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Principal component analysis plot shows the distribution of global populations based on KIR genes. All estimated KIR genes frequencies ( gF ) of the populations used are listed in S5 Table. A = Argentina; B = Brazil; I = Indonesia; M = Malay; S. A = South Africa; Tai = Taiwan; Vnz = Venezuela. doi:10.1371/journal.pone.0141536.g003 

Principal component analysis plot shows the distribution of global populations based on KIR genes. All estimated KIR genes frequencies ( gF ) of the populations used are listed in S5 Table. A = Argentina; B = Brazil; I = Indonesia; M = Malay; S. A = South Africa; Tai = Taiwan; Vnz = Venezuela. doi:10.1371/journal.pone.0141536.g003 

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The aboriginal populations of Peninsular Malaysia, also known as Orang Asli (OA), comprise three major groups; Semang, Senoi and Proto-Malays. Here, we analyzed for the first time KIR gene polymorphisms for 167 OA individuals, including those from four smallest OA subgroups (Che Wong, Orang Kanaq, Lanoh and Kensiu) using polymerase chain reaction-s...

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... of KIR2DL2 and KIR2DS2 genes and relatively low frequency of KIR2DS3 ( Fig 1, Tables 1 and 2). All these factors might underlie the significant differences observed between Proto-Malays (Orang Kanaq) and Deutro-Malay subgroups in the present account of Austronesian origins and migration patterns (Fig 3 and [48]). In contrast, the Deutro-Malay subgroups form a major component of multiracial population of Malaysia and their genepools are becoming more diverse due to intermarriages with other ethnicities. However, this observation should be interpreted with caution due the small sample size in this study with only 11 individuals of Orang Kanaq analyzed. Unfortunately, we were unable to improve on this situation because there is only small number of Orang Kanaq still in existence (approximately 80 individuals only). The strict sampling selection criteria that we used has also contributed to the low number of samples obtained. Overall, comprehensive KIR gene-content datasets generated from the present survey provides essential knowledge on the genetic relationships within the OA subgroups and with other world populations. The observed distribution of KIR profiles of OA is heterogenous; Haplotype B is the most frequent in the Semang subgroups (especially Batek) while Haplotype A is the most common type in the Senoi. In the PCA plot, the Batek is grouped together with Africans, Indians, Papuans and Australia Aborigines, showing closer affinity to these populations. Given that these populations also display high frequencies of Haplotype B , it is interesting to speculate that relatively high frequencies of Haplotype B may be a general feature of ancient populations, which fits well with molecular age estimation made using mtDNA sequence data analysis [45]. In contrast, the Senoi who show high frequencies of Haplotype A could be linked to the Southern China populations. The Orang Kanaq (Proto Malays) do not seems to have any particular common haplotype which is similar to other Austronesian speakers in the ...
