Publications by authors named "Boon Peng Hoh"

26 Publications

  • Page 1 of 1

Shared Signature of Recent Positive Selection on the TSBP1-BTNL2-HLA-DRA Genes in Five Native Populations from North Borneo.

Genome Biol Evol 2020 12;12(12):2245-2257

Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

North Borneo (NB) is home to more than 40 native populations. These natives are believed to have undergone local adaptation in response to environmental challenges such as the mosquito-abundant tropical rainforest. We attempted to trace the footprints of natural selection from the genomic data of NB native populations using a panel of ∼2.2 million genome-wide single nucleotide polymorphisms. As a result, an ∼13-kb haplotype in the Major Histocompatibility Complex Class II region encompassing candidate genes TSBP1-BTNL2-HLA-DRA was identified to be undergoing natural selection. This putative signature of positive selection is shared among the five NB populations and is estimated to have arisen ∼5.5 thousand years (∼220 generations) ago, which coincides with the period of Austronesian expansion. Owing to the long history of endemic malaria in NB, the putative signature of positive selection is postulated to be driven by Plasmodium parasite infection. The findings of this study imply that despite high levels of genetic differentiation, the NB populations might have experienced similar local genetic adaptation resulting from stresses of the shared environment.
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http://dx.doi.org/10.1093/gbe/evaa207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738747PMC
December 2020

Analysis of five deep-sequenced trio-genomes of the Peninsular Malaysia Orang Asli and North Borneo populations.

BMC Genomics 2019 Nov 12;20(1):842. Epub 2019 Nov 12.

Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

Background: Recent advances in genomic technologies have facilitated genome-wide investigation of human genetic variations. However, most efforts have focused on the major populations, yet trio genomes of indigenous populations from Southeast Asia have been under-investigated.

Results: We analyzed the whole-genome deep sequencing data (~ 30×) of five native trios from Peninsular Malaysia and North Borneo, and characterized the genomic variants, including single nucleotide variants (SNVs), small insertions and deletions (indels) and copy number variants (CNVs). We discovered approximately 6.9 million SNVs, 1.2 million indels, and 9000 CNVs in the 15 samples, of which 2.7% SNVs, 2.3% indels and 22% CNVs were novel, implying the insufficient coverage of population diversity in existing databases. We identified a higher proportion of novel variants in the Orang Asli (OA) samples, i.e., the indigenous people from Peninsular Malaysia, than that of the North Bornean (NB) samples, likely due to more complex demographic history and long-time isolation of the OA groups. We used the pedigree information to identify de novo variants and estimated the autosomal mutation rates to be 0.81 × 10 - 1.33 × 10, 1.0 × 10 - 2.9 × 10, and ~ 0.001 per site per generation for SNVs, indels, and CNVs, respectively. The trio-genomes also allowed for haplotype phasing with high accuracy, which serves as references to the future genomic studies of OA and NB populations. In addition, high-frequency inherited CNVs specific to OA or NB were identified. One example is a 50-kb duplication in DEFA1B detected only in the Negrito trios, implying plausible effects on host defense against the exposure of diverse microbial in tropical rainforest environment of these hunter-gatherers. The CNVs shared between OA and NB groups were much fewer than those specific to each group. Nevertheless, we identified a 142-kb duplication in AMY1A in all the 15 samples, and this gene is associated with the high-starch diet. Moreover, novel insertions shared with archaic hominids were identified in our samples.

Conclusion: Our study presents a full catalogue of the genome variants of the native Malaysian populations, which is a complement of the genome diversity in Southeast Asians. It implies specific population history of the native inhabitants, and demonstrated the necessity of more genome sequencing efforts on the multi-ethnic native groups of Malaysia and Southeast Asia.
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http://dx.doi.org/10.1186/s12864-019-6226-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852992PMC
November 2019

PGG.SNV: understanding the evolutionary and medical implications of human single nucleotide variations in diverse populations.

Genome Biol 2019 10 22;20(1):215. Epub 2019 Oct 22.

Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, CAS, Shanghai, 200031, China.

Despite the tremendous growth of the DNA sequencing data in the last decade, our understanding of the human genome is still in its infancy. To understand the implications of genetic variants in the light of population genetics and molecular evolution, we developed a database, PGG.SNV ( https://www.pggsnv.org ), which gives much higher weight to previously under-investigated indigenous populations in Asia. PGG.SNV archives 265 million SNVs across 220,147 present-day genomes and 1018 ancient genomes, including 1009 newly sequenced genomes, representing 977 global populations. Moreover, estimation of population genetic diversity and evolutionary parameters is available in PGG.SNV, a unique feature compared with other databases.
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http://dx.doi.org/10.1186/s13059-019-1838-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805450PMC
October 2019

Prevalence, intensity and associated risk factors of soil transmitted helminth infections: A comparison between Negritos (indigenous) in inland jungle and those in resettlement at town peripheries.

