Sample interview questions: How do you handle the challenges of working with rare or low-abundance genetic variants in genomics rare variant association studies?
Sample answer:
Challenges in Working with Rare Variants
- Detection and genotyping: Rare variants are often difficult to detect and genotype accurately due to their low frequency. This can lead to false negatives or false positives, reducing the reliability of association studies.
- Statistical power: Since rare variants are present in few individuals, statistical power to detect associations is limited. Large sample sizes or targeted sequencing panels are often required.
- Confounding effects: Rare variants can be enriched in certain populations or have pleiotropic effects, potentially confounding association studies.
- Functional interpretation: Understanding the functional impact of rare variants is challenging, especially if they are non-coding or located in unannotated regions of the genome.
Strategies to Overcome Challenges
Detection and Genotyping
- High-coverage sequencing: Using next-generation sequencing (NGS) with high coverage (>30x) improves the sensitivity for detecting rare variants.
- Targeted sequencing panels: Designing custom sequencing panels to focus on specific genes or regions of interest can enhance detection efficiency.
- Statistical methods: Algorithms such as the read-depth approach or the likelihood-based method can increase the accuracy o… Read full answer