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... Che Wong subgroup has the highest number of KIR genotypes (12 KIR profiles among 28 individuals), followed by Batek (10 KIR profiles among 27 individuals), and the lowest is Semai (9 KIR profiles among 37 individuals). The AB2 genotype is the most common genotype in Orang Kanaq (0.73) while the genotype AA1 (0.46) and AB4 (0.27) are the most frequent genotypes in Semai (Fig 1 and Table 2). The KIR genotype and haplotype frequencies are presented in Table 3. Semai showed the highest frequency of Haplotype A (0.66), followed by Che Wong (0.52). Haplotype B is predomi- nant in all Semang subgroups; Batek (0.83), Lanoh (0.56) and Kensiu (0.54). The HW analysis indicated that all OA subgroups are in equilibrium except for Orang Kanaq (S2A and S2B Table). The distribution of haplotype A and B frequencies among OA subgroups and worldwide populations is displayed in Fig 2. Batek has the highest frequency of haplotype B when compared with other world populations reported so far. On the other hand, the Semai are closer to Northeast Asian populations which consistently show high frequencies of haplotype A . The LD analyses between pairs of KIR genes in OA subgroups are listed in S3A – S3L Table. Any KIR genes that are completely fixed or absent in the sample group were excluded from the LD analyses. In general, there were strong positive association between the KIR2DL2-KIR2DS2 and KIR2DS1 - KIR3DS1 pairs in all six OA subgroups. Strong positive associations were also detected between pairs of KIR2DL5 - KIR2DS3 in Lanoh, KIR2DS4-KIR3DL1 in Batek, Kensiu and Orang Kanaq and KIR2DS5-KIR2DS1 / KIR3DS1 in Semai and Orang Kanaq. The homogeneity tests between pairs of OA subgroups are shown in S4A – S4F Table. All six OA subgroups showed no significant differences for KIR2DL1 and KIR3DL1 genes. However, several genes in Batek (i.e. KIR2DL2 , KIR2DL3 , KIR2DS1 , KIR2DS2 , KIR2DS3 and KIR3DS1 ), Semai (i.e. KIR2DL5 , KIR2DS1 , KIR2DS3 and KIR3DS1 ) and Orang Kanaq (i.e. KIR2DL2 , KIR2DS2 , KIR2DS3 and KIR2DS5 ) were significantly different compared with other OA subgroups. In the PCA plot, all reference populations are distributed according to their ethnogeogra- phical regions; Northeast Asian, Southeast Asian, South Asian, African, Amerindian and Ocea- nia (Fig 3). The Semang subgroups showed some degree of genetic affinity to the Africans, South Asians, Papuans and Australia Aborigines as Lanoh, Kensiu and Batek are plotted in between these populations. Che Wong and Semai, the subgroups of Senoi are plotted closer to the Southeast Asian and African populations, respectively. In contrast, Orang Kanaq is well separated from other reference datasets including the Austronesian speaking populations. Malaysia is a multiethnic country that received multiple sucessive waves of more or less ancient migrations giving rise to Semang, Senoi and Proto-Malay subgroups. This followed by re-set- tlements of various Austronesian speakers (Malayo-Polynesian) from neigbouring islands including Jawa (Java), Banjar (Kalimantan), Bugis (Sulawesi) and Minangkabau (Sumatera) Malays [42, 43] and an influx of traders and labourers during Malacca Sultanate (1402 – 1511). British colonization (1824 – 1956) has added further genetic diversity to the population in more recent times. Thus, any genetic study of people in Malaysia is complicated as it involves these repeated waves of migration and/or admixture of people from different genetic backgrounds. Our findings showed that the Semang subgroups (Lanoh, Kensiu and Batek) exhibit high frequencies of KIR haplotype B (see Fig 1 and Table 3) and share three KIR genotypes; AB6 (14 individuals), BB71 (12 individuals) and BB73 (8 individuals) that were previously reported as the most common genotypes in African and Indian populations [19 – 22] (Table 2). They were also plotted closest to African, Indian, Papuan and Australian Aborigine populations in the haplotype fraction and PCA graphs (Figs 2 and 3). This is an evidence of their ancient genetic affinities as part of the first wave out of Africa movement by modern human travelling along southern coast of Arabian Peninsula towards India, Southeast Asia (Peninsular Malaysia) and finally arriving in Australia and Papua New Guinea [44, 45]. Other genetic signatures of the ancient lineage in Semang is demonstrated by the presence of KIR genotype BB159 in Batek, which is also a common KIR genotype in Africans, Indians, Australian Aborigines and Papuans [15,22]. Senoi is the largest OA population in Peninsular Malaysia and frequently migrate in small groups from one settlement to another [46]. This practice may reduce genetic variation in the Senoi, especially for the Semai subgroup where AA1 and AB4 represent more than 70% of all their observed KIR genotype profiles (see Fig 1). Overall, the two Senoi subgroups (Semai and Che Wong) were observed to have high frequencies of haplotype A (Table 3). Che Wong is plotted closer to the Southeast Asia populations (see Fig 3) and is entirely consistent with their proposed origins from Southern China [29] whereas the Semai is displaced towards African populations. The genetic differences between Senoi subgroups (Che Wong and Semai) are probably due to different admixture level with the earlier Semang groups that carry the negrito phenotype. This observation indicates the gene flow from Semang have significantly changed the genetic composition of Semai. Their ancestral genepool are retained by being isolated in the deep rainforest of Banjaran Titiwangsa compared with the smaller number of Che Wong individuals who are now frequently exposed to outsiders as their village, Kuala Gandah has been commercialized for tourism. The Proto-Malays are suggested to be the introducer of Austronesian language into the Island of Southeast Asia. However, Orang Kanaq is significantly different from other Austronesian speaking populations and showing evidence of becoming a distinct population (Fig 3). They were also distant from the neighbouring Deutro-Malay subgroups [47], even though both speak similar language (Malayo-Polynesian) and express similar phenotypes. Their ...