PLoS Negl Trop Dis 2019 04 22;13(4):e0007331. Epub 2019 Apr 22.

Department of Parasitology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

Background: Formerly known as the Malaysian hunter gatherers, the Negrito Orang Asli (OA) were heavily dependent on the forest for sustenance and early studies indicated high prevalence of intestinal parasitism. Initiation of a redevelopment program in the 1970s aimed to demarginalize the OA was expected to reduce soil transmitted helminth (STH) infections. Gradually, the OA were relocated to new resettlement areas at the peripheries. The aim of this study was to compare STH infections between Negritos who are still living in the inland jungle with those living in resettlements.

Methodology/principal Findings: A total of 416 Negrito participants were grouped into two categories of communities based on location; Inland Jungle Villages (IJV); and Resettlement Plan Scheme (RPS). Iodine wet mount, formalin-ether sedimentation, modified Trichrome and modified Ziehl-Neelsen staining and Kato-Katz methods were performed on stool samples. A questionnaire was used to collect information regarding demographic, socioeconomic, environmental and hygiene behaviors. Prevalence of STH was significantly higher in IJV (91.3%) versus RPS (83.1%) (P = 0.02). However, the percentage of individuals with severe intensity of Trichuris trichiura infections was significantly higher in the RPS (17.2%) compared to IJV (6.5%) (P = 0.01). Severe Ascaris lumbricoides infection was observed at 20.0% amongst RPS Negritos and 15.0% amongst IJV (P = 0.41). Whilst for hookworm infection, both prevalence and individuals with moderate to severe infections were higher in the IJV (26.2%, 41.0%) versus RPS (18.7%, 24.0%) (P values = 0.08, 0.09), accordingly. The prevalence other intestinal parasitic infections (e.g. Entamoeba sp., Blastocystis and flukes) was also higher in IJV versus RPS. Apart from poor hygienic behaviors as significant risk factors in both communities, low socio-economic status was highly associated with STH infections in RPS (P<0.001) but not significantly associated in IJV.

Conclusions: The findings showed that ex situ development plan by RPS has not profoundly contributed to the STH reduction among the OA. Conversely, burden rate of T. trichiura infections increased due to their extreme poverty and poor hygienic behaviors. Here, we are suggesting biannual mass albendazole intervention (triple dose regimens in RPS, but a single dose in IJV) and community empowerment to both communities. For a long-term and better uptake, these strategies must be done together with the community input and participation, respecting their traditional customs and accompanied by recruitment of more OA people in the health-care taskforce.
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http://dx.doi.org/10.1371/journal.pntd.0007331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497322PMC
April 2019

Natural selection and local adaptation of blood pressure regulation and their perspectives on precision medicine in hypertension.

Hereditas 2019 7;156. Epub 2019 Jan 7.

1Faculty of Medicine and Health Sciences, UCSI University, Cheras, 56000 Kuala Lumpur, Malaysia.

Prevalence of hypertension (HTN) varies substantially across different populations. HTN is not only common - affecting at least one third of the world's adult population - but is also the most important driver for cardiovascular diseases. Yet up to a third of hypertensive patients are resistant to therapy, contributed by secondary hypertension but more commonly the hitherto inability to precisely predict response to specific antihypertensive agents. Population and individual genomics information could be useful in guiding the selection and predicting the response to treatment - an approach known as precision medicine. However this cannot be achieved without the knowledge of genetic variations that influence blood pressure (BP). A number of evolutionary factors including population demographics and forces of natural selection may be involved. This article explores some ideas on how natural selection influences BP regulation in ethnically and geographically diverse populations that could lead to them being susceptible to HTN. We explore how such evolutionary factors could impact the implementation of precision medicine in HTN. Finally, in order to ensure the success of precision medicine in HTN, we call for more initiatives to understand the genetic architecture within and between diverse populations with ancestry from different parts of the world, and to precisely classify the intermediate phenotypes of HTN.
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http://dx.doi.org/10.1186/s41065-019-0080-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323824PMC
March 2019

Observational study of the status of coronary risk biomarkers among Negritos with metabolic syndrome in the east coast of Malaysia.

BMJ Open 2018 12 4;8(12):e021580. Epub 2018 Dec 4.

Faculty of Medicine and Health Sciences, UCSI University, Cheras, Kuala Lumpur, Malaysia.

Objectives: To determine the prevalence of metabolic syndrome (MS), ascertain the status of coronary risk biomarkers and establish the independent predictors of these biomarkers among the Negritos.

Settings: Health screening programme conducted in three inland settlements in the east coast of Malaysia and Peninsular Malaysia.

Subjects: 150 Negritos who were still living in three inland settlements in the east coast of Malaysia and 1227 Malays in Peninsular Malaysia. These subjects were then categorised into MS and non-MS groups based on the International Diabetes Federation (IDF) consensus worldwide definition of MS and were recruited between 2010 and 2015. The subjects were randomly selected and on a voluntary basis.

