When 23andMe offered a few select clients the opportunity to have the protein-encoding portion of their genome sequenced, Gabe Rudy jumped at the chance. On Wednesday, he walked strangers through the results. His conclusion: most detected genetic “variants of interest” are either not variants or not interesting. “Clinics beware,” he writes in a blog post detailing the analysis.
The standard service offered by 23andMe (based in Mountain View, California) does not sequence people’s DNA but instead probes for common variants, then lists these variants with an analysis of health, ancestry and other information, such as whether you carry a variant more often found in people who find that cilantro tastes soapy.
The exome sequence contained no such information, says Rudy; it was simply a list of ‘variant calls’ or differences that had been found between the sequenced individual and the reference genome. There are several research software pipelines available to call variants. 23andMe used what is probably the most popular one, which is available from the Broad Institute in Cambridge, Massachusetts.
Analysis of pathogenic variant{credit}Gabe Rudy, Golden Helix{/credit}
An executive at DNA analysis company Golden Helix, Rudy was much better prepared than most to tackle this list.
He took the files he received for himself (as well as for his wife and son) and poured them into his own company’s software: the SNP and Variation Suite (SVS) and a freely available visualization and inspection tool called GenomeBrowse. Next, he began to assess the evidence behind his 151,000 variant calls and put them in their biological context.
Whereas whole-genome sequences cover all the DNA on all the chromosomes, exomes focus on the 2% or so of the genome that contains genes. Exome sequencing aims to provide data for all protein-encoding genes, but only about three-quarters of genetic regions are profiled with enough accuracy for variants to be called confidently in a “research grade” (30×) exome. Even with “clinical grade” exomes, in which each DNA fragment is sampled 80 times or more, 5–15% of variants will still not be called variants. And those ‘low-coverage’ regions vary with each exome. As a result, Rudy had variants that had been called in his genome that he couldn’t compare with those in his wife and son.