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Table 1 Overview of whole-genome haplotyping methods

From: Whole-genome haplotyping approaches and genomic medicine

Method Minimal cohort Advantages Limitations*
Molecular Single and paired-end physical reads Individual Haplotype is directly observed from sequence data Produces short haplotypes, even after assembly
Simple
Can resolve private and rare haplotypes
Can phase de novo variants
Chromosome sorting, clone-by-clone, dilution, proximity ligation Individual Haplotype is directly observed from sequence data May be labor intensive, time-consuming and expensive, therefore
Highly accurate difficult to translate to large sample sizes
Can resolve private and rare haplotypes
Can phase de novo variants
Can resolve long-range and chromosome-length haplotypes (depending on method)
Ideal for generating personalized genome-resolved haplotypes
  Haplotype assembly Individual Leverages molecular haplotype information from WGS data and/or from sorted chromosomes, clones Assembly requires variants in overlapping sequence reads
Works well when molecular haplotypes are long (that is, from cosmid or BAC) Limited by the accuracy and availability of suitable reference data
Generate short-range haplotypes
May introduce phase errors
Genetic analysis   Trios, nuclear families Can accurately phase high-throughput short-read sequencing reads Cannot resolve sites where all family members are heterozygous
Low error rate
Precisely maps recombinations and inheritance states May not be possible to ascertain family members
Enables detection of sequencing errors
Can phase private and rare alleles
Can phase entire chromosomes
Suitable for clinical applications
Population inference   Unrelated individuals, duos, trios Cost-effective Can only phase common variants
Facilitates haplotype imputation in samples with low-density microarray panels Difficult to impute private variants or rare haplotypes
Useful when family members cannot be ascertained Limited by the accuracy and availability of suitable reference data
Large sample sizes increase accuracy Generates short-range haplotypes
Good for large samples of unrelated individuals Sample size impacts haplotype frequency estimations
Incorporation of family duos and trios improves accuracy Methods are probabilistic and accuracy must be balanced against computational costs
  1. *All of these methods are limited by the accuracy of the sequence data.