Effectiveness of computational methods in haplotype prediction

Abstract

Haplotype analysis has been used for narrowing down the location of disease-susceptibility genes and for investigating many population processes. Computational algorithms have been developed to estimate haplotype frequencies and to predict haplotype phases from genotype data for unrelated individuals. However, the accuracy of such computational methods needs to be evaluated before their applications can be advocated. We have experimentally determined the haplotypes at two loci, the N-acetyltransferase 2 gene ( NAT2, 850 bp, n=81) and a 140-kb region on chromosome X ( n=77), each consisting of five single nucleotide polymorphisms (SNPs). We empirically evaluated and compared the accuracy of the subtraction method, the expectation-maximization (EM) method, and the PHASE method in haplotype frequency estimation and in haplotype phase prediction. Where there was near complete linkage disequilibrium (LD) between SNPs (the NAT2 gene), all three methods provided effective and accurate estimates for haplotype frequencies and individual haplotype phases. For a genomic region in which marked LD was not maintained (the chromosome X locus), the computational methods were adequate in estimating overall haplotype frequencies. However, none of the methods was accurate in predicting individual haplotype phases. The EM and the PHASE methods provided better estimates for overall haplotype frequencies than the subtraction method for both genomic regions.

Polymorphisms of XRCC1 gene, alcohol consumption and colorectal cancer

“…32 Even though the statistical method to construct haplotypes does not provide information of phase structure exactly, it was reported to be sufficiently accurate for the reconstruction of haplotypes, particularly for genomic regions with high linkage disequilibrium and less ambiguity. 32,33 Because the region studied was relatively small, covering approximately 1.9 kb for the 3 polymorphisms of XRCC1 gene, and the 4 possible allele combinations were estimated to be absent in the analysis, there is likely to be strong linkage disequilibrium in the region. We confirmed the linkage disequilibrium by showing that D0 values were 0.997 or more among the 3 SNP.…”

Molecular diversity at the CYP2D6 locus in the Mediterranean region

“…PHASE does not rely on other assumptions, such as Hardy -Weinberg equilibrium. Computer simulations studies 25,26 clearly suggest that PHASE performs better than other algorithms, such as EM, in a wide range of conditions.…”

A maximum-likelihood estimation of pairwise relatedness for autopolyploids

“…For example, there are three types of partial heterozygotes (that is, A i A i A i A j , A i A i A i A j and A i A j A j A j ) if two alleles (A i and A j ) are present in an ambiguous genotype. Although some methods are able to determine tetraploid genotype (that is, Xu et al, 2002;Pfeiffer et al, 2011;Serang et al, 2012;Voorrips et al, 2011;Uitdewilligen et al, 2013), additional instrument or software may be required.…”

“…Furthermore, where genotypes are ambiguous, biallelic loci are also problematic as the bias is too large (Figure 5). However, single nucleotide polymorphism data can still be used, especially with newer genotyping-by-sequencing and haplotype prediction technologies (Xu et al, 2002;Uitdewilligen et al, 2013). These techniques provide means for unambiguous genotyping and also determine the haplotype.…”