Primary And Secondary Outcome Measures: This study was a cross-sectional study. Serum samples were collected for analysis of inflammatory (hsCRP), endothelial activation (sICAM-1) and prothrombogenesis [lp(a)] biomarkers.

Results: MS was significantly higher among the Malays compared with Negritos (27.7%vs12.0%). Among the Malays, MS subjects had higher hsCRP (p=0.01) and sICAM-1 (p<0.05) than their non-MS counterpart. There were no significant differences in all the biomarkers between MS and the non-MS Negritos. However, when compared between ethnicity, all biomarkers were higher in Negritos compared with Malays (p<0.001). Binary logistic regression analysis affirmed that Negritos were an independent predictor for Lp(a) concentration (p<0.001).

Conclusions: This study suggests that there may possibly be a genetic influence other than lifestyle, which could explain the lack of difference in biomarkers concentration between MS and non-MS Negritos and for Negritos predicting Lp(a).
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http://dx.doi.org/10.1136/bmjopen-2018-021580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286619PMC
December 2018

Genetic polymorphism and natural selection in the C-terminal 42 kDa region of merozoite surface protein-1 (MSP-1) among Plasmodium knowlesi samples from Malaysia.

Parasit Vectors 2018 Dec 5;11(1):626. Epub 2018 Dec 5.

Department of Parasitology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.

Background: The merozoite surface protein-1 (MSP-1) gene encodes for a leading malaria vaccine candidate antigen. However, its extensive polymorphic nature represents a major obstacle to the development of a protective vaccine. Previously, a pilot study was carried out to explore the sequence variation of the C-terminal 42 kDa fragment within P. knowlesi MSP-1 gene (PkMSP-1) based on 12 clinical samples; however, further study on an adequate sample size is vital in estimating the genetic diversity of the parasite population.

Methods: In the present study, we included a larger sample size of P. knowlesi (83 samples) covering eight states of Malaysia to determine the genetic polymorphism, natural selection and haplotype groups of the gene fragment coding PkMSP-1. The region flanking PkMSP-1 was amplified by PCR and directly sequenced. Genetic diversity, haplotype diversity, population genetic differentiation and natural selection were determined in order to study the polymorphic characteristic of PkMSP-1.

Results: A high level of genetic diversity (Hd = 0.970 ± 0.007; л = 0.01079 ± 0.00033) was observed among the 83 P. knowlesi samples, confirming the extensive genetic polymorphism exhibited among the P. knowlesi population found in Malaysia. A total of 18 distinct haplotypes with 17 amino acid changes were identified, whereby 15 were new haplotypes. High population differentiation values were observed within samples from Peninsular Malaysia and Malaysian Borneo. The 42 kDa fragments of P. knowlesi from Malaysian Borneo were found to be acting on balancing selection whilst purifying selection was suggested to act on isolates from Peninsular Malaysia. The separation of PkMSP-1 haplotypes into two main groups based on geographical separation has further supported the existence of two distinct P. knowlesi lineages.

Conclusions: A high level of genetic diversity was observed among PkMSP-1 in Malaysia, whereby most of the polymorphisms were found within the 33 kDa region. Taken together, these data will be useful in order to understand the nature of P. knowlesi population in Malaysia as well as the design and development of a MSP-1 based knowlesi malaria vaccine.
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http://dx.doi.org/10.1186/s13071-018-3234-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282282PMC
December 2018

Genetic relatedness of indigenous ethnic groups in northern Borneo to neighboring populations from Southeast Asia, as inferred from genome-wide SNP data.

Ann Hum Genet 2018 07 9;82(4):216-226. Epub 2018 Mar 9.

Biotechnology Research Institute, Universiti Malaysia Sabah, Jalan UMS, Sabah, Malaysia.

The region of northern Borneo is home to the current state of Sabah, Malaysia. It is located closest to the southern Philippine islands and may have served as a viaduct for ancient human migration onto or off of Borneo Island. In this study, five indigenous ethnic groups from Sabah were subjected to genome-wide SNP genotyping. These individuals represent the "North Borneo"-speaking group of the great Austronesian family. They have traditionally resided in the inland region of Sabah. The dataset was merged with public datasets, and the genetic relatedness of these groups to neighboring populations from the islands of Southeast Asia, mainland Southeast Asia and southern China was inferred. Genetic structure analysis revealed that these groups formed a genetic cluster that was independent of the clusters of neighboring populations. Additionally, these groups exhibited near-absolute proportions of a genetic component that is also common among Austronesians from Taiwan and the Philippines. They showed no genetic admixture with Austro-Melanesian populations. Furthermore, phylogenetic analysis showed that they are closely related to non-Austro-Melansian Filipinos as well as to Taiwan natives but are distantly related to populations from mainland Southeast Asia. Relatively lower heterozygosity and higher pairwise genetic differentiation index (F ) values than those of nearby populations indicate that these groups might have experienced genetic drift in the past, resulting in their differentiation from other Austronesians. Subsequent formal testing suggested that these populations have received no gene flow from neighboring populations. Taken together, these results imply that the indigenous ethnic groups of northern Borneo shared a common ancestor with Taiwan natives and non-Austro-Melanesian Filipinos and then isolated themselves on the inland of Sabah. This isolation presumably led to no admixture with other populations, and these individuals therefore underwent strong genetic differentiation. This report contributes to addressing the paucity of genetic data on representatives from this strategic region of ancient human migration event(s).
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http://dx.doi.org/10.1111/ahg.12246DOI Listing
July 2018

A genome-wide characterization of copy number variations in native populations of Peninsular Malaysia.

