Explanation Of Heterozygous Variants Presence On Male X Chromosome (Exome Data)
Entering edit mode
10.6 years ago
sa9 ▴ 840


I am investigating novel variants in two male sibs under X-linked inheritance model. When looking at the shared novel functional variants on X-chromosome between the sibs I found many heterozygous variants which doesn't make sense (I expect most to be hemizygous).

The possible explanations I came up so far:

  1. A possible swap with female samples -> but there are variants on Y-chromosome in both samples.

  2. Variants are on one of the two pseudoautosomal regions (PARs) which are exact duplicates:

    chrY:10001-2649520 and chrY:59034050-59363566

    chrX:60001-2699520 and chrX:154931044-155260560 (from UCSC GRCh37)

    -> Yes, this explained about third of those variants found on X-chromosome but the rest are on different regions.

The variants were called using SamTools/GATK using hg19 reference genome.

I would like to know if you've faced similar issue, what is your explanation and what would you do to verify your explanation/hypothesis.

exome • 7.3k views
Entering edit mode
10.6 years ago
Philippe ★ 1.9k


I never worked on exome data but I think I can provide some insights about some X chromosome properties.

  1. Some X-linked genes have gametologs, counterparts on the Y chromosome which are not located within the PAR. Nonetheless they are generally quite divergent in term of sequence and should be distinguishable. Example of paper relative to gametologs evolution, some of your genes might be described there.

  2. It has been documented that X-linked genes tend to duplicate more than autosomal genes (or they just happen to be more often fixed) for several reasons. The X chromosomes produced and excess of autosomal retrogenes (intronless rna-mediated copies) but also through segmental duplications. This excess has happened several times and there is also a recent excess in the recent human history. Then it is likely you find some pretty homologous copies of some X-linked genes (on the X or autosomal). Some relevant publications Gene traffic on the X Gene traffic on the X, again patterns of duplication on the X To test this you can see if there is no paralogs described for some of your genes you want to check. You still can have some cases of really recent paralogs which have not been annotated and it is then difficult to conclude something. It seems you have quite many cases which is then not likely to happen.


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