There’s a great new podcast interview with Stanford clinical geneticist and oncologist Hanlee Ji about targeting extremely large stretches of DNA by combining CRISPR methods, automated DNA purification with the SageHLS instrument, and 10x Genomics technology. The approach works with minute amounts of DNA, far less than is needed for long-read sequencing platforms, but can still resolve large and complex structural variations. (For readers who want a deeper dive, his lab also posted slides from an AGBT presentation of this work.)
As Ji described it, the method targets sub-megabase regions — as long as about 500 Kb — and his team has validated it with the BRCA1 gene, the MHC locus, and other examples. By getting large, intact DNA molecules, scientists can delineate structural variants, rearrangements, and more. The long-range information generated “would have been impossible” using short-read sequencing technology that requires fragmenting these large molecules, Ji noted. The protocol also makes it feasible to enrich for tumor DNA or other types of DNA that might get drowned out by normal DNA. “Our approach represents a solution to be able to pull that out, tease that information out, even when you have these complex mixtures and your event of interest is underrepresented compared to the normal genome,” he said.
Such information is clinically useful for everything from cancer to schizophrenia. As Ji pointed out, this method is a strong alternative to the FISH technology typically used for pediatric congenital disorders, finding somatic rearrangements in cancer, and more. His team’s work offers higher resolution and potentially lower cost to generate clinically relevant results.
The interview wraps up with a segment about precision medicine and its most promising applications in the oncology realm. Ji said he is particularly excited about personalized cancer vaccines and immunotherapy, and he stressed the importance of enrolling more patients in clinical trials. He also urged cancer centers to bank more samples than they do now, noting that samples considered unsuitable for use now could one day become important sources for population studies as technology continues to improve.