Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Sep;80(9):633-643.
doi: 10.1016/j.humimm.2019.01.010. Epub 2019 Feb 5.

Tools for building, analyzing and evaluating HLA haplotypes from families

Kazutoyo Osoegawa  1 , Steven J Mack  2 , Matthew Prestegaard  3 , Marcelo A Fernández-Viña  4
Affiliations
Review

Tools for building, analyzing and evaluating HLA haplotypes from families

Kazutoyo Osoegawa et al. Hum Immunol. 2019 Sep.

Abstract

The highly polymorphic classical human leukocyte antigen (HLA) genes display strong linkage disequilibrium (LD) that results in conserved multi-locus haplotypes. For unrelated individuals in defined populations, HLA haplotype frequencies can be estimated using the expectation-maximization (EM) method. Haplotypes can also be constructed using HLA allele segregation from nuclear families. It is straightforward to identify many HLA genotyping inconsistencies by visually reviewing HLA allele segregation in family members. It is also possible to identify potential crossover events when two or more children are available in a nuclear family. This process of visual inspection can be unwieldy, and we developed the "HaplObserve" program to standardize the process and automatically build haplotypes using family-based HLA allele segregation. HaplObserve facilitates systematically building haplotypes, and reporting potential crossover events. HLA Haplotype Validator (HLAHapV) is a program originally developed to impute chromosomal phase from genotype data using reference haplotype data. We updated and adapted HLAHapV to systematically compare observed and estimated haplotypes. We also used HLAHapV to identify haplotypes when uninformative HLA genotypes are present in families. Finally, we developed "pould", an R package that calculates haplotype frequencies, and estimates standard measures of global (locus-level) LD from both observed and estimated haplotypes.

Keywords: 17th International HLA and Immunogenetics Workshop; HLA; Haplotype; Linkage disequilibrium; Next generation sequencing.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interests

The authors declared no conflicting interests.

Figures

Figure 1:
Figure 1:
Figure 1 shows the flow of concepts behind the software suite. Detailed description of each step with the section numbers and titles can be found in Materials and Methods. HaplObserve, HLAHapV and pould were developed and updated to accomplish: [1] building HLA haplotypes from families (light gray highlight: sections 2.2.2.1 – 2.2.2.7); [2] validating the haplotypes (dark gray highlight: 2.2.2.7 – 2.3.2); [3] calculating haplotype frequencies (2.4); [4] estimating measures of LD from the family haplotypes (2.5).
Figure 2:
Figure 2:
A pedigree of a quartet family is shown with father, mother and two children as indicated with thin solid lines. A set of parental haplotypes is built from Trio1 with father, mother and child1, as shown with a black bold triangle. A second set of parental haplotypes is built independently from Trio2 with father, mother and child2, as shown with a gray bold dotted triangle. The resulting two sets of parental haplotypes are compared for validation; both sets of parental haplotypes are identical if no meiotic crossover event occurred in either of the children. This validation facilitates identification of not only a recombination event but also inconsistent HLA allele segregation within the same haplotype due to HLA typing errors.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Stewart CA, Horton R, Allcock RJ, Ashurst JL, Atrazhev AM, Coggill P et al. : Complete MHC haplotype sequencing for common disease gene mapping. Genome Res 2004;14:1176. - PMC - PubMed
    1. Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L et al. : The DNA sequence and analysis of human chromosome 6. Nature 2003;425:805. - PubMed
    1. Shiina T, Hosomichi K, Inoko H, Kulski JK: The HLA genomic loci map: expression, interaction, diversity and disease. J Hum Genet 2009;54:15. - PubMed
    1. Robinson J, Halliwell JA, Hayhurst JD, Flicek P, Parham P, Marsh SG: The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res 2015;43:D423. - PMC - PubMed
    1. Slatkin M: Linkage disequilibrium-understanding the evolutionary past and mapping the medical future. Nat Rev Genet 2008;9:477. - PMC - PubMed