography alone. In addition to the average recombination rate in the human genome, we also perform CRL and GOF tests under lower (Rn = 4 x 10–5 and 4 x 10–6) recombination rates. Although the strength of selection decreased to less than 1/10 of the original estimate, we cannot still reject complete sweep model by these tests.
To determine whether the sweep is complete or not, we then compared LR2 values obtained from polymorphism data in Europeans with those obtained by simulation data under the complete sweep model (Meiklejohn et al. 2004). The LR2 values from polymorphism data in Europeans were not significant. Based on this, we cannot reject a complete sweep model in Europeans. In addition, the selection coefficient s was estimated to be about 0.01 when Ne is assumed to be 10,000 (Takahata 1993) because = 2Nes was estimated to be 200 by the CLR test (table 5).
The age of a recently derived haplotype can be estimated on the basis of the number of new mutations that have occurred among the alleles since they last shared a common ancestor. Thus, the age of alleles containing 374F (haplotype 12) of the AIM1 gene was estimated by following the method of Meiklejohn et al. (2004). There are 32 sequences containing 374F with two derived mutations (positions 33339 and 33890) in the 5,766-bp region (7,551–1,785 bp); thus, the expected number of mutations in the European sample is 32 tµ, where µ is the mutation rate per sequence per year and t is the time since the common ancestor. On the basis of the observed silent site divergence, comparing 57 sites (synonymous and noncoding sites) in AIM1 between human and chimpanzee, and assuming a divergence time of 5 Myr for these two species, µ is estimated to be 5.7 x 10–6. The maximum-likelihood estimate of t is 10,965 years. Ninety-five percent confidence intervals for this age can be calculated by finding tmax and tmin such that 
and 
This produces the values tmin = 1,328 and tmax = 39,609 years.
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Discussion |
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Sunshine exerts both beneficial and harmful effects on human health. In the presence of substantial ambient UV radiation, those with pale skin are more at risk of major skin cancers and more likely to suffer from one of a range of porphyrias. However, pale skin is advantageous for vitamin D synthesis at higher latitudes (Rees 2004
). Short-wavelength UV (UVB) converts 7-dehydrocholesterol into an essential precursor of cholecaliferol (vitamin D3); a deficiency of vitamin D causes rickets, a characteristic pattern of growth abnormalities and bone deformities. Most variance in skin color is between continents rather than within continents, which is compatible with the view that there has been strong and recent selection on skin pigmentation. Pigmentation results from the production and deposition of melanin, which is synthesized from tyrosine as either black/brown eumelanin or yellow/red pheomelanin. Melanin biosynthesis takes place in melanosomes within melanocytes. Melanosomes differ in their shape, size, number, and distribution, depending on the type of melanin they contain, and this determines the pigmentation phenotype of hair and skin. Despite a large number of murine coat-color mutations, only one gene in humans, the melanocortin 1 receptor (MC1R), is known to account for substantial variation in skin and hair color and skin cancer incidence (Rees 2004). Although the MC1R gene has been studied extensively and can explain some of the normal pigmentation variation in humans, little is understood about other key pigmentation genes and their effects on normal pigmentation. However, one SNP in the 3' untranslated region of another pigmentation gene, the agouti signaling protein (ASIP) gene, is recently reported to be associated with human pigmentation (Kanetsky et al. 2002; Bonilla et al. 2005). In addition, both 272K and 374L of the AIM1 locus have been reported to have a strong association with dark hair, skin, and eye color in Europeans in Queensland, Australia (Graf, Hodgson, and van Daal 2005). However, the 374L allele is an ancestral allele and common in other populations, including Africans, whereas the 272K allele is derived and rare in Africans. In addition, 374L and 272K are in complete linkage disequilibrium in Europeans (|D'| = 1). Thus, it is likely that 374L rather than the 272K allele plays an important role in dark hair, skin, and eye pigmentation in Europeans. In other words, individuals having the AIM1 allele 374F might exhibit pale hair, skin, and eye pigmentation and have advantages for vitamin D synthesis at higher latitudes.
