A hidden Markov approach for ascertaining cSNP genotypes from RNA sequence data in the presence of allelic imbalance by exploiting linkage disequilibrium

BACKGROUND: Allelic specific expression (ASE) increases our understanding of the genetic control of gene expression and its links to phenotypic variation. ASE testing is implemented through binomial or beta-binomial tests of sequence read counts of alternative alleles at a cSNP of interest in heterozygous individuals. This requires prior ascertainment of the cSNP genotypes for all individuals. To meet the needs, we propose hidden Markov methods to call SNPs from next generation RNA sequence data when ASE possibly exists. RESULTS: We propose two hidden Markov models (HMMs), HMM-ASE and HMM-NASE that consider or do not consider ASE, respectively, in order to improve genotyping accuracy. Both HMMs have the advantages of calling the genotypes of several SNPs simultaneously and allow mapping error which, respectively, utilize the dependence among SNPs and correct the bias due to mapping error. In addition, HMM-ASE exploits ASE information to further improve genotype accuracy when the ASE is likely to be present. Simulation results indicate that the HMMs proposed demonstrate a very good prediction accuracy in terms of controlling both the false discovery rate (FDR) and the false negative rate (FNR). When ASE is present, the HMM-ASE had a lower FNR than HMM-NASE, while both can control the false discovery rate (FDR) at a similar level. By exploiting linkage disequilibrium (LD), a real data application demonstrate that the proposed methods have better sensitivity and similar FDR in calling heterozygous SNPs than the VarScan method. Sensitivity and FDR are similar to that of the BCFtools and Beagle methods. The resulting genotypes show good properties for the estimation of the genetic parameters and ASE ratios. CONCLUSIONS: We introduce HMMs, which are able to exploit LD and account for the ASE and mapping errors, to simultaneously call SNPs from the next generation RNA sequence data. The method introduced can reliably call for cSNP genotypes even in the presence of ASE and under low sequencing coverage. As a byproduct, the proposed method is able to provide predictions of ASE ratios for the heterozygous genotypes, which can then be used for ASE testing. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12859-015-0479-2) contains supplementary material, which is available to authorized users.