Eur J Hum Genet 2018 06 23;26(6):886-897. Epub 2018 Feb 23.

Chinese Academy of Sciences (CAS), Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai, 200031, China.

Copy number variations (CNVs) are genomic structural variations that result from the deletion or duplication of large genomic segments. The characterization of CNVs is largely underrepresented, particularly those of indigenous populations, such as the Orang Asli in Peninsular Malaysia. In the present study, we first characterized the genome-wide CNVs of four major native populations from Peninsular Malaysia, including the Malays and three Orang Asli populations; namely, Proto-Malay, Senoi, and Negrito (collectively called PM). We subsequently assessed the distribution of CNVs across the four populations. The resulting global CNV map revealed 3102 CNVs, with an average of more than 100 CNVs per individual. We identified genes harboring CNVs that are highly differentiated between PM and global populations, indicating that these genes are predominantly enriched in immune responses and defense functions, including APOBEC3A_B, beta-defensin genes, and CCL3L1, followed by other biological functions, such as drug and toxin metabolism and responses to radiation, suggesting some attributions between CNV variations and adaptations of the PM groups to the local environmental conditions of tropical rainforests.
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http://dx.doi.org/10.1038/s41431-018-0120-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974366PMC
June 2018

Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia.

Hum Genet 2018 Feb 30;137(2):161-173. Epub 2018 Jan 30.

Faculty of Medicine and Health Sciences, UCSI University, Jalan Menara Gading, Taman Connaught, Cheras, 56000, Kuala Lumpur, Malaysia.

Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50-33 thousand years ago (kya), followed by East Asian (~ 40-15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.
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http://dx.doi.org/10.1007/s00439-018-1869-0DOI Listing
February 2018

Characterising private and shared signatures of positive selection in 37 Asian populations.

Eur J Hum Genet 2017 04 18;25(4):499-508. Epub 2017 Jan 18.

Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

The Asian Diversity Project (ADP) assembled 37 cosmopolitan and ethnic minority populations in Asia that have been densely genotyped across over half a million markers to study patterns of genetic diversity and positive natural selection. We performed population structure analyses of the ADP populations and divided these populations into four major groups based on their genographic information. By applying a highly sensitive algorithm haploPS to locate genomic signatures of positive selection, 140 distinct genomic regions exhibiting evidence of positive selection in at least one population were identified. We examined the extent of signal sharing for regions that were selected in multiple populations and observed that populations clustered in a similar fashion to that of how the ancestry clades were phylogenetically defined. In particular, populations predominantly located in South Asia underwent considerably different adaptation as compared with populations from the other geographical regions. Signatures of positive selection present in multiple geographical regions were predicted to be older and have emerged prior to the separation of the populations in the different regions. In contrast, selection signals present in a single population group tended to be of lower frequencies and thus can be attributed to recent evolutionary events.
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http://dx.doi.org/10.1038/ejhg.2016.181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386408PMC
April 2017

Rare Copy Number Variants Identified Suggest the Regulating Pathways in Hypertension-Related Left Ventricular Hypertrophy.

PLoS One 2016 1;11(3):e0148755. Epub 2016 Mar 1.

UCSI University, Jalan Menara Gading, UCSI Heights, 56000 Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia.

Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality, and a powerful predictor of adverse cardiovascular outcomes in the hypertensive patients. It has complex multifactorial and polygenic basis for its pathogenesis. We hypothesized that rare copy number variants (CNVs) contribute to the LVH pathogenesis in hypertensive patients. Copy number variants (CNV) were identified in 258 hypertensive patients, 95 of whom had LVH, after genotyping with a high resolution SNP array. Following stringent filtering criteria, we identified 208 rare, or private CNVs that were only present in our patients with hypertension related LVH. Preliminary findings from Gene Ontology and pathway analysis of this study confirmed the involvement of the genes known to be functionally involved in cardiac development and phenotypes, in line with previously reported transcriptomic studies. Network enrichment analyses suggested that the gene-set was, directly or indirectly, involved in the transcription factors regulating the "foetal cardiac gene programme" which triggered the hypertrophic cascade, confirming previous reports. These findings suggest that multiple, individually rare copy number variants altering genes may contribute to the pathogenesis of hypertension-related LVH. In summary, we have provided further supporting evidence that rare CNV could potentially impact this common and complex disease susceptibility with lower heritability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148755PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773219PMC
July 2016

Dissecting the genetic structure and admixture of four geographical Malay populations.