Our present study suggests that the genetic variation is low in the nonsynonymous sites but higher in the silent sites in the African population, while the variation is low in both synonymous and silent sites in Europeans. On the other hand, the diversity is the highest in both nonsynonymous and silent sites in Asians. As in AIM1, a low genetic diversity of nonsynonymous sites in MC1R was observed in Africans (Rees 2004). These observations suggest that these two genes are probably under strong functional constraints in Africa where any deviation from eumelanin production appears to be evolutionarily deleterious. In contrast to African pattern, European polymorphic pattern of AIM1 is quite different from that of MC1R. We found skewed allele frequency in AIM1 while diversity is increased without an overrepresented derived allele at MC1R (Rana et al. 1999; Harding et al. 2000). Thus, it is likely that there was a recent selective sweep possibly by a mutation (374F) at AIM1 but no such event occurred at MC1R in Europeans.
In this study, all four statistical tests and the haplotype test detected statistically significant deviations from selective neutrality for Europeans because of the skewed allele frequency (table 2). However, most of the tests we applied are sensitive to demographic history. For example, Tajima's D can become strongly negative when the population has gone through a prolonged bottleneck and expanded thereafter (Sano and Tachida 2005). However, our previous studies suggest that such a severe population bottleneck is unlikely to be the cause (Koda et al. 2004; Soejima et al. 2005). In addition, the GOF test proposed by Jensen et al. (2005) suggested that the original rejection of neutrality in Europeans by the CLR test is more likely to be due to a selective sweep than demography alone. To examine the possibility of an incomplete sweep on the putative target, 374F, we performed the CLR test on the European population, but the result of this test cannot reject the complete selective sweep model. This may be because the 374F allele is almost fixed in Europeans. In fact, the CLRs obtained by the polymorphic data in Europeans were quite similar to the average values from 1,000 simulation data of the incomplete sweep model using the assumption that 374F is the beneficial allele (target site is 32985, beneficial allele frequency is 0.94, and is 4000). Thus, the polymorphic pattern of AIM1 in Europeans could be explained by the incomplete sweep acting on 374F, and the strength of selection might be greater than = 200 obtained from the complete sweep assumption (table 5).
To date, several examples of incomplete selective sweeps have been reported. Malaria is one of the selective agents that has influenced genetic diversity in humans. Sabeti et al. (2002) used extended haplotype homozygosity (EHH) analysis to investigate recent positive selection at two genes carrying common variants implicated in resistance to malaria, G6PD and the CD40 ligand gene (TNFSF5). One haplotype that carries the protection-associated alleles in both genes was common in Africa (18% for G6PD and 34% for TNFSF5), where malaria is endemic, but was absent outside Africa and had a much higher relative EHH of 413 kb for G6PD and 506 kb for TNFSF5 than other haplotypes of comparable frequency. The estimated ages of these haplotypes were about 2,500 years for G6PD and 6,600 years for TNFSF5 (and none of the test statistics showed significant values for these genes). We can speculate that the origin of the selective force acting on AIM1 is older than that of malaria and that the selective sweep is more complete at AIM1 in Europeans than at these malaria-resistance genes in Africans.
Recently, Graf, Hodgson, and van Daal (2005) proposed that the 374F allele results in a reduction of function that alters the intracellular trafficking of melanosomal proteins, creating an environment for decreased melanin production. Such a functional difference allows those in high latitudes to absorb the UVB necessary for the synthesis of vitamin D3. Conversely, this newly arisen allele does not confer a benefit in the equatorial areas but rather enhances the harmful effects of UV radiation. Functional analysis to determine the differences in melanogenesis of both alleles is necessary to understand not only the selective force but also the function of this molecule in normal pigmentation.
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This paper is dedicated to the memory of Osamu Takenaka. We thank Yuseob Kim for kindly giving us the computer program. We thank Hiroshi Kimura (Chiba Institute of Science, Choshi, Japan) for helpful advice and support and also thank Ernette D. du Toit (Department of Immunology, Medical School, Cape Town, South Africa) for providing DNA samples. This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Science, Culture and Sports of Japan and Mitsui Life Social Welfare Foundation. We thank Katherine Ono for the English editing of this manuscript.
