Methods, systems and processes of identifying genetic variation in highly similar genes

A computer-implemented method for determining a likelihood of a presence or absence of a genetic variation in a gene of interest for a subject where the subject's genome also contains at least one counterpart gene to the gene of interest such that the at least one counterpart gene is at least 80% identical to the gene of interest, comprising the steps of:

• (a) providing a modified reference genome comprising (i) the gene of interest and (ii) one or more counterpart genes to the gene of interest that are substantially altered, wherein at least 30% of nucleotides of the one or more counterpart genes of the modified reference genome are substituted with different nucleotides such that sequence reads obtained from the gene of interest of the subject or the at least one counterpart gene of the subject map to the gene of interest of the modified reference genome instead of to the one or more counterpart genes of the reference genome;
• (b) mapping sequence reads obtained from the subject to the modified reference genome, wherein (i) the sequence reads are obtained from a sample obtained from a diploid subject using a massively parallel sequencing method, and (ii) the sequence reads obtained from the gene of interest and the at least one counterpart gene of the subject map to the gene of interest of the modified reference genome and not to the one or more counterpart genes of the modified reference genome, thereby providing sequence reads mapped to the gene of interest of the modified reference genome;
• and
• (c) determining the likelihood of a presence or absence of a genetic variation in the gene of interest of the subject according to the sequence reads mapped to the gene of interest of the modified reference genome.