Theory 03/Structural variants/Long-read sequencing
Structural Variants Act at Boundaries
The phenotypic effect of a structural variant is set by the ratio of disrupted regulatory sequence to the number of genes it disturbs, so a large inversion can be harmless while a small deletion is severe.
01Mechanism
Effect depends on which elements are broken, not on the number of bases; boundary elements are small and consequential.
02Prediction
Severity should track the boundary ratio rather than size.
03Refutation
Severity tracking variant length would remove the boundary argument.
04What makes it checkable
Long reads now span entire structural variants and their breakpoints, allowing the disrupted elements to be identified rather than inferred from array data.
05Why it was not testable before
Short reads could not cross a breakpoint, so structural variants were guessed at from copy-number proxies.