Sci Rep 2015 Sep 23;5:14375. Epub 2015 Sep 23.

Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

The Malay people are an important ethnic composition in Southeast Asia, but their genetic make-up and population structure remain poorly studied. Here we conducted a genome-wide study of four geographical Malay populations: Peninsular Malaysian Malay (PMM), Singaporean Malay (SGM), Indonesian Malay (IDM) and Sri Lankan Malay (SLM). All the four Malay populations showed substantial admixture with multiple ancestries. We identified four major ancestral components in Malay populations: Austronesian (17%-62%), Proto-Malay (15%-31%), East Asian (4%-16%) and South Asian (3%-34%). Approximately 34% of the genetic makeup of SLM is of South Asian ancestry, resulting in its distinct genetic pattern compared with the other three Malay populations. Besides, substantial differentiation was observed between the Malay populations from the north and the south, and between those from the west and the east. In summary, this study revealed that the genetic identity of the Malays comprises a mixed entity of multiple ancestries represented by Austronesian, Proto-Malay, East Asian and South Asian, with most of the admixture events estimated to have occurred 175 to 1,500 years ago, which in turn suggests that geographical isolation and independent admixture have significantly shaped the genetic architectures and the diversity of the Malay populations.
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http://dx.doi.org/10.1038/srep14375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585825PMC
September 2015

Fine-scale population structure of Malays in Peninsular Malaysia and Singapore and implications for association studies.

Hum Genomics 2015 Jul 22;9:16. Epub 2015 Jul 22.

Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

Fine scale population structure of Malays - the major population in Malaysia, has not been well studied. This may have important implications for both evolutionary and medical studies. Here, we investigated the population sub-structure of Malay involving 431 samples collected from all states from peninsular Malaysia and Singapore. We identified two major clusters of individuals corresponding to the north and south peninsular Malaysia. On an even finer scale, the genetic coordinates of the geographical Malay populations are in correlation with the latitudes (R(2) = 0.3925; P = 0.029). This finding is further supported by the pairwise FST of Malay sub-populations, of which the north and south regions showed the highest differentiation (FST [North-south] = 0.0011). The collective findings therefore suggest that population sub-structure of Malays are more heterogenous than previously expected even within a small geographical region, possibly due to factors like different genetic origins, geographical isolation, could result in spurious association as demonstrated in our analysis. We suggest that cautions should be taken during the stage of study design or interpreting the association signals in disease mapping studies which are expected to be conducted in Malay population in the near future.
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http://dx.doi.org/10.1186/s40246-015-0039-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509480PMC
July 2015

A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence.

Am J Hum Genet 2015 Jul 11;97(1):54-66. Epub 2015 Jun 11.

Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China; Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China. Electronic address:

Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a method developed in this study, we detected in microarray data a Tibetan-enriched deletion (TED) carried by 90% of Tibetans; 50% were homozygous for the deletion, whereas only 3% carried the TED and 0% carried the homozygous deletion in 2,792 worldwide samples (p < 10(-15)). We employed long PCR and Sanger sequencing technologies to determine the exact copy number and breakpoints of the TED in 70 additional Tibetan and 182 diverse samples. The TED had identical boundaries (chr2: 46,694,276-46,697,683; hg19) and was 80 kb downstream of EPAS1. Notably, the TED was in strong linkage disequilibrium (LD; r(2) = 0.8) with EPAS1 variants associated with reduced blood concentrations of hemoglobin. It was also in complete LD with the 5-SNP motif, which was suspected to be introgressed from Denisovans, but the deletion itself was absent from the Denisovan sequence. Correspondingly, we detected that footprints of positive selection for the TED occurred 12,803 (95% confidence interval = 12,075-14,725) years ago. We further whole-genome deep sequenced (>60×) seven Tibetans and verified the TED but failed to identify any other copy-number variations with comparable patterns, giving this TED top priority for further study. We speculate that the specific patterns of the TED resulted from its own functionality in HAA of Tibetans or LD with a functional variant of EPAS1.
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http://dx.doi.org/10.1016/j.ajhg.2015.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572470PMC
July 2015

Unravelling the genetic history of Negritos and indigenous populations of Southeast Asia.

Genome Biol Evol 2015 Apr 14;7(5):1206-15. Epub 2015 Apr 14.

