A Comprehensive Genomic Insight into Unique Genetic Features of the Bruneian Malays unraveled through Whole-Genome Sequencing and Genotyping Data Analysis. Homo sapiens

Although the number of human genomes sequenced has recently reached the million landmark, population genomics of the Southeast Asian Malays remains very much understudied. This is especially true for the Malays in Brunei where only two were sequenced and a handful other genotyped very recently. Aiming to gain further genomic insights into the Malay population in Brunei, the raw whole-genome sequencing data of two local Malays were first mapped against the latest human reference genome. Short genetic variations, specifically short nucleotide polymorphisms (SNPs) and insertions/deletions (INDELs), were called using three different variant callers and the consensus set of variants were then merged with genotyping data of the local Malays before being annotated. A total of ~5 million short genetic variants, encompassing ~4.7 million SNPs and ~500 thousand INDELs, were identified from the 41 local Malays. 182,833 of the total variants were novel, i.e., they have not been reported or published in any public genomic databases. Of these, 17,854 were non-synonymous found in the protein coding regions of the genome. Interestingly, some of these non-synonymous variants are predicted to be deleterious and may be associated with disease risk factors, e.g., lung cancer, diabetes mellitus, and asthma, as well as drug responses. In addition to the short variants, regions of either poor or missing coverage were also discovered in the two local genomes; indicating the presence of yet to be discovered novel sequences. Furthermore, principal component and admixture analysis comparing the genetic structure of the local Malays against other Asian populations revealed that the Bruneian Malays were genetically related to some population groups in the Philippines than the Malays in Malaysia and Singapore. Lastly, unlike other whole-genome sequence analysis, the unmapped sequencing reads of the two Malay genomes were further analysed to reveal unique sequences and oral microbiome of the individuals which, to our best knowledge, the first oral microbiome study done in Brunei. There were ~224 Kbp of unique sequences uncovered from both the Malay genomes and one of these sequences was able to translate into a small zinc finger protein. Taken together, our works have uncovered many unique genetic features in the local Bruneian Malay genome. These results can form the basis of precision medicine in the country. Indeed, another side project on the exact identification of the causative genetic factors of osteopetrosis, a rare genetic bone disorder, using whole exome sequence data was also done to demonstrate the application of our work in genomic.