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What determines an active region? Different HaplotypeCaller results for small vs. large cohorts

mlindermmlinderm Posts: 19Member

We observed a de-novo mutation identified by HC in a single trio that was not called when the same trio is included in a larger 95-sample cohort. The immediate cause seems to be that in the larger cohort the region surrounding this variant is no longer considered active. I also observe that whether the region is "active" depends on how large of an interval I supply. A 100bp interval centered on the site has active regions, a 300bp interval does not. When I "forceActive" the variant is called as expected in all intervals.

I can't find much information about how active regions are determined. At first, I hypothesized that the activity profile scores were smaller in the larger cohort (and thus no longer crossing the fixed threshold in ActivitiProfile.java, but the scores as dumped by --activityProfileOut look to have similar magnitude. What other information does active region determination take into account? How can I interpret the --activeRegionOut output? For the 300bp interval where the variant (@ chr3:51992816) is not called I get

#track graphType=line
Chromosome  Start   End Feature ActiveRegions
chr3    51992665    51992666    end-marker  0.00000
chr3    51992665    51992778    size=113    -1.00000
chr3    51992778    51992779    end-marker  0.00000
chr3    51992778    51992948    size=170    1.00000
chr3    51992948    51992949    end-marker  0.00000
chr3    51992948    51992966    size=18 -1.00000

When I use a smaller 100bp interval, I get the following active regions output:

#track graphType=line
Chromosome  Start   End Feature ActiveRegions
chr3    51992765    51992766    end-marker  0.00000
chr3    51992765    51992778    size=13 -1.00000
chr3    51992778    51992779    end-marker  0.00000
chr3    51992778    51992853    size=75 1.00000
chr3    51992853    51992854    end-marker  0.00000
chr3    51992853    51992866    size=13 -1.00000

The one noticeable difference between the two is the length of the potential active regions (75 vs 170), does that impact anything? Why despite the above output suggesting that there is indeed an active region does local assembly not get performed? Of note, in the larger cohort there is another singleton variant 82bp downstream in another sample (i.e. not in the original trio). I presume it is that variant that is leading to the longer active region.

Thanks,

Michael

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