Development of a methodology for analysis of heritable rearrangements: a case study at the human CYP2D6 locus

Authors

• L Masoumzadeh
• J Yang
• A Bax

Abstract

Meiosis is the reductional cellular division leading to the formation of gametes. At the onset of meiosis, DNA damage in the form of double strand breaks (DSBs) are both purposefully created and necessary for meiotic completion. DSBs cluster at regions in the genome called hotspots which vary in location between human populations. Meiotic DNA repair canonically uses homologous allelic sequences as a template for repair. However, non-allelic homologous sequences can also act as a template which can lead to genomic rearrangements which can be heritable. Whether the location of DSBs predisposes offspring to genomic rearrangements/disorders is relatively unknown. To test this, we designed two methodologies to analyze rearrangements at the repetitive CYP2D6 locus previously shown to harbour hotspots. CYP2D6 is a target of major clinical importance having a vital function in metabolizing ~25% of all prescription drugs and is highly variable with over 400 annotated alleles including large copy number variations. We examined 144 unrelated individuals and 58 parent-offspring trios and found seven different possible rearrangements at this locus including a novel rearrangement. ~23% of individuals were found to have at least one gross rearrangement, higher than what is described in the literature (~5-12%). In addition, we have an ongoing familial analysis with at least one example of a heritable de novo rearrangement. In summary, we have designed a methodology and analysis pipeline to examine variability which can be implemented to further understand the origins of variation in human genomes.

Scientific Focus Area: Genetics and Genomics

This page was last updated on Monday, September 25, 2023