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Footnotes |
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Jianzhi Zhang, Associate Editor
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References |
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Bandelt, H., P. Forster, and A. Rohl. 1999. Median-joining networks for inferring intraspecific phylogenies. Mol. Biol. Evol. 16:37–48.[Abstract]
Bonilla, C., L.-A. Boxill, S. A. M. Donald, T. Williams, N. Sylvester, E. J. Parra, S. Dios, H. L. Norton, M. D. Shriver, and R. A. Kittles. 2005. The 8818G allele of the agouti signaling protein ASIP gene is ancestral and is associated with darker skin color in African Americans. Hum. Genet. 116:402–406.[CrossRef][Web of Science][Medline]
Costin, G.-E., J. C. Valencia, W. D. Vieira, M. L. Lamoreux, and V. J. Hearing. 2003. Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4. J. Cell Sci. 116:3203–3212.
Fay, J. C., and C.-I. Wu. 2000. Hitchhiking under positive Darwinian selection. Genetics 155:1405–1413.
Fu, Y. X., and W. H. Li. 1993. Statistical tests of neutrality of mutations. Genetics 133:693–709.[Abstract]
Fukamachi, S., A. Shimada, and A. Shima. 2001. Mutations in the gene encoding B, a novel transporter protein, reduce melanin content in medaka. Nat. Genet. 28:381–385.[CrossRef][Web of Science][Medline]
Graf, J., R. Hodgson, and A. van Daal. 2005. Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation. Hum. Mutat. 25:278–284.[CrossRef][Web of Science][Medline]
Harada, M., Y. F. Li, M. El-Gamil, S. A. Rosenberg, and P. F. Robbins. 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.
Harding, R. M., E. Healy, A. J. Ray et al. (11 co-authors). 2000. Evidence for variable selective pressures at MC1R. Am. J. Hum. Genet. 66:1351–1361.[CrossRef][Web of Science][Medline]
Hudson, R. R. 2002. Generating samples under a Wright-Fisher neutral model of genetic variation. Bioinformatics 18:337–338.
Hudson, R. R., K. Bailey, D. Skarecky, J. Kwiatowski, and F. J. Ayala. 1994. Evidence for positive selection in the superoxide dismutase (Sod) region of Drosophila melanogaster. Genetics 136:1329–1340.[Abstract]
Inagaki, K., T. Suzuki, H. Shimizu et al. (14 co-authors). 2004. Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan. Am. J. Hum. Genet. 74:466–471.[CrossRef][Web of Science][Medline]
Jensen, J. D., Y. Kim, V. Bauer DuMont, C. F. Aquadro, and C. D. Bustamante. 2005. Distinguishing between selective sweeps and demography using DNA polymorphism data. Genetics 170:1401–1410.
Kanetsky, P. A., J. Swoyer, S. Panossian, R. Holmes, D. Guerry, and T. R. Rebbeck. 2002. A polymorphism in the agouti signaling protein gene is associated with human pigmentation. Am. J. Hum. Genet. 70:770–775.[CrossRef][Web of Science][Medline]
Kim, Y., and W. Stephan. 2002. Detecting a local signature of genetic hitchhiking along a recombining chromosome. Genetics 160:765–777.
Koda, Y., H. Tachida, M. Soejima, O. Takenaka, and H. Kimura. 2004. Population differences in DNA sequence variation and linkage disequilibrium at the PON1 gene. Ann. Hum. Genet. 68:110–119.[CrossRef][Web of Science][Medline]
Kong, A., D. F. Gudbjartsson, S. Jesus et al (16 co-authors). 2002. A high-resolution recombination map of the human genome. Nat. Genet. 31:241–247.[CrossRef][Web of Science][Medline]
Li, W. H., and L. A. Sadler. 1991. Low nucleotide diversity in man. Genetics 129:513–523.[Abstract]
Maynard Smith, J., and J. Haigh. 1974. The hitch-hiking effect of a favourable gene. Genet. Res. 23:23–35.[Web of Science][Medline]
McDonald, J. H., and M. Kreitman. 1991. Adaptive protein evolution at the Adh locus in Drosophila. Nature 351:652–654.[CrossRef][Medline]
Meiklejohn, C. D., Y. Kim, D. L. Hartl, and J. Parsch. 2004. Identification of a locus under complex positive selection in Drosophila simulans by haplotype mapping and composite-likelihood estimation. Genetics 168:265–279.
