Ever since the introduction of high-throughput sequencing following the human genome project, assembling short reads into a reference of sufficient quality posed a significant problem as a large portion of the human genome—estimated 50–69%—is repetitive. As a result, a sizable proportion of sequencing reads is multi-mapping, i.e., without a unique placement in the genome. The two key parameters for whether or not a read is multi-mapping are the read length and genome complexity. Long reads are now able to span difficult, heterochromatic regions, including full centromeres, and characterize chromosomes from telomere to telomere. Moreover, identical reads or repeat arrays can be differentiated based on their epigenetic marks, such as methylation patterns, aiding in the assembly process. This is despite the fact that long reads still contain a modest percentage of sequencing errors, disorienting the aligners and assemblers both in accuracy and speed. Here, I review the proposed and implemented solutions to the repeat resolution and the multi-mapping read problem, as well as the downstream consequences of reference choice, repeat masking, and proper representation of sex chromosomes. I also consider the forthcoming challenges and solutions with regards to long reads, where we expect the shift from the problem of repeat localization within a single individual to the problem of repeat positioning within pangenomes.
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