I have a high-quality set of structural variant breakpoints from tumour/normal WGS data, and I am interested in digging into the various mechanisms that might be involved in each event.
There are several mechanisms that are proposed to play a role in generating structural variants, including Non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ/MMEJ), alternative end joining (Alt-EJ) and several replicative mechanisms such as Fork Stalling and Template Switching (FoSTeS/MMBIR).
Each of these are distinct processes, that occur at different time points in the cell cycle and have different potential for generating genomic rearrangements. However, there seems to be little consensus on how to distinguish between them based on micro homology/insertions at breakpoints.
I would like to know if anyone can suggest an authoritative source for criteria I could use to form a working hypothesis as to the mechanism underlying each variant.
For example, a 10 Kb deletion with 4 bases of microhomolgy at breakpoints would be classified as an Alt-EJ event based on the criteria I list below.
Several specific questions:
Microhomology at breakpoints is an essential requirement for several of these mechanisms (FoSTes/MMBIR). However, there appears to be no consensus as to whether this must occur exactly at the breakpoint, or whether it can be several bases away (for example: https://www.nature.com/articles/nrc3537.pdf).
Secondly, according to this paper: Article Diverse Mechanisms of Somatic Structural Variations in Human...
The criteria used to classify structural variants are as follows (taken from the MeerKat manual):
- NAHR: non-allellic homologous recombination, >100bp homology.
- alt-EJ: alternative end joining, 3-100bp homology.
- NHEJ: non-homologous end joining, 0-2bp homology or 1-10bp insertion at deletion break point.
- FoSTeS: fork stalling and template switching, template switch, >10bp insertion at deletion break points.
However, almost every paper I read mentions different criteria, for example FoSTes events are often associated with microhomologies at breakpoints rather than insertions.
Can anyone suggest a "consensus" of requirements for each mechanism?
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