PERHAPS: Paired-End short Reads-based HAPlotyping from next-generation Sequencing data

Area of Science:

• Genetics
• Bioinformatics
• Genomic Medicine

Background:

• Rare haplotypes are crucial for understanding complex and monogenic traits.
• Direct haplotype calling from sequencing data remains challenging.

Purpose of the Study:

• Introduce PERHAPS, a novel method for direct haplotype calling from paired-end next-generation sequencing data.
• Validate PERHAPS using the well-characterized APOE polymorphism in a large, multi-ethnic cohort.

Main Methods:

• PERHAPS reconstructs haplotypes by assembling paired-end reads.
• Applied PERHAPS to Whole Exome Sequencing and SNP-array data from the UK BioBank (N=48,855).
• Benchmarked PERHAPS against established statistical phasing and imputation methods.

Main Results:

• PERHAPS achieved high concordance rates (>99%) with existing methods for diplotype calling.
• Validated haplotype frequencies against the 1000 Genomes Project and Hardy-Weinberg Equilibrium.
• Identified the rare APOE*1 haplotype in African subjects, suggesting a 0.5% frequency in the Yoruba population.

Conclusions:

• PERHAPS offers a simple and effective approach for direct haplotype calling from short-read sequencing data.
• The method enhances the study of genetic architecture, particularly for rare variants.
• PERHAPS overcomes limitations in current direct haplotype calling techniques.