Genetic characterization of variants and population inference through multiple independent pool-seq: The Cyprus Genome Project

The Cyprus Genome project, the first large-scale study of human genetic variation in Cyprus, addresses the island’s complex genetic makeup resulting from its unique geographic location and historical immigration. This intricate genetic heritage, combined with the limitations of existing genetic data in representing the full spectrum of population-level diversity in Cyprus, necessitates a more comprehensive approach to studying the Cypriot gene pool. Here, we present a genetically diverse population study which demonstrates the power of pool-sequencing (pool-seq methodology) using DNA from 10,000 randomly selected healthy bone marrow donors collected over a period of several years. This study highlights the use of pool-seq as a viable way to elucidate both rare and common variants specific to the population which is also a proven, cost-effective and time-efficient method. DNA samples were pooled for whole exome and gene panel sequencing enabling statistical analysis of variant frequencies and read numbers between pools, resulting in confidence intervals. The resulting variant database was validated across established resources like gnomAD and published Cypriot clinical research cohort data, ensuring fidelity. Enhanced sensitivity in (rare) variant detection was achieved by combining WES and gene panel sequencing to maximise read depth. The results, including an interactive genome map with annotations from gnomAD and ClinVar, are publicly accessible at www.cyprusgenome.org, facilitating clinical research.