I'm doing some variant discovery in a human trio (affected child, non-affected mother, non-affected father) and I have found what looks like a homozygous novel mutation. All of the aligned reads in the child have the same nucleotide in that position, but neither of the parents do.

In looking at a small handful of variants, I've seen plenty of novel heterozygous SNVs. But on first blush a novel homozygous SNV seems extremely unlikely. Two independent germline mutations at the same position on both paternal chromosomes is all but impossible, right? Are there other mechanisms by which a novel mutation would become homozygous? Or am I right to be skeptical here?

  • $\begingroup$ I was going to make a hilarious joke, but then I thought some modicum of tact may be prudent. Is it possible that one of the parents isn't actually a parent? $\endgroup$
    – canadianer
    Commented May 9, 2017 at 21:27
  • $\begingroup$ What technology are you using. Illumina? Sanger? Have you "eyeballed" the variant? $\endgroup$
    – swbarnes2
    Commented May 9, 2017 at 23:36
  • 1
    $\begingroup$ A heterozygous allele can become a homozygous via homologous recombination. You can check if the region around the SNV is also homozygous. $\endgroup$
    Commented May 10, 2017 at 4:40
  • $\begingroup$ @WYSIWYG But remember, this isn't a heterozygous allele. It's a novel allele that didn't exist in either parent. Although from the context of homologous recombination, it the novel mutation had already occurred by that point it would be considered heterozygous. But could you clarify how heterozygous alleles can become homozygous? I'm rusty with my molecular genetics, but I thought homologous recombination swaps DNA between paired chromosomes, not copy from one to the other. $\endgroup$ Commented May 10, 2017 at 17:59
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    $\begingroup$ @DanielStandage en.wikipedia.org/wiki/Gene_conversion $\endgroup$
    Commented May 11, 2017 at 9:31


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