Nakayama, K., S. Fukamachi, H. Kimura, Y. Koda, A. Soemantri, and T. Ishida. 2002. Distinctive distribution of AIM1 polymorphism among major human populations with different skin color. J. Hum. Genet. 47:92–94.[CrossRef][Web of Science][Medline]
Nei, M., and F. Tajima. 1981. DNA polymorphism detectable by restriction endonucleases. Genetics 97:145–163.
Newton, J. M., O. Cohen-Barak, N. Hagiwara, J. M. Gardner, M. T. Davisson, R. A. King, and M. H. Brilliant. 2001. Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Am. J. Hum. Genet. 69:981–988.[CrossRef][Web of Science][Medline]
Rana, B. K., D. Hewett-Emmett, L. Jin et al. (12 co-authors). 1999. High polymorphism at the human melanocortin 1 receptor locus. Genetics 151:1547–1557.
Rees, J. L. 2004. The genetics of sun sensitivity in humans. Am. J. Hum. Genet. 75:739–751.[CrossRef][Web of Science][Medline]
Rozas, J., and R. Rozas. 1999. DnaSP version 3: an integrated program for molecular population genetics and molecular evolution analysis. Bioinformatics 15:174–175.
Rundshagen, U., C. Zuhlke, S. Opitz, E. Schwinger, and B. Kasmann-Kellner. 2004. Mutations in the MATP gene in five German patients affected by oculocutaneous albinism type 4. Hum. Mutat. 23:106–110.[CrossRef][Web of Science][Medline]
Sabeti, P. C., D. E. Reich, J. M. Higgins et al. (17 co-authors). 2002. Detecting recent positive selection in the human genome from haplotype structure. Nature 419:832–837.[CrossRef][Medline]
Sano, A., and H. Tachida. 2005. Gene genealogy and properties of test statistics of neutrality under population growth. Genetics 169:1687–1697.
Soejima, M., H. Tachida, M. Tsuneoka, O. Takenaka, H. Kimura, and Y. Koda. 2005. Nucleotide sequence analyses of human complement 6 (C6) gene suggest balancing selection. Ann. Hum. Genet. 69:239–252.[Web of Science][Medline]
Stephens, M., and P. Donnelly. 2003. A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet. 73:1162–1169.[CrossRef][Web of Science][Medline]
Stephens, M., N. J. Smith, and P. Donnelly. 2001. A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68:978–989.[CrossRef][Web of Science][Medline]
Suzuki, T., K. Inagaki, K. Fukai, A. Obana, S. T. Lee, and Y. Tomita. 2005. A Korean case of oculocutaneous albinism type IV caused by a D157N mutation in the MATP gene. Br. J. Dermatol. 152:174–175.[CrossRef][Web of Science][Medline]
Tajima, F. 1989. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595.
Takahata, N. 1993. Allelic genealogy and human evolution. Mol. Biol. Evol. 10:2–22.[Abstract]
Watterson, G. A. 1975. On the number of segregating sites in genetical models without recombination. Theor. Popul. Biol. 7:256–276.[CrossRef][Web of Science][Medline]
Yuasa, I., K. Umetsu, G. Watanabe, H. Nakamura, M. Endoh, and Y. Irizawa. 2004. MATP polymorphisms in Germans and Japanese: the L374F mutation as a population marker for Caucasoids. Int. J. Leg. Med. 118:364–366.[CrossRef][Web of Science][Medline]
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