Whole genome sequencing services: choosing short against long reads, setting a depth that answers the question, and agreeing the analysis scope

The choices that decide the data

1. Short or long reads. Short reads are cheap, accurate per base and excellent for small variants. Long reads resolve repeats, structural variation and phasing and cost more per base. A project that could involve structural change or repetitive regions needs long reads or a combination, and no amount of short-read depth substitutes.
2. Depth follows the variant class. Germline variant calling needs far less depth than detecting a variant present in a small fraction of cells, and de novo assembly is different again. State the variant class and the lowest fraction you must detect, and let that set the depth rather than accepting a default.
3. Input quality decides the library. Long-read library preparation needs high molecular weight DNA that ordinary column extraction damages. If long reads are the plan, the extraction method is part of the plan, and a sample already extracted on a column may not be usable.
4. Analysis scope, stated explicitly. Reads only, aligned data, variant calls, annotation or interpretation are different products at different prices. Establish which you are buying, in which file formats, and against which reference build and annotation release.
5. Data volume, delivery and retention. Genome data is large. Agree how it is delivered, how long the provider keeps it, what a second copy costs, and where it is stored, because the storage question is a real cost and, for human data, a compliance question.

Genome or exome

An exome covers coding regions at high depth for a fraction of the cost and sees nothing outside the capture design. A genome at lower depth covers everything including regulatory regions and structural variation, and it is increasingly the better value when the question is not confined to coding variants.

Where the budget forces a choice, decide from the biological question rather than from cost per sample. An exome that cannot see the answer is not cheaper.

Human data carries obligations

Consent, data protection and a policy on incidental findings all apply to human genome sequencing, and the genome is more identifying than most data a laboratory handles. Settle the incidental findings position before sequencing rather than when something appears.

Confirm where data is processed and stored and whether that meets the obligations attached to your samples. This is a contractual question that is simple to ask beforehand and awkward to unwind afterwards.

Common questions

Short reads or long reads?

Short reads for small variants at low cost; long reads for structural variation, repeats and phasing. A question that could involve structural change needs long reads, and short-read depth does not substitute.

What depth do I need?

It depends on the variant class and the lowest fraction you must detect. Germline calling needs far less than low-fraction detection, and de novo assembly is different again. State the requirement and let it set the depth.

Does extraction method matter?

For long reads, considerably. Library preparation needs high molecular weight DNA that ordinary column extraction damages, so the extraction method has to be planned with the sequencing.

What analysis is included?

It varies from raw reads to full interpretation. Establish the scope, the file formats and the reference build and annotation release explicitly, because this is where similar-looking quotes differ most.

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