Supplementary Figure 2: Alternative approaches to graph representation.

In a and b, a reference consisting of only alleles of genes of interest can introduce significant mapping bias by mapping reads from regions not included in the restricted reference, as illustrated in more detail in Supplementary Fig. 3. In c, an aligner using the current human reference may not be able to map many reads if they originated from alleles that are substantially different from the human reference allele. In d, a reference consisting of the human reference plus numerous alleles of HLA genes enables mapping of reads from even substantially different alleles. Most HLA-typing methods, such as HLA-VBSeq, HLA*PRG, Kourami, and Graphtyper, are based on c, d, or a combination thereof to initially identify HLA reads, after which HLA-VBSeq uses approach a, and HLA*PRG, Kourami, and Graphtyper use a small-scale graph representation as described in b to perform typing. Kourami assembles only exons of HLA genes, while HISAT-genotype is able to assemble full-length sequences of HLA genes including exons and introns.