DNA Research, Scientist holding up a multi well plate containing DNA samples with results on the computer screen
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For more than 20 years, Ricky Ramon endured multiple surgeries to remove mysterious benign tumors from various parts of his body, including inside his heart. Though his doctors suspected a genetic disease called Carney syndrome, genetic testing using standard short-read DNA sequencing failed to find any changes to the relevant genes. This outcome is all too common: Sequencing only identifies the cause of genetic disorders about 30 percent of the time.

When Ramon was 21, his doctors recommended a heart transplant, but his eligibility for the procedure depended on whether a new heart would remain tumor-free—a possibility they could not rule out. In a last-ditch effort to uncover the genetic cause of Ramon’s tumors (and determine his eligibility for a new heart), a research team led by Stanford University professor of medicine Euan Ashley, M.D., Ph.D., decided to give DNA sequencing another chance. This time they turned to long-read sequencing (LRS) using PacBio’s Sequel system. That decision paid off: The team found a large deletion overlapping a gene implicated in Carney Syndrome. Having found the genetic cause, Ramon is likely eligible for a new heart.

Published in 2017 in Genetics in Medicine, this research also offers hope that new genomic technologies will yield genetic information that has long been unavailable. “There is a lot of genetic variation that has been missed, and there are now technologies that can interrogate that,” said Jonas Korlach, Ph.D., chief scientific officer at PacBio. In addition to long-read sequencing, those technologies include (among others) linked-reads developed by 10X Genomics; and optical mapping, offered by Bionano 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 promise 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 single 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, insertions, 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,” Korlach 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 information for discovering disease-causing genes.

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