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

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 enrichedhomozygosityfoundinOAsreflectisolationandbottlenecksexperienced.EstimatesbasedonNe andLDindicatedthatthese populationsdivergedfromEastAsiansduringthelatePleistocene(14.5to8KYA).ThecontinuumindivergencetimefromNegritosto 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

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

BackgroundRecent 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.ResultsWe analyzed the whole-genome deep sequencing data (30x) 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 0.81x10(-8) - 1.33x10(-8), 1.0x10(-9) - 2.9x10(-9), 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.ConclusionOur 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

Discerning the origins of the Negritos, First Sundaland People : deep divergence and archaic admixture

Human presence in Southeast Asia dates back to at least40,000 years ago, when the current islands for meda continental shelf called Sundaland. In the Philippine Islands, Peninsular Malaysia, and Andaman Islands, there exist indigenous groups collectively called Negritos whose ancestry can be traced to the “First Sundaland People.” To understand the relationship between these Negrito groupsand theirdemographic histories, wegeneratedgenome-wide single nucleotide polymorphism datain the Philippine Negritos and compared them with existing data from other populations. Phylogenetic tree analyses show that Negritos are basal to other East and Southeast Asians, and that they diverged from West Eurasians at least 38,000 years ago. We also found relatively high traces of Denisovan admixture in the Philippine Negritos, but not in the Malaysian and Andamanese groups, suggesting independent introgression and/or parallel losses involving Denisovan introgressed regions. Shared genetic loci between all three Negrito groups could be related to skin pigmentation, height, facial morphology and malarial resistance. These results show the unique status of Negrito groups as descended from the First Sundaland People

Shared signature of recent positive selection on the TSBP1-BTNL2-HLA-DRA genes in five native populations from North Borneo

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 population sandis estimated to have arisen5.5thousand years(220generations) 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

Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells

Sjögren’s disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren’s cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.Research reported in this publication was supported by the National Institutes of Health (NIH): R01AR073855 (C.J.L.), R01AR065953 (C.J.L.), R01AR074310 (A.D.F.), P50AR060804 (K.L.S.), R01AR050782 (K.L.S), R01DE018209 (K.L.S.), R33AR076803 (I.A.), R21AR079089 (I.A.); NIDCR Sjögren’s Syndrome Clinic and Salivary Disorders Unit were supported by NIDCR Division of Intramural Research at the National Institutes of Health funds - Z01-DE000704 (B.W.); Birmingham NIHR Biomedical Research Centre (S.J.B.); Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2155 – Projektnummer 390874280 (T.W.); Research Council of Norway (Oslo, Norway) – Grant 240421 (TR.R.), 316120 (M.W-H.); Western Norway Regional Health Authority (Helse Vest) – 911807, 912043 (R.O.); Swedish Research Council for Medicine and Health (L.R., G.N., M.W-H.); Swedish Rheumatism Association (L.R., G.N., M.W-H.); King Gustav V’s 80-year Foundation (G.N.); Swedish Society of Medicine (L.R., G.N., M.W-H.); Swedish Cancer Society (E.B.); Sjögren’s Syndrome Foundation (K.L.S.); Phileona Foundation (K.L.S.). The Stockholm County Council (M.W-H.); The Swedish Twin Registry is managed through the Swedish Research Council - Grant 2017-000641. The French ASSESS (Atteinte Systémique et Evolution des patients atteints de Syndrome de Sjögren primitive) was sponsored by Assistance Publique-Hôpitaux de Paris (Ministry of Health, PHRC 2006 P060228) and the French society of Rheumatology (X.M.).publishedVersio

Genetic structure and variation in Negrito, Senoi and Proto-Malay ethnic groups in Malaysia

The indigenous populations of Peninsular Malaysia also known as “Orang Asli” or “original people” are putative isolated populations which comprise approximately 0.6 percent of Malaysia. Orang Aslis are categorized based on their demographic, linguistic and phonotypical characteristics in three subgroups namely Negrito, Senoi and Proto-Malay. The objective of this project was to study genetic structure in Orang Aslis through High-density SNP genotyping and Whole Genome Sequencing (WGS) technologies, and compare them to other population Southeast Asia. The results of our study showed that Malaysian Negritos are genetically distinct from other populations in East and Southeast Asia while other Orang Asli groups such as Senoi and Proto-Malay seemed to be admixed between Negritos and East Asians. We identified a genetic affinity between Andamanese and Malaysian Negritos which may suggest an ancient link between these two groups. Our results also showed gene flow between Austro-Asiatic speaking Orang Aslis and East Asian populations. The existence gene flow between these two major genetic components provided further evidences in support of an “Early Train” hypothesis, which suggests an early migration from Indochina or southern China to mainland Southeast Asia before the “Austronesian Expansion” and after “Out of Africa’ for human dispersal in Asia. Many novel genomic variants have also been discovered from whole-genome sequencing. We also found that Negrito, MahMeri, Seletar and Jakun communities are genetically isolated making them valuable resources for medical genetics researches. Our study also suggests that conventional categorization of Orang Aslis based on linguistics and anthropological characteristics may be incorrect

Prioritising positively selected variants in whole-genome sequencing data using FineMAV

10.1186/s12859-021-04506-9BMC Bioinformatics22160

A genomic insight into the origin and dispersal of Austroasiatic speakers in South and Southeast Asia

India and Southeast Asia are home to diverse linguistic groups; the Austroasiatic language group being one of them. The Austroasiatic speakers live in scattered settlements in these regions. What led to such dispersed distribution over this vast geographical space is yet to be resolved. Our work is aimed at reconstructing the migration route of early Austroasiatic settlers and examines their relationship with other linguistic groups. We genotyped 511 unrelated individuals from India and Malaysia out of which 189 were Austroasiatic. The rest belonged to Indo-European, Dravidian, Tibeto-Burman and Austronesian language families. Jarawa and Onge populations from Andaman and Nicobar Islands were also included. Our genotype data was combined with that of 940 individuals from HGDP dataset. We analyzed nearly 0.3 million autosomal SNPs and found that allele frequency correlation between Malaysian Austroasiatics and Indian Tibeto-Burmans was slightly higher (R2= 0.77) than with Indian Austroasiatics (R2= 0.72). Principal Components Analysis revealed that Malaysian Austroasiatic clustered closer to Tibeto-Burman than to Indian Austroasiatic. Similar clustering pattern was obtained by fineSTRUCTURE cluster dendrogram. The ADMIXTURE analysis inferred genetic component that is modal to the Malaysian Austroasiatic, is also significantly higher amongst Tibeto-Burman than Indian Austroasiatic (P < 2.117e-10), indicating that genetic distance correlates better with geography than language. Studying segments which were Identity by descent between individuals belonging to two different linguistic groups; i.e. Austroasiatic and Tibeto-Burman, we found Tibeto-Burman sharing larger number of segments with Malaysian Austroasiatic, but overall smaller in size. On the other hand the segments shared between the two Austroasiatic populations (India and Malaysia) are comparatively larger in size (P= 0.034) but smaller in number. Our analyses indicate that Malaysian Austroasiatic and Tibeto-Burman initially split from a common ancestor. Then a small group of individuals separated from Malaysian Austroasiatic giving rise to the present day Indian Austroasiatic. Treemix and D-statistics analysis provided evidence for gene flow between Malaysian Austroasiatic and Tibeto-Burman post split. Meanwhile, the southward migration of East Asians resulted in an extensive genetic exchange between East Asians and Tibeto-Burman as was evident in our ADMIXTURE analysis. This subsequent genetic exchange might have shaped the present day language structure