SHAPEIT5

SHAPEIT5 performs haplotype estimation (genotype phasing) of genotype data from whole-genome sequencing, whole-exome sequencing and SNP array platforms to resolve parental chromosome copies in large-scale cohorts.

Key Features:

• Genotype phasing: Estimates haplotypes by separating the two parentally inherited chromosome copies for each sample.
• Supports sequencing and arrays: Operates on whole-genome sequencing (WGS), whole-exome sequencing (WES) and SNP array genotype datasets.
• Scalability and speed: Designed to process very large datasets such as the UK Biobank with emphasis on computational speed and scalability.
• Rare-variant phasing: Phases rare variants with low switch error rates, achieving below 5% for variants present in one sample out of 100,000.
• Singleton phasing method: Implements a novel approach for phasing singletons (variants observed in a single individual), noted as less precise but novel.
• Imputation-ready phasing: Produces phased haplotypes that improve genotype imputation accuracy when using the UK Biobank as a reference panel.
• Compound heterozygous screening: Has been applied to detect loss-of-function compound heterozygous events, identifying 549 genes with both copies knocked out in the UKB cohort.

Scientific Applications:

• Haplotype reconstruction: Resolving parental chromosome copies for downstream genetic analyses.
• Rare variant analysis: Phasing and interpretation of rare alleles and singleton variants to study inheritance patterns.
• Genotype imputation: Improving imputation accuracy by providing accurately phased reference haplotypes using the UK Biobank panel.
• Loss-of-function discovery: Identifying compound heterozygous loss-of-function events and genes knocked out in large cohorts, informing gene essentiality studies.

Methodology:

Performs genotype phasing (haplotype estimation) including a novel singleton phasing method, evaluates performance using switch error rates (reporting <5% for singletons present once per 100,000), and applies phased haplotypes for imputation with the UK Biobank reference and for detection of loss-of-function compound heterozygous events.