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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22 Clinical OMICs March/April 2018 www.clinicalomics.com are common culprits in neurodegenerative disorders, Aro noted. For example, in the FMRI gene on the X chromosome, most normal people carry a 30-unit CGG repeat with one or two AGG interruptions. By comparison, in people with Fragile X syndrome, one of the most common forms of inherited intellectual disability and autism, the CGG repeat is much longer (200–750 units). Research- ers have used LRS to look at these repeats and found that the risk of Fragile X syn- drome increases the more CGG repeats are present and fewer AGG interruptions. Long reads also enable the separation of an indi- vidual's two chromosomes. "Instead of both alleles col- lapsed into one, you actually have two sequence files, one for each chromosome," said Tina Graves-Lindsay, leader of the reference genomes group at the McDonnell Genome Institute at Wash- ington University in St. Louis. It's an important step forward, she said. "If there's a disease gene on one chro- mosome you won't necessarily see it if you've done the compressed alleles." To date, one downside of long-read sequencing has been the cost. But that is coming down, Korlach says. Graves-Lindsay agrees: "Although PacBio has always been fairly expensive, at least compared with Illumina sequenc- ing, they are having a ramp up with their new instrument, so it's making sequencing cheaper." Linked Reads What if, instead of designing a brand-new machine to sequence longer molecules, you simply found a way to add long-range information onto short-read data? That's the approach taken by 10X Genomics. Their system dilutes a small part of the genome in an oil droplet in such a way that there are only a few longer molecules in each droplet. Then, they add a bead with unique barcode to each droplet so that each short read from the longer molecule in a droplet will have the same bar code, allowing reconstruction of the longer molecule. The 10X approach is more affordable than LRS because it only involves changing sample prep rather than moving away from SRS altogether, Narayanan said. Another advantage is linked reads require only 1 nano- gram of material, whereas LRS needs several micro- grams. Moreover, like long reads, linked reads can resolve haplotypes. This is particularly valuable for autosomal recessive disor- ders (where a person inher- its two copies of a defective gene, one from each parent), noted Narayanan. With linked-reads, "you can actu- ally tease apart each parent's chromosome," she said. That's one reason research- ers from the geographically isolated Faroe Islands have turned to 10X Genomics. They were concerned about an autosomal recessive dis- order that kept cropping up on the island. Using 10X, they plan to sequence the genomes of the entire island's popula- tion (50,000 people) to look at each person's maternal and paternal copies of the problematic allele. It helps, Narayanan addeed, that 10X needs only a small blood prick to provide a complete picture—not just of SNPs but also of SVs—all in one assay. Building a Genome Ladder Bionano Genomics offers yet another way to find SVs. Rather than "fix sequencing with more sequencing," said Sven Bocklandt, Ph.D., Bionano's senior application special- ist, the company builds a structural ladder of the genome that reveals large (greater than 1,000 base pair) structural (continued from previous page) (continued on page 24) SMALL VARIANTS < 50 BASE PAIRS / VARIANT > 50 BASE PAIRS / VARIANT STRUCTURAL VARIANTS DELETION INVERSION INSERTION TANDEM DUPLICATION INTERSPERSED DUPLICATION TRANSLOCATION TYPES OF GENOMIC VARIATION STRUCTURAL VARIANTS COMPRISE MORE THAN HALF OF GENOMIC VARIATION 60% 1 BASE PAIR / VARIANT 1-49 BASE