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

Abstract

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 (~ 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− 8 – 1.33 × 10− 8, 1.0 × 10− 9 – 2.9 × 10− 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.

Improvement of large copy number variant detection by whole genome nanopore sequencing

“…As reported, this issue seemed to be worse for larger CNVs, and more recent tools have not improved this, and the problem does not seem to be observed or addressed. Large CNVs, and SVs in general, are still of interest for the impact they have [17] – [19] . We presented that the coverage analysis from the same sequencing experiment that was used to call variants could alleviate the problem.…”

“…As we demonstrate, this seems to be worse for larger (>50 kb) SVs. While these variants may be less common, they are linked to neurological and rare diseases [17] , are associated to blood serum levels of biological compounds [18] and may be linked to adaptations to different environments of human populations [19] ; therefore, detecting them accurately is of scientific interest.…”

The indigenous populations as the model by nature to understand human genomic‐phenomics interactions

“…Archaeological and population genetic studies suggest the possibility of these populations inhabiting the Southeast Asia region more than 50,000 years ago [54,55]. Although genome sequencing of these populations has been reported, such research has been rather modest [54,56] compared to many genome sequencing initiatives worldwide.…”

“…Indeed, most global largescale genomic research studies lack representation of indigenous populations (to name a few, the HapMap Project; 1,000 Genomes Project; Genome Aggregation Database (gnomAD); Simons Genome Diversity Project). Unfortunately, only a handful of studies reported their respective genomic structures and population histories [56,[63][64][65][66][67][68][69][70]. Studies that correlate their genomic structure and phenotypes have been primarily focusing on identifying signatures of positive selection [71][72][73][74].…”