MCNV reference copy states in chr X and chr Y

Structural Variation
1

Hi,

I have a question regarding multiallelic CNVs. In my work, I’m aiming to represent each MCNV as a DEL and a DUP, summing the allele frequencies from each copy state into two new totals. For autosomal chromosomes it is quite straightforward, with CN = 0 and CN = 1 being deletion states and everything CN > 2 being duplication states. For chr X and Y it is important to know what copy state is to be considered the “reference”.
The strategy that I wanted to implement is the following:

  • (1) For XX counts on X and XY counts on X inside PAR, CN = 2 is the reference as for autosomal chromosomes.
  • (2) For XY counts on X outside PAR, CN = 1 is the reference (so CN = 0 is a deletion, CN > 1 is a duplication)
  • (3) For SVs on chr Y, CN = 1 is the reference as well

However, when inspecting the data (using gnomAD VCFs), the most frequent copy states for (3) seem to be CN = 2, suggesting that the counts were normalized to have similar reference states as the other chromosomes. The copy number distribution visualization in the gnomAD browser also shows CN = 2 in a different color as the other copy states (e.g. this example). For (2) cases, it seems that this normalization did not happen in v4 and CN = 1 is indeed the reference, although the v2 SV data seems to also show the normalization to CN = 2 for these cases.

These are just observations from inspecting the data, so it would be great to know how I can correctly interpret these X and Y MCNVs.

Thanks in advance for any help!

2

Hi,
Thank you for your question. We did not normalize copy states of mCNVs on sex chromosomes, so theoretically, the expected reference copy number for chrY outside of the PAR region is 1. Regarding the gray shade for CN=2, I suspect this may be a discrepancy between the browser display and the VCF. We will investigate further.

1 Like