Clinical OMICS

MAR-APR 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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www.clinicalomics.com March/April 2018 Clinical OMICs 21 by 10X Genomics; and optical mapping, offered by Bion- ano Genomics. Missing Variation "When genomics started, we hoped to have all of the answers and be able to cure diseases in the next 5 to 10 years," said Anjana Narayanan, Ph.D., the linked-reads product manager at 10X Genomics. "That's what the prom- ise of the human genome project was: to end the diagnostic odyssey. That really hasn't happened." In part, that's because most genomic technology relies on short-read sequencing (SRS), she said, which provides reads of 100–600 base-pairs. SRS is good at finding sin- gle base-pair changes to the genome—single nucleotide polymorphisms, or SNPs—but it is not as good at finding larger structural variants (SVs) such as deletions, inser- tions, or inversions. Researchers now know that SVs account for about two- thirds of all human genetic variation. "The community has only been looking at about a quarter of the variation," Kor- lach said. "It's therefore not surprising that diagnostic yield is only about 25 to 30 percent." Standard SRS also cannot reveal which short reads come from which parental chromosome. Analyses of SRS data are forced to average the two parental haplotypes, making it impossible to know whether an observed genetic change affects both chromosomes or only one—a key piece of infor- mation for discovering disease-causing genes. Going Long One way to capture more SVs is to lengthen the stretch of base-pairs per read. That is the approach taken by PacBio with its single-molecule real-time (SMRT) sequencing tech- nology, which can read segments of DNA averaging 10,000 base pairs. It's right at the sweet spot for finding SVs, which are typically 50 to 1,500 bases long, said Lori Aro, senior director of clinical genomics at PacBio. The hope is that LRS will greatly increase sequencing's diagnostic capabilities and put an end to diagnostic odys- seys such as Ramon's. Beyond that, Korlach said, "there are myriad of application spaces that we're pleased to see appear now." These include molecular diagnostic applica- tions not only for genetic disease but also for cancer and infectious diseases, as well as targeted sequencing for immunologic phenotyping. The long-read approach is also particularly good at defining the extent of repetitive stretches of DNA, which (continued on next page) Andrew Brookes / Getty Images

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