My review: "Toward a statistically explicit understanding of de novo sequence assembly"

The paper Howison et al., 2013, just appeared in early form in Bioinformatics. Here is my first round review, which they handily addressed in their revisions; since I was quite positive I felt I might as well post the whole thing, though.

Note that a relevant paper from Mihai Pop et al. came out right around the time this paper was accepted; looks interesting. "De novo likelihood-based measures for comparing genome assemblies".

My review

Howison et al. provide a very good and timely review of efforts and frameworks for assessing "assembly confidence", the likelihood that any given assembly is correct. I found the review very well written and comprehensive. I see no reason to require any changes.

However, if you asked me what I thought should be added to the paper... :) I think some discussion of the following three topics would be useful.

The Assemblathon 2 paper reached the interesting, if unspoken, conclusion that the current notion of "an assembly" is a fiction when it comes to complex eukaryotic genomes, and that what we really have is a series of oft rather significantly non-overlapping approximations to the "true" genome. Which approximation you get is a function of who does the assembly, what they're interested in, and how motivated they are in doing parameter optimization and assembly evaluation. We seriously need a set of unambiguous quality metrics for evaluation that can be presented to assembly consumers... I think this is a strong motivation for this question of confidence, and this point (that assemblies are simply not that good, comprehensive, or comparable) should be made clearly and strongly right up front in the paper. I don't think most people realize how bad the situation is!

Current efforts on confidence assessment are really focused on variant calling, primarily SNPs but (as the authors note) also structural variation. I haven't seen much work on evaluating repeat content or assembly sensitivity, or -- what I would think is most fundamental -- on the limits of what could be produced from the data vs what is actually in the assembly. Some work on this was done in the Assemblathon paper but it was rather unsatisfactory, to my mind; mostly focused on short-insert paired ends. Another way to put it is, assemblers throw away an awful lot of data; what is theoretically recoverable from there?

Mihai Pop had an interesting comment here:

regarding amnesia about earlier efforts on assembly correctness. Might be worth chasing him down for earlier references.

Titus Brown


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