Jeffrey Cheah School of Medicine and Health Sciences, Monash University (Malaysia), Selangor, Malaysia

Indigenous populations of Malaysia known as Orang Asli (OA) show huge morphological, anthropological, and linguistic diversity. However, the genetic history of these populations remained obscure. We performed a high-density array genotyping using over 2 million single nucleotide polymorphisms in three major groups of Negrito, Senoi, and Proto-Malay. Structural analyses indicated that although all OA groups are genetically closest to East Asian (EA) populations, they are substantially distinct. We identified a genetic affinity between Andamanese and Malaysian Negritos which may suggest an ancient link between these two groups. We also showed that Senoi and Proto-Malay may be admixtures between Negrito and EA populations. Formal admixture tests provided evidence of gene flow between Austro-Asiatic-speaking OAs and populations from Southeast Asia (SEA) and South China which suggest a widespread presence of these people in SEA before Austronesian expansion. Elevated linkage disequilibrium (LD) and enriched homozygosity found in OAs reflect isolation and bottlenecks experienced. Estimates based on Ne and LD indicated that these populations diverged from East Asians during the late Pleistocene (14.5 to 8 KYA). The continuum in divergence time from Negritos to Senoi and Proto-Malay in combination with ancestral markers provides evidences of multiple waves of migration into SEA starting with the first Out-of-Africa dispersals followed by Early Train and subsequent Austronesian expansions.
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http://dx.doi.org/10.1093/gbe/evv065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453060PMC
April 2015

Cardio-metabolic health risks in indigenous populations of Southeast Asia and the influence of urbanization.

BMC Public Health 2015 Jan 31;15:47. Epub 2015 Jan 31.

Jeffrey Cheah School of Medicine, Monash University Sunway, Sunway, Malaysia.

Background: South East Asia (SEA) is home to over 30 tribes of indigenous population groups who are currently facing rapid socio-economic change. Epidemiological transition and increased prevalence of non-communicable diseases (NCD) has occured. In Peninsular Malaysia, the Orang Asli (OA) indigenous people comprise 0 · 6% (150,000) of the population and live in various settlements. OA comprise three distinct large tribes with smaller sub-tribes. The three large tribes include Proto-Malay (sub-tribes: Orang Seletar and Jakun), Senoi (sub-tribes: Mahmeri and Semai), and Negrito (sub-tribes: Jehai, Mendriq and Batek).

Methods: We studied the health of 636 OA from seven sub-tribes in the Peninsular. Parameters that were assessed included height, weight, BMI and waist circumference whilst blood pressure, cholesterols, fasting blood glucose and HbA1c levels were recorded. We then analysed cardio-metabolic risk factor prevalences and performed multiple pair-wise comparisons among different sub-tribes and socio-economic clusters.

Results: Cardio-metabolic risk factors were recorded in the seven sub-tribes.. Prevalence for general and abdominal obesity were highest in the urbanized Orang Seletar (31 · 6 ± 5 · 7%; 66 · 1 ± 5 · 9%). Notably, hunter gatherer Jehai and Batek tribes displayed the highest prevalence for hypertension (43 · 8 ± 9 · 29% and 51 · 2 ± 15 · 3%) despite being the leanest and most remote, while the Mendriq sub-tribe, living in the same jungle area with access to similar resources as the Batek were less hypertensive (16.3 ± 11.0%), but displayed higher prevalence of abdominal obesity (27.30 ± 13.16%).

Conclusions: We describe the cardio-metabolic risk factors of seven indigenous communities in Malaysia. We report variable prevalence of obesity, cholesterol, hypertension and diabetes in the OA in contrast to the larger ethnic majorities such as Malays, Chinese and Indians in Malaysia These differences are likely to be due to socio-economic effects and lifestyle changes. In some sub-tribes, other factors including genetic predisposition may also play a role. It is expected that the cardio-metabolic risk factors may worsen with further urbanization, increase the health burden of these communities and strain the government's resources.
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http://dx.doi.org/10.1186/s12889-015-1384-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314805PMC
January 2015

Differential positive selection of malaria resistance genes in three indigenous populations of Peninsular Malaysia.

Hum Genet 2015 Apr 30;134(4):375-92. Epub 2015 Jan 30.

NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, 117456, Singapore.

The indigenous populations from Peninsular Malaysia, locally known as Orang Asli, continue to adopt an agro-subsistence nomadic lifestyle, residing primarily within natural jungle habitats. Leading a hunter-gatherer lifestyle in a tropical jungle environment, the Orang Asli are routinely exposed to malaria. Here we surveyed the genetic architecture of individuals from four Orang Asli tribes with high-density genotyping across more than 2.5 million polymorphisms. These tribes reside in different geographical locations in Peninsular Malaysia and belong to three main ethno-linguistic groups, where there is minimal interaction between the tribes. We first dissect the genetic diversity and admixture between the tribes and with neighboring urban populations. Later, by implementing five metrics, we investigated the genome-wide signatures for positive natural selection of these Orang Asli, respectively. Finally, we searched for evidence of genomic adaptation to the pressure of malaria infection. We observed that different evolutionary responses might have emerged in the different Orang Asli communities to mitigate malaria infection.
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http://dx.doi.org/10.1007/s00439-014-1525-2DOI Listing
April 2015

A comparison of assays for accurate copy number measurement of the low-affinity Fc gamma receptor genes FCGR3A and FCGR3B.

