Identifying founder variants in the Maltese population via identity by descent

Abstract

The genetic architecture of populations has been significantly shaped by various evolutionary mechanisms. Bottleneck and founder effects cause an enrichment of variants known as founder variants, and their frequency tends to be higher than expected in certain populations. Founder variants are inherited across generations as part of a haplotype block. This leads to the occurrence of a shared pattern of genetic variation between individuals who share a common ancestor, a process known as Identity-by-Descent (IBD). The small population and geographical position of Malta made the island susceptible to many invasion and migration events, increasing the likelihood of founder effects. One Maltese founder variant has been recorded; related to 5,6,7,8-tetrahydrobiopterin deficiency (QDPR p.Gly23Asp). Identification of more founder variants would allow for a more specific approach in genetic testing of the Maltese population and the development of preventive measures and treatments, saving lives and resources. In this dissertation 1,076 Maltese genomes were used to analyse a list of variants and identify whether IBD segments can be used to determine the variant’s founder status in the Maltese. The benchmarking tool IBD Benchmark was used to test six IBD detection tools and identify the best performing one. This was optimised and used to perform IBD detection on a representative Maltese dataset. A list of variants of interest to the Maltese population was compiled, consisting of 15 variants locally relevant to a variety of disorders. A bioinformatics pipeline was developed to generate horizontal bar plots, heatmaps and variant genetic frameworks for founder variant analysis. Six variants were found to be very likely founder variants of the Maltese population. The heatmaps showed these variants as part of a genetic framework, which is shared among all of the individuals that have the variant. Four variants remained inconclusive upon interpretation of the results, while no IBD segments were detected for five other variants. Having successfully met the key objectives of this study, numerous avenues for further research into founder variants have emerged. The bioinformatics pipeline developed in this project can be applied to any other variant, facilitating the process of identifying founder variants.