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... so far. On the other hand, the Semai are closer to Northeast Asian populations which consistently show high frequencies of haplotype A . The LD analyses between pairs of KIR genes in OA subgroups are listed in S3A – S3L Table. Any KIR genes that are completely fixed or absent in the sample group were excluded from the LD analyses. In general, there were strong positive association between the KIR2DL2-KIR2DS2 and KIR2DS1 - KIR3DS1 pairs in all six OA subgroups. Strong positive associations were also detected between pairs of KIR2DL5 - KIR2DS3 in Lanoh, KIR2DS4-KIR3DL1 in Batek, Kensiu and Orang Kanaq and KIR2DS5-KIR2DS1 / KIR3DS1 in Semai and Orang Kanaq. The homogeneity tests between pairs of OA subgroups are shown in S4A – S4F Table. All six OA subgroups showed no significant differences for KIR2DL1 and KIR3DL1 genes. However, several genes in Batek (i.e. KIR2DL2 , KIR2DL3 , KIR2DS1 , KIR2DS2 , KIR2DS3 and KIR3DS1 ), Semai (i.e. KIR2DL5 , KIR2DS1 , KIR2DS3 and KIR3DS1 ) and Orang Kanaq (i.e. KIR2DL2 , KIR2DS2 , KIR2DS3 and KIR2DS5 ) were significantly different compared with other OA subgroups. In the PCA plot, all reference populations are distributed according to their ethnogeogra- phical regions; Northeast Asian, Southeast Asian, South Asian, African, Amerindian and Ocea- nia (Fig 3). The Semang subgroups showed some degree of genetic affinity to the Africans, South Asians, Papuans and Australia Aborigines as Lanoh, Kensiu and Batek are plotted in between these populations. Che Wong and Semai, the subgroups of Senoi are plotted closer to the Southeast Asian and African populations, respectively. In contrast, Orang Kanaq is well separated from other reference datasets including the Austronesian speaking populations. Malaysia is a multiethnic country that received multiple sucessive waves of more or less ancient migrations giving rise to Semang, Senoi and Proto-Malay subgroups. This followed by re-set- tlements of various Austronesian speakers (Malayo-Polynesian) from neigbouring islands including Jawa (Java), Banjar (Kalimantan), Bugis (Sulawesi) and Minangkabau (Sumatera) Malays [42, 43] and an influx of traders and labourers during Malacca Sultanate (1402 – 1511). British colonization (1824 – 1956) has added further genetic diversity to the population in more recent times. Thus, any genetic study of people in Malaysia is complicated as it involves these repeated waves of migration and/or admixture of people from different genetic backgrounds. Our findings showed that the Semang subgroups (Lanoh, Kensiu and Batek) exhibit high frequencies of KIR haplotype B (see Fig 1 and Table 3) and share three KIR genotypes; AB6 (14 individuals), BB71 (12 individuals) and BB73 (8 individuals) that were previously reported as the most common genotypes in African and Indian populations [19 – 22] (Table 2). They were also plotted closest to African, Indian, Papuan and Australian Aborigine populations in the haplotype fraction and PCA graphs (Figs 2 and 3). This is an evidence of their ancient genetic affinities as part of the first wave out of Africa movement by modern human travelling along southern coast of Arabian Peninsula towards India, Southeast Asia (Peninsular Malaysia) and finally arriving in Australia and Papua New Guinea [44, 45]. Other genetic signatures of the ancient lineage in Semang is demonstrated by the presence of KIR genotype BB159 in Batek, which is also a common KIR genotype in Africans, Indians, Australian Aborigines and Papuans [15,22]. Senoi is the largest OA population in Peninsular Malaysia and frequently migrate in small groups from one settlement to another [46]. This practice may reduce genetic variation in the Senoi, especially for the Semai subgroup where AA1 and AB4 represent more than 70% of all their observed KIR genotype profiles (see Fig 1). Overall, the two Senoi subgroups (Semai and Che Wong) were observed to have high frequencies of