iXora: exact haplotype inferencing and trait association

Abstract

Background: We address the task of extracting accurate haplotypes from genotype data of individuals of large F1 populations for mapping studies. While methods for inferring parental haplotype assignments on large F1 populations exist in theory, these approaches do not work in practice at high levels of accuracy.

Results: We have designed iXora (Identifying crossovers and recombining alleles), a robust method for extracting reliable haplotypes of a mapping population, as well as parental haplotypes, that runs in linear time. Each allele in the progeny is assigned not just to a parent, but more precisely to a haplotype inherited from the parent. iXora shows an improvement of at least 15% in accuracy over similar systems in literature. Furthermore, iXora provides an easy-to-use, comprehensive environment for association studies and hypothesis checking in populations of related individuals.

Conclusions: iXora provides detailed resolution in parental inheritance, along with the capability of handling very large populations, which allows for accurate haplotype extraction and trait association. iXora is available for non-commercial use from http://researcher.ibm.com/project/3430.

Figure 1

Outline of the iXora phasing approach. The eight steps in the iXora haplotype extraction algorithm. Eqn and Obs refer to the Equations and Observations discussed in Methods. The task is to estimate the haplotypes of the two parents, say a and b, as well as those of the four progeny.

Figure 2

Transition diagram for computing the final phasing output. The diagram shows the permissible state transitions for computing the phasing result matrices F. The states S are discussed in detail in Methods.

Figure 3

Expected haplotype distributions visualization. Expected haplotype frequencies ${ĉ}_{k_1{k}_2}$ are shown for the simulated use case detailed in Additional file 1, for the two phenotypic groups: A) tall progeny, B) short progeny. The variance ${\Delta }_{k_1{k}_2}$ due to uncertainty in crossover locations is shown as shaded regions. Clear distortion is visible near marker 30 (marked by the dashed rectangle), evident from under-representation of haplotype combinations involving paternal haplotype H2 in the short progeny (green and yellow lines in B).

Figure 4

Results from Fisher’s exact test for phenotype-haplotype association for A) Father and B) Mother, including the p-value significance thresholds from randomizations, for the simulated use case detailed in Additional file 1. In this case only one region of the genome from the father is significantly associated with the phenotype (marked by the dashed rectangle), according to the Fisher’s exact test and the randomization thresholds. [Legend: real data (red), randomized data (blue), smallest value in randomized data (green)].