Bioinformatic Pipeline Development and Exploration of Low Frequency Somatic CHIP Genetic Variants

Clonal haematopoiesis of indeterminate potential (CHIP), is observed as genetically distinct subpopulations of blood cells that have acquired somatic genetic variation (mutations). These CHIP-associated genetic variants have been associated with an increased risk of blood malignancies and cardiovascular disease. The most frequent CHIP-associated variants are found in epigenetic modifiers or driver genes such as DNMT3A, TET2, ASXL1, and JAK2. By current definition, CHIP requires the variant allele fractions (VAF) of these somatically acquired genetic variation to be 2% or higher. However, there is some research suggesting that CHIP-associated variants below this 2% VAF threshold are clinically relevant. Assessment of variants at this low VAF has several technical challenges including i) the generation of massively parallel sequencing data adequate to confidently call variants at the level and ii) the capacity of the bioinformatic pipeline (including the specific variant caller) to detect and correctly call variants at VAFs below 2%. This project will explore somatically acquired genetic variation that falls below the 2% VAF in a massively parallel sequencing dataset generated from blood-derived DNA from individuals over the age of 65 years. The student will be introduced to bioinformatics and somatic variant calling, gaining skills in programming languages such as Bash, R, and SQL. Additionally, they will learn how databases are applied in genetic research on human disease.