haplotype A (Table 3). Che Wong is plotted closer to the Southeast Asia populations (see Fig 3) and is entirely consistent with their proposed origins from Southern China [29] whereas the Semai is displaced towards African populations. The genetic differences between Senoi subgroups (Che Wong and Semai) are probably due to different admixture level with the earlier Semang groups that carry the negrito phenotype. This observation indicates the gene flow from Semang have significantly changed the genetic composition of Semai. Their ancestral genepool are retained by being isolated in the deep rainforest of Banjaran Titiwangsa compared with the smaller number of Che Wong individuals who are now frequently exposed to outsiders as their village, Kuala Gandah has been commercialized for tourism. The Proto-Malays are suggested to be the introducer of Austronesian language into the Island of Southeast Asia. However, Orang Kanaq is significantly different from other Austronesian speaking populations and showing evidence of becoming a distinct population (Fig 3). They were also distant from the neighbouring Deutro-Malay subgroups [47], even though both speak similar language (Malayo-Polynesian) and express similar phenotypes. Their ...
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... nAB)/2N, where nAA, nAB and nBB are the numbers of individuals with genotype pro fi le AA , AB and BB , respectively, and N is the sample size of each subgroup. Scatter plot of haplotype B vs A frequency was constructed to assess the genetic relationship of the OA subgroups with other global populations. Next, HW analysis was applied to test if variation in the OA subgroups are at genetic equilibrium using the conventional chi-square ( χ 2 ) goodness of fi t test [41]. Subgroups with χ 2 value < 3.841 are considered to be in HW equilibrium. Principal component analysis (PCA) was used to demonstrate genetic af fi nity among the populations compared. The PCA was constructed using Multivariate Statistical Package software v3.22 (Kovach Comput- ing Services, UK; based on a set of seven gF values (i.e. those for KIR3DL1 , KIR2DL1 , KIR2DL3 , KIR2DL2 , KIR3DS1 , KIR2DS1 and KIR2DS2 ) which are available for all of the selected reference populations. Linkage disequilibrium (LD) was per- formed using XLSTAT software to measure the possibility that any two particular KIR genes were inherited together in each OA subgroup. A value toward ‘ 1.00 ’ shows high tendency of two genes to be inherited together with p -value < 0.05 as a level of signi fi cance. Homogeneity tests were conducted to analyze the distribution of single gene between two populations using χ 2 with Yates' correction by using Graphpad software () with p -values < 0.05 as level of signi fi cance. All of the 16 KIR genes presently known were detected in all of the OA subgroups, except for KIR2DL2 and KIR2DS2 genes which are completely absent in Orang Kanaq (Table 1). There were also relatively low frequencies of KIR2DS3 (0.05) in Orang Kanaq and KIR2DS1 , KIR2DS5 and KIR3DS1 genes (0.04 each) in Semai. There were high frequencies of KIR inhibitory genes (0.32 – 1.00) in Lanoh, Kensiu and Che Wong. On the contrary, Batek and Orang Kanaq have a balance distribution of both functional types of KIR genes. We have also exam- ined the frequencies of KIR genes in the ‘ unrelated ’ OA subgroups, but only minor differences were observed when compared with the corresponding total OA subgroups (Table 1 and S1 Table). The framework genes; KIR2DL4 , KIR3DL2 , KIR3DL3 and KIR3DP1 together with one pseudogene KIR2DP1 were present in all individuals. Fifteen individuals were observed to have all 16 KIR genes; 9 Kensiu, 3 Batek, 2 Lanoh and 1 individual from Semai (Fig 1). A total of 25 KIR genotype profiles were discovered among the 167 OA individuals, (Fig 1 and Table 2). The distribution of unique and shared genotypes is presented in Table 2. The BB71 and BB73 genotypes were present in all OA subgroups