A genome-wide study of Hardy-Weinberg equilibrium with next generation sequence data

Area of Science:

• Genetics
• Bioinformatics
• Population Genetics

Background:

• Hardy-Weinberg equilibrium statistical tests are crucial for quality control in genetic data analysis.
• These tests historically identified genotyping errors and remain vital for next-generation sequencing (NGS) data.

Purpose of the Study:

• To analyze complete chromosomes from the 1000 Genomes Project using exact tests for autosomal and X-chromosomal variants.
• To assess the prevalence and causes of Hardy-Weinberg disequilibrium in large-scale sequencing datasets.

Main Methods:

• Utilized exact test procedures on autosomal and X-chromosomal variants across complete chromosomes.
• Analyzed data from the 1000 Genomes Project to evaluate Hardy-Weinberg equilibrium.
• Investigated relationships between disequilibrium, heterozygote excess, read depth, and genomic regions.

Main Results:

• A significant rate of Hardy-Weinberg disequilibrium was observed across all chromosomes, exceeding chance expectations.
• Approximately 60% of disequilibrium cases were attributed to heterozygote excess, likely stemming from sequencing problems.
• Higher disequilibrium rates were noted in the MHC region, centromere-flanking regions, and acrocentric chromosome p-arms.
• Read depth and specific genomic regions (segmental duplications, simple tandem repeats) were strongly associated with increased disequilibrium.

Conclusions:

• Hardy-Weinberg disequilibrium is a prevalent issue in NGS data, often indicating sequencing artifacts.
• Excess heterozygosity and disequilibrium are linked to copy number variations, highlighting its utility as an indicator.
• Specific genomic features like segmental duplications and repeat regions are hotspots for disequilibrium and potential errors.