Evaluation of computational methods for the reconstruction of HLA haplotypes

Abstract

Human leukocyte antigen (HLA) haplotypes are frequently evaluated for population history inferences and association studies. However, the available typing techniques for the main HLA loci usually do not allow the determination of the allele phase and the constitution of a haplotype, which may be obtained by a very time-consuming and expensive family-based segregation study. Without the family-based study, computational inference by probabilistic models is necessary to obtain haplotypes. Several authors have used the expectation-maximization (EM) algorithm to determine HLA haplotypes, but high levels of erroneous inferences are expected because of the genetic distance among the main HLA loci and the presence of several recombination hotspots. In order to evaluate the efficiency of computational inference methods, 763 unrelated individuals stratified into three different datasets had their haplotypes manually defined in a family-based study of HLA-A, -B, -DRB1 and -DQB1 segregation, and these haplotypes were compared with the data obtained by the following three methods: the Expectation-Maximization (EM) and Excoffier-Laval-Balding (ELB) algorithms using the arlequin 3.11 software, and the PHASE method. When comparing the methods, we observed that all algorithms showed a poor performance for haplotype reconstruction with distant loci, estimating incorrect haplotypes for 38%-57% of the samples considering all algorithms and datasets. We suggest that computational haplotype inferences involving low-resolution HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1 haplotypes should be considered with caution.

Self-Assessment of Color Categories and Its Relationship with HLA Profiling in Brazilian Bone Marrow Donors

“…This haplotype is not represented in the parental populations investigated, but it has already been observed in another Brazilian population (.5% in Ribeirão Preto, São Paulo state) [26]. Indeed, the existence of new haplotypes is expected in admixed populations.…”

Concomitant autoimmunity in myasthenia gravis — Lack of association with IgA deficiency

“…It should be noted that the presence of B8 and DR3, DQ2 is not absolutely indicative of a complete haplotype since recombined alleles may be inherited from each parent. We tested this by imputing haplotypes using PHASE 2.1.1, which has shown to have superior HLA haplotype reconstruction than the Expectation-Maximization algorithm (Bettencourt et al 2008);(Castelli et al 2010). The frequency of imputed B8, DR3, DQ2 haplotypes was 14.1% in MG, 24.7% in EOMG, 25.3% in IgAD, and 9.7% in a control population (n=672) previously typed (Ferreira et al n.d.).…”

Allele and haplotype frequencies of HLA‐A, B, C, DRB1 and DQB1 genes in polytransfused patients in ethnically diverse populations from Brazil

“…In relation to B locus , HLA‐B*15 , B*35 and B*51 were most frequent and common in all three groups, similar to the results of other studies with populations from north/north‐west regions of Parana State (Ruiz et al ., ), north‐east of Sao Paulo State (Castelli et al ., ), Pernambuco State (Nigam et al ., ) and Piaui State (Carvalho et al ., ). HLA‐B*57 showed a significant difference among groups 1 and 3, being more frequent in the Afro‐Brazilian group (4.2%).…”