except for Orang Kanaq. The Che Wong subgroup has the highest number of KIR genotypes (12 KIR profiles among 28 individuals), followed by Batek (10 KIR profiles among 27 individuals), and the lowest is Semai (9 KIR profiles among 37 individuals). The AB2 genotype is the most common genotype in Orang Kanaq (0.73) while the genotype AA1 (0.46) and AB4 (0.27) are the most frequent genotypes in Semai (Fig 1 and Table 2). The KIR genotype and haplotype frequencies are presented in Table 3. Semai showed the highest frequency of Haplotype A (0.66), followed by Che Wong (0.52). Haplotype B is predomi- nant in all Semang subgroups; Batek (0.83), Lanoh (0.56) and Kensiu (0.54). The HW analysis indicated that all OA subgroups are in equilibrium except for Orang Kanaq (S2A and S2B Table). The distribution of haplotype A and B frequencies among OA subgroups and worldwide populations is displayed in Fig 2. Batek has the highest frequency of haplotype B when compared with other world populations reported so far. On the other hand, the Semai are closer to Northeast Asian populations which consistently show high frequencies of haplotype A . The LD analyses between pairs of KIR genes in OA subgroups are listed in S3A – S3L Table. Any KIR genes that are completely fixed or absent in the sample group were excluded from the LD analyses. In general, there were strong positive association between the KIR2DL2-KIR2DS2 and KIR2DS1 - KIR3DS1 pairs in all six OA subgroups. Strong positive associations were also detected between pairs of KIR2DL5 - KIR2DS3 in Lanoh, KIR2DS4-KIR3DL1 in Batek, Kensiu and Orang Kanaq and KIR2DS5-KIR2DS1 / KIR3DS1 in Semai and Orang Kanaq. The homogeneity tests between pairs of OA subgroups are shown in S4A – S4F Table. All six OA subgroups showed no significant differences for KIR2DL1 and KIR3DL1 genes. However, several genes in Batek (i.e. KIR2DL2 , KIR2DL3 , KIR2DS1 , KIR2DS2 , KIR2DS3 and KIR3DS1 ), Semai (i.e. KIR2DL5 , KIR2DS1 , KIR2DS3 and KIR3DS1 ) and Orang Kanaq (i.e. KIR2DL2 , KIR2DS2 , KIR2DS3 and KIR2DS5 ) were significantly different compared with other OA subgroups. In the PCA plot, all reference populations are distributed according to their ethnogeogra- phical regions; Northeast Asian, Southeast Asian, South Asian, African, Amerindian and Ocea- nia (Fig 3). The Semang subgroups showed some degree of genetic affinity to the Africans, South Asians, Papuans and Australia Aborigines as Lanoh, Kensiu and Batek are plotted in between these populations. Che Wong and Semai, the subgroups of Senoi are plotted closer to the Southeast Asian and African populations, respectively. In contrast, Orang Kanaq is well separated from other reference datasets including the Austronesian speaking populations. Malaysia is a multiethnic country that received multiple sucessive waves of more or less ancient migrations giving rise to Semang, Senoi and Proto-Malay subgroups. This followed by re-set- tlements of various Austronesian speakers (Malayo-Polynesian) from neigbouring islands including Jawa (Java), Banjar (Kalimantan), Bugis (Sulawesi) and Minangkabau (Sumatera) Malays [42, 43] and an influx of traders and labourers during Malacca Sultanate (1402 – 1511). British colonization (1824 – 1956) has added further genetic diversity to the population in more recent times. Thus, any genetic study of people in Malaysia is complicated as it involves these repeated waves of migration and/or admixture of people from different genetic backgrounds. Our findings showed that the Semang subgroups (Lanoh, Kensiu and Batek) exhibit high frequencies of KIR haplotype B (see Fig 1 and Table 3) and share three KIR genotypes; AB6 (14 individuals), BB71 (12 individuals) and BB73 (8 individuals) that were previously reported as the most common genotypes in African and Indian populations [19 – 22] (Table 2). They were also plotted closest to African, Indian, Papuan and Australian Aborigine populations in the haplotype fraction and PCA graphs (Figs 2 and 3). This is an evidence of their ancient genetic affinities as part of the first wave out of Africa movement by modern human travelling along southern coast of Arabian Peninsula towards India, Southeast Asia (Peninsular Malaysia) and finally arriving in Australia and Papua New Guinea [44, 45]. Other genetic signatures of the ancient lineage in Semang is demonstrated by the presence of KIR genotype BB159 in Batek, which is also a common KIR genotype in Africans, Indians, Australian Aborigines and Papuans [15,22]. Senoi is the largest OA population in Peninsular Malaysia and frequently migrate in small groups from one settlement to another [46]. This practice may reduce genetic variation in the Senoi, especially for the Semai subgroup where AA1 and AB4 represent more than 70% of all their observed KIR genotype profiles (see Fig 1). Overall, the two Senoi subgroups (Semai and Che Wong) were observed to have high frequencies of haplotype A (Table 3). Che Wong is plotted closer to the Southeast Asia populations (see Fig 3) and is entirely consistent with their proposed origins from Southern China [29] whereas the Semai is displaced towards African populations. The genetic differences between Senoi subgroups (Che Wong and Semai) are probably due to different admixture level with the earlier Semang groups that carry the negrito phenotype. This observation indicates the gene flow from Semang have significantly changed the genetic composition of Semai. Their ancestral genepool are retained by being isolated in the deep rainforest of Banjaran Titiwangsa compared with the smaller number of Che Wong individuals who are now frequently exposed to outsiders as their village, Kuala Gandah has been commercialized for tourism. The Proto-Malays are suggested to be the introducer of Austronesian language into the Island of Southeast Asia. However, Orang Kanaq is significantly different from other Austronesian speaking populations and showing evidence of becoming a distinct population (Fig 3). They were also distant from the neighbouring Deutro-Malay subgroups [47], even though both speak similar language (Malayo-Polynesian) and express similar phenotypes. Their ...

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... We have completed and reported a comprehensive set of ancestrally informative genetic data across many Asia/Pacific populations. These systems include HLA, MICA, KIR, blood group, cytokine, HNA and HPA [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. These new datasets not only provide special insights into the ancestry of these people, but also is of significant value in health; as recently reviewed by [21][22]. ...
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Information about genetic ancestry has a great value in health studies and other related areas of expertise such as anthropology, forensics and pharmacogenomics. In this review, we highlight several aspects of health that can be significantly improved by better understanding of genetic ancestry. These observations were made possible based on our own medical genetic research in Asia/Pacific populations (i.e. in particular regarding Maori and Orang Asli of New Zealand and Peninsular Malaysia, respectively). The major objectives of this programme of investigations has been to capture and understand genetic diversity in these populations and subsequently to make recommendations in order to maximise the health benefits of this type of population genetic research.
... Genetic differentiation within Orang Asli subgroups (specifically, between Semang subgroups) and between Proto-Malays and Malay subethnic groups has also been reported by others. 25 In contrast, there are no obvious differences between the two Senoi subgroups (Lanoh and Semai) who are members of the largest Orang Asli group in Peninsular Malaysia (Table 6 and Fig. 1). This finding might be attributable to the relatively small sizes of the Semang and Proto-Malay populations. ...
