Factors affecting the size of a structural variant

Question

[tacrolimus]

Dear Biostars,

Does anyone have a good journal article discussing the factors that determine the length of a structural variant in humans? I ask because I have done a genomewide SV burden analysis in a case-control cohort and have found two genes to have a higher SV burden in cases versus controls. However, in the first gene the signal stems from SVs <10kb, but in the latter gene the signal is from SVs >10kb. I am trying to get my head around the biology that may be at play here and would appreciate a reference!

Note I have ready plenty about SV/CNVs generally but specifically I would like something on what affects their length.

All the best

Answer 1

[tacrolimus]

In the end I found this review to be most helpful:

https://www.nature.com/articles/nrg.2015.25

Answer 2

[LauferVA]

The bottom line is that the answer to your question flows directly from the mechanisms for genome recombination, as influenced and selected for/against by natural selection.

For this question specifically, I would favor manuscripts published in 2022 and 2023 (after completion of T2T), because T2T has had the effect of clarifying several mechanisms of SV formation as well as provided more accurate quantificaiton of SV burden than was possible in the next gen era.

For instance, check out Nurk et al. 2022 and Porubsky et al 2022 for an examples & updates to the information found in the review you mention.

[tacrolimus]

Many thanks for taking time to reply. Will check these out!

Answer 3

[cmdcolin]

this does not directly address your size question but I was always curious "why would the genome have tandem duplications"... a review article I found mentioned these mechanisms factors

• replication slippage
• retrotransposition
• unequal crossing over (UCO)
• imperfect repair of double-strand breaks by nonhomologous end joining (NHEJ) (specifically contributing to 1-100bp length indels)

ref https://academic.oup.com/mbe/article/24/5/1190/1038942?login=false

there are many other classes of SVs but it's worth checking the literature for mechansisms...a deletion is probably not "just a deletion", it may be mechanistically caused by some DNA repair fault, or any other class of weird causes

see also other mechanistic patterns like "inverted duplications"

[tacrolimus]

Great read, many thanks for taking the time to reply