De novo assembly of an admixed South African genome and its clinical application to genetic susceptibility to tuberculosis

Despite ongoing efforts, the current human reference genome lacks diversity. Consequently, research using this resource might miss disease-causing variants in individuals whose ancestry does not correspond to that of the standard reference. Most individuals from South Africa are admixed to some extent, with ancestral contributions from several continental populations. This study set out to create a population-specific reference genome for admixed South Africans with the same coordinate system as the widely used GRCh38 reference. This approach was tested in diagnosing a South African individual with Mendelian susceptibility to mycobacterial disease (MSMD) using a novel approach that replaced portions of the reference genome with corresponding, but more variable portions of the population-specific sequences. We implemented the algorithm in a tool we named PopPatch. Short sequencing reads from two individuals were used for a rudimentary genome assembly which was then aligned to GRCh38p13. To test the algorithm and the generated reference genome, whole genome sequencing data from a TB-susceptible individual was aligned to SA_PopPatch and GRCh38, with variant call sets compared. The GRCh38p13 reference yielded no discoveries, while the SA_PopPatch reference identified a homozygous, non-synonymous single nucleotide variant in exon 20 of the JAK1 gene. This project introduces a novel method for creating population-specific reference genomes that align with the standard reference, ensuring congruency with databases based on the most widely used reference genome, GRCh38, while minimizing additional costs.