... The Orang Asli are the indigenous people of Peninsular Malaysia and the estimated population size is only~180,000 people [31]. The Senoi tribe, which consists of six sub-tribes (Che Wong, Jahut, Mah Meri, Semoq Beri, Semai and Temiar) formed the largest group of Orang Asli with~98,000 people followed by the Proto-Malays with~75,000 people from 6 sub-tribes (Kanaq, Kuala, Seletar, Jakun, Semelai and Temuan) and the smallest group are those that expressed the negrito phenotypes (Bateq, Jahai, Kensiu, Kintaq, Mendriq and Lanoh) with an estimated number of only 5,000 people [32]. Their settlements are scattered across the Peninsular Malaysia whereby the Negritos and Senoi are generally localized in the northern and central regions while Proto-Malays settlements are found in the central and southern regions [33]. ...
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The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme’s activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.
... The Orang Asli are the indigenous people of Peninsular Malaysia and the estimated population size is only~180,000 people [31]. The Senoi tribe, which consists of six sub-tribes (Che Wong, Jahut, Mah Meri, Semoq Beri, Semai and Temiar) formed the largest group of Orang Asli with~98,000 people followed by the Proto-Malays with~75,000 people from 6 sub-tribes (Kanaq, Kuala, Seletar, Jakun, Semelai and Temuan) and the smallest group are those that expressed the negrito phenotypes (Bateq, Jahai, Kensiu, Kintaq, Mendriq and Lanoh) with an estimated number of only 5,000 people [32]. Their settlements are scattered across the Peninsular Malaysia whereby the Negritos and Senoi are generally localized in the northern and central regions while Proto-Malays settlements are found in the central and southern regions [33]. ...
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We conducted a systematic characterization of CYP2C9 variants in 61 Orang Asli and 96 Singaporean Malays using the whole genome sequences data and compared the variants with the other 11 HapMap populations. The frequency of rs1057910 (CYP2C9*3) is the highest in the Orang Asli compared to other populations. Three alleles with clinical implication were detected in the Orang Asli while 2 were found in the Singaporean Malays. Large numbers of the Orang Asli are predicted to have reduced metabolic capacity and therefore they would require a lower dose of drugs which are metabolized by CYP2C9. They are also at increased risks of adverse effects and therapeutic failures. A large number of CYP2C9 variants in the Orang Asli were not in the Hardy Weinberg Equilibrium which could be due to small sample size or mutations that disrupt the equilibrium of allele frequencies. In conclusion, different polymorphism patterns, allele frequencies, genotype frequencies and LD blocks are observed between the Orang Asli, the Singaporean Malays and the other populations. The study provided new information on the genetic polymorphism of CYP2C9 which is important for the implementation of precision medicine for the Orang Asli.
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Next-generation DNA sequencing (NGS) technology advancements provide new insight into the level of variation in killer immunoglobulin-like receptor (KIR) genes. High resolution allele genotyping of seven KIR genes was conducted among 94 unrelated Malay and Orang Asli (OA) individuals of Peninsular Malaysia. A manual bioinformatics analysis is performed and optimised by Sanger sequencing method. The Malays expressed a total of 22 alleles, as compared to only 15 alleles in the OA population. In total, 12 centromeric and 9 telomeric allelic haplotypes were identified in the Malays, whereas 8 centromeric and 5 telomeric allelic haplotypes were identified in the OA. The KIR2DL1, KIR2DL3, and KIR2DS4 genes exhibited a high degree of variation and balanced distribution in the Malay and OA populations. On the other hand, KIR2DL4, KIR3DL1, KIR3DL2 and KIR3DL3 genes exhibited a high degree of conservation, with less number of alleles identified and the dominance of a single allele at high frequency. High-resolution KIR allele genotyping has revealed unique sequence variations and allelic haplotypes between individuals and populations. The distributions of KIR alleles and haplotypes are useful for genetic population studies and serve as a baseline for future transplantation matching and disease association research.