PLoS One 2015 16;10(1):e0116791. Epub 2015 Jan 16.

Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia.

The FCGR3 locus encoding the low affinity activating receptor FcγRIII, plays a vital role in immunity triggered by cellular effector and regulatory functions. Copy number of the genes FCGR3A and FCGR3B has previously been reported to affect susceptibility to several autoimmune diseases and chronic inflammatory conditions. However, such genetic association studies often yield inconsistent results; hence require assays that are robust with low error rate. We investigated the accuracy and efficiency in estimating FCGR3 CNV by comparing Sequenom MassARRAY and paralogue ratio test-restriction enzyme digest variant ratio (PRT-REDVR). In addition, since many genetic association studies of FCGR3B CNV were carried out using real-time quantitative PCR, we have also included the evaluation of that method's performance in estimating the multi-allelic CNV of FCGR3B. The qPCR assay exhibited a considerably broader distribution of signal intensity, potentially introducing error in estimation of copy number and higher false positive rates. Both Sequenom and PRT-REDVR showed lesser systematic bias, but Sequenom skewed towards copy number normal (CN = 2). The discrepancy between Sequenom and PRT-REDVR might be attributed either to batch effects noise in individual measurements. Our study suggests that PRT-REDVR is more robust and accurate in genotyping the CNV of FCGR3, but highlights the needs of multiple independent assays for extensive validation when performing a genetic association study with multi-allelic CNVs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297192PMC
October 2015

The high-affinity human IgG receptor Fc gamma receptor I (FcγRI) is not associated with vascular leakage of dengue.

J Negat Results Biomed 2015 Jan 8;14. Epub 2015 Jan 8.

Institute of Molecular Medical Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, 47000, Sungai Buloh, Selangor, Malaysia.

Background: Dengue is a major public health problem in many tropical and sub-tropical countries. Vascular leakage and shock are identified as the major causes of deaths in patients with severe dengue. Studies have suggested the potential role of Fc gamma receptors I (FcγRI) in the pathogenesis of dengue. We hypothesized that the circulating level of Fcγ receptor I could potentially be used as an indicator in assisting early diagnosis of severe dengue.

Results: A selected cohort of 66 dengue patients including 42 dengue with signs of vascular leakage, and 24 dengue without signs of vascular leakage were identified and were afterwards referred to as 'cases' and 'controls' respectively. Thirty seven normal healthy controls were also recruited in this study. The circulating level of FcγRI was quantified from the serum using enzyme-link immunosorbent assay (ELISA). The levels of FcγRI in both groups of patients with and without vascular leakage were found to be significantly higher than the normal healthy controls (P < 0.001). However, there was no significant difference found between patients with vascular leakage and those without vascular leakage (p = 0.777).

Conclusion: We suggest that FcγRI is not associated with the vascular leakage in dengue. However, further studies are necessary to delineate the role of FcγRI in antibody-dependent enhancement (ADE) mechanism.
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http://dx.doi.org/10.1186/s12952-014-0020-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300171PMC
January 2015

Human gene copy number variation and infectious disease.

Hum Genet 2014 Oct 5;133(10):1217-33. Epub 2014 Jun 5.

Department of Genetics, University of Leicester, University Road, Leicester, LE1 7RH, UK,

Variability in the susceptibility to infectious disease and its clinical manifestation can be determined by variation in the environment and by genetic variation in the pathogen and the host. Despite several successes based on candidate gene studies, defining the host variation affecting infectious disease has not been as successful as for other multifactorial diseases. Both single nucleotide variation and copy number variation (CNV) of the host contribute to the host's susceptibility to infectious disease. In this review we focus on CNV, particularly on complex multiallelic CNV that is often not well characterised either directly by hybridisation methods or indirectly by analysis of genotypes and flanking single nucleotide variants. We summarise the well-known examples, such as α-globin deletion and susceptibility to severe malaria, as well as more recent controversies, such as the extensive CNV of the chemokine gene CCL3L1 and HIV infection. We discuss the potential biological mechanisms that could underly any genetic association and reflect on the extensive complexity and functional variation generated by a combination of CNV and sequence variation, as illustrated by the Fc gamma receptor genes FCGR3A, FCGR3B and FCGR2C. We also highlight some understudied areas that might prove fruitful areas for further research.
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http://dx.doi.org/10.1007/s00439-014-1457-xDOI Listing
October 2014

An evaluation of the World Health Organization's 1997 and 2009 dengue classifications in hospitalized dengue patients in Malaysia.

J Infect Dev Ctries 2014 Jul 14;8(7):869-75. Epub 2014 Jul 14.

Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia.

Introduction: The latest revised version of the World Health Organization's dengue classification was released in 2009. A handful of studies have taken initiatives to evaluate the old and revised guidelines to determine early signs and symptoms of severe dengue. This retrospective study aimed to compare the classification of dengue using both the 1997 and 2009 guidelines in a selected cohort of dengue patients from Peninsular Malaysia between 2008 and 2012.

