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This is a follow-up of my other question. I have been having trouble calling variants in the human SMN1 and SMN2 genes, because the human genome has a large segmental duplication there and these two genes (and their surrounding sequences) are essentially identical :

UCSC browser screenshot Click here to see the original image on the UCSC browser.

Since variants in the SMN1 gene have been linked to disease, it is important for me to be able to call them in my NGS data. However, because of this segmental duplication, aligning reads to this region correctly is very hard since the presence of the duplication makes each read align almost perfectly to separate locations in the genome, leading to low alignment scores. The low scores will, in turn, block variant callers from calling in those regions.

I thought that the only real solution for this would be to mask the SMN2 gene and its associated duplication in my reference genome which would allow the aligner to align all reads to the region of SMN1. I would then miss any real variants in SMN2, but since the primary gene of interest for spinal muscular atrophy is SMN1 and not SMN2, I would be OK with that.

My questions are:

  1. Is this a reasonable approach? I was told that "generally, masking segdups is not recommended" by someone who most certainly knows what he's talking about. So is this not a good approach for my stated goal?

  2. If not, then what else can I do that will let me call variants in the SMN1 gene?

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  • $\begingroup$ If you haven't seen it already, I think the approach in this paper might be of interest genomebiology.biomedcentral.com/articles/10.1186/… $\endgroup$ – Wouter De Coster Jul 15 '19 at 13:10
  • $\begingroup$ @WouterDeCoster the approach in that paper is precisely what I am suggesting here: mask one of the regions to rescue mutations in the other. Thanks for the reference though, I hadn't seen that one. $\endgroup$ – terdon Jul 15 '19 at 19:06

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