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Genomics in the Understanding of Human Origins and Disease in Southeast Asia

Saturday 21 March 2015, 1630 – 1830, Lecture Theatre 5

Stephen Oppenheimer
University of Oxford

Stephen Oppenheimer
University of Oxford

Southeast Asia (SEA) is culturally and genetically the most diverse region of East Asia and retains the richest record of initial founding genetic diversity in Eurasia, from the  modern human exit from Africa c. 60Ka. This diversity is reflected in the distribution of ancient infectious diseases and the genetic defences against them. A subset of this human founding diversity moved north into China before and around the Last Glacial Maximum (LGM). From the end of the LGM onwards, sea level rise and land loss in the Sunda shelf of SEA resulted in southward recolonisation from northern Mainland SEA (MSEA), with greatest effects in southern MSEA, but also substantially into what is now ISEA via land-bridges. This north south gene flow continued and increased into the Neolithic period, but mainly into the Malay Peninsula and is most clearly delineated as intrusive among non-hunter-gatherer Orang Asli populations of the south but is also seen among Malay populations, who have comparatively more indigenous Sunda lineages and less from ISEA except in recent settlements, less than 5% of the ISEA component is likely derived from Taiwan.


Paper 1: The Maternal Ancestry of the Orang Asli in Peninsular Malaysia

Sean K. K. Eng
Universiti Sains Malaysia

Complete mitochondrial DNA (mtDNA) genome sequences allow the high-resolution reconstruction of phylogenetic relationships between lineages, along with relatively accurate and precise dating of nodes and, by inference, migration events. MtDNA analysis of Orang Asli groups from the Malay Peninsula has hitherto been restricted to a small number of populations and largely based on the mtDNA control region hypervariable segment I (HVS-I), supplemented by a small number of whole-mtDNA genomes. We have expanded the number of Orang Asli populations (Semang, Senoi and Aboriginal Malays) examined for HVS-I and analysed 40 lineages at the level of whole-mtDNA genomes covering most of the extant Orang Asli mtDNA diversity. We used these data to help us reassess and extend some of the suggestions about the prehistory of the region, put forward on the basis of the earlier, more limited datasets. We also compared the Orang Asli lineages with the Peninsular Malays and Southeast Asians’ variation, in order to elucidate past dispersals and admixture of maternal ancestry. Our work has confirmed that the Orang Asli populations indeed experienced high genetic drift, likely due to their extremely small group sizes and population subdivision. All Orang Asli groups have local roots that trace back to ~50 ka, and all have been affected to a greater or lesser extent by subsequent migrations to Peninsular Malaysia. The Semang and Senoi show less haplogroup diversity than the Aboriginal Malays, although the latter have some indigenous ancestry that is as deep as that of the Semang and Senoi in Peninsular Malaysia.

Paper 2: Genetic prehistory of Mainland Southeast Asia over the past 60 ka, from a mitochondrial DNA perspective

Stephen Oppenheimer
University of Oxford

Anatomically Modern Humans colonised Island and Mainland Southeast Asia (ISEA&MSEA) 50-60 kyr ago when the Sunda shelf (or Sundaland) was continuous dry land from Thailand to Bali. Substantial levels (c. 50%) of founding-source genetic diversity still persists locally, as indicated by ancient, uniquely-local surviving mitochondrial (mtDNA) lineages in mainstream populations throughout SEA. Different degrees of this Sunda-Pleistocene local-founder persistence can be seen in MSEA, the greatest being among the three aboriginal (Orang Asli) populations of the southern interior (76%-94%), and lower in pre-colonial mainstream MSEA populations: 56% in West Malaysia, and 44% in rural Northern MSEA (Laos). The MSEA/Sunda region was geographically the main route for Palaeolithic colonising lineage-expansions north to China, Japan and Eastern Siberia. Such south-north movements can be inferred from mtDNA phylogeography, and are also reflected in relevant population-based PCA analysis. From 25 ka onwards, SEA received multiple southward-colonisations of derived mtDNA lineages from East Asia, mostly descended from the original NMSEA founders (e.g. R9, M9), but some East Asian lineages (e.g. derivatives of A,B,D, M7, M8, N9) returning from South China back south into MSEA/ISEA. Throughout the Holocene, more internal movement and expansion of these intrusive lineages occurred within SEA, partly associated with the Neolithic but, as far as MSEA was concerned, mainly confined within MSEA. Looked at from this Holocene perspective of internal Sunda migration, even larger proportions (86%-100%) of the three Orang Asli populations of the southern interior of MSEA could be described as ‘locally derived’, including lineages arriving from NMSEA during the Neolithic.


Paper 3: The Oceanian Genome Variation Project: Understanding Asia-Pacific Population Structure, History, and Diversity through Human Genotyping

Alexander Mentzer
University of Oxford

Background: Understanding the origin of the Island inhabitants of Asia and the Pacific is a topic of major historical interest. Yet it remains one of the largest geographic areas in the world to be under-represented in modern surveys of genome variation. Technological advancements in human genetics now provide the opportunity to test existing theories of settlement and potentially make novel discoveries relating to Pacific Island history through insights into migration patterns and population admixture.

Methods: The Oceanian Genome Variation Project is a collaboration between the Universities of Oxford and Stanford that will direct the genetic analysis of over 2500 samples collected from Island residents over several decades. The first phase of analysis will involve dense genome-wide genotyping of approximately 40 individuals from over 30 Island Nations across Asia and the Pacific. This data will be analysed using methods that have estimated the timings and extent of population admixture in other human populations. It is envisaged that this collaboration will faciliate more comprehensive genotyping and eventual sequencing of increasing numbers of diverse population subgroups that will in turn increase our appreciation of Island population heritage and diversity. The resultant genetic data will be released onto publicly available repositories to further facilitate genetics and genomics research and capacity.

Implications: This collaborative effort will not only improve our appreciation of population history throughout Asia and the Pacific but it will also serve as an invaluable resource towards better understanding of the genetic basis of health and disease in the area.

Paper 4: Target identification and mechanism of action of Carica papaya leaf juice in the management of dengue – A genetic approach.

Soobitha Subenthiran
Institute for Medical Research

Dengue is emerging as a serious global concern with more than 40% of the world’s population living at risk of the infection and an estimated 400 million cases reported annually. Scientists have faced challenges in identifying a specific antiviral compound due to the narrow window of viraemia upon diagnosis and significant differences in the viral core proteins among the four serotypes. In the absence of any specifying therapy, in recent times researchers have resorted to exploring the scientific value of traditional therapies. Carica papaya leaf juice (CPLJ) have been traditionally used in the treatment of dengue in many parts of Asia. A clinical trial using CPLJ on dengue patients conducted in Malaysia demonstrated the acceleration of thrombocytosis (p<0.001) at 40 hours since the initiation of treatment and defervescence of fever (p=0.02) as well as the amelioration of disease progression. Preliminary findings showed that the ALOX 12 (FC=15.00), PTAFR (FC=13.42) and the PDE4D (FC=7.14) were highly expressed among patients who received the juice as compared to the control group. The current approach focuses on identifying the mechanism by which CPLJ, treated as a single entity, is able to induce an immune-modulatory cascade which will address the pressing issue of plasma leakage. Expression as well as down regulation of targeted genes which were previously shown to be associated with plasma leakage shall be determined by conducting gene expression studies using the highly specific Taqman probe based real time PCR techniques and the findings analysed using the comparative critical threshold method.