Methodology: Adult dengue patients were recruited from tertiary hospitals in two different states, Selangor and Kelantan, in Peninsular Malaysia. Their clinical manifestations were assessed.

Results: A total of 281 confirmed dengue patients were enrolled; the mean duration of illness at admission was five days. Of these, 88.6%, 10.7%, and 0.7% were classified according to the 1997 guidelines as having dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), respectively. When the WHO 2009 guidelines were applied, 17.1%, 78.3%, and 4.6% were classified as dengue without warning signs, dengue with warning signs, and severe dengue, respectively.

Conclusions: Our data suggests that the revised WHO 2009 guidelines stratify a much larger proportion of patients into a category that requires a higher level of medical and nursing care.
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http://dx.doi.org/10.3855/jidc.4283DOI Listing
July 2014

The population genomic landscape of human genetic structure, admixture history and local adaptation in Peninsular Malaysia.

Hum Genet 2014 Sep 11;133(9):1169-85. Epub 2014 Jun 11.

Max Planck Independent Research Group on Population Genomics, Chinese Academy of Sciences and Max Planck Society (CAS-MPG) Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.

Peninsular Malaysia is a strategic region which might have played an important role in the initial peopling and subsequent human migrations in Asia. However, the genetic diversity and history of human populations--especially indigenous populations--inhabiting this area remain poorly understood. Here, we conducted a genome-wide study using over 900,000 single nucleotide polymorphisms (SNPs) in four major Malaysian ethnic groups (MEGs; Malay, Proto-Malay, Senoi and Negrito), and made comparisons of 17 world-wide populations. Our data revealed that Peninsular Malaysia has greater genetic diversity corresponding to its role as a contact zone of both early and recent human migrations in Asia. However, each single Orang Asli (indigenous) group was less diverse with a smaller effective population size (N(e)) than a European or an East Asian population, indicating a substantial isolation of some duration for these groups. All four MEGs were genetically more similar to Asian populations than to other continental groups, and the divergence time between MEGs and East Asian populations (12,000--6,000 years ago) was also much shorter than that between East Asians and Europeans. Thus, Malaysian Orang Asli groups, despite their significantly different features, may share a common origin with the other Asian groups. Nevertheless, we identified traces of recent gene flow from non-Asians to MEGs. Finally, natural selection signatures were detected in a batch of genes associated with immune response, human height, skin pigmentation, hair and facial morphology and blood pressure in MEGs. Notable examples include SYN3 which is associated with human height in all Orang Asli groups, a height-related gene (PNPT1) and two blood pressure-related genes (CDH13 and PAX5) in Negritos. We conclude that a long isolation period, subsequent gene flow and local adaptations have jointly shaped the genetic architectures of MEGs, and this study provides insight into the peopling and human migration history in Southeast Asia.
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http://dx.doi.org/10.1007/s00439-014-1459-8DOI Listing
September 2014

Systematic pharmacogenomics analysis of a Malay whole genome: proof of concept for personalized medicine.

PLoS One 2013 23;8(8):e71554. Epub 2013 Aug 23.

Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM) Malaysia, Puncak Alam, Selangor, Malaysia.

Background: With a higher throughput and lower cost in sequencing, second generation sequencing technology has immense potential for translation into clinical practice and in the realization of pharmacogenomics based patient care. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the next step in future medicine in line with the vision of personalizing medicine.

Methods: Genomic DNA obtained from a 55 years old, self-declared healthy, anonymous male of Malay descent was sequenced. The subject's mother died of lung cancer and the father had a history of schizophrenia and deceased at the age of 65 years old. A systematic, intuitive computational workflow/pipeline integrating custom algorithm in tandem with large datasets of variant annotations and gene functions for genetic variations with pharmacogenomics impact was developed. A comprehensive pathway map of drug transport, metabolism and action was used as a template to map non-synonymous variations with potential functional consequences.

Principal Findings: Over 3 million known variations and 100,898 novel variations in the Malay genome were identified. Further in-depth pharmacogenetics analysis revealed a total of 607 unique variants in 563 proteins, with the eventual identification of 4 drug transport genes, 2 drug metabolizing enzyme genes and 33 target genes harboring deleterious SNVs involved in pharmacological pathways, which could have a potential role in clinical settings.

Conclusions: The current study successfully unravels the potential of personal genome sequencing in understanding the functionally relevant variations with potential influence on drug transport, metabolism and differential therapeutic outcomes. These will be essential for realizing personalized medicine through the use of comprehensive computational pipeline for systematic data mining and analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071554PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751891PMC
April 2014

Mapping human genetic diversity in Asia.

Science 2009 Dec;326(5959):1541-5

Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations.
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http://dx.doi.org/10.1126/science.1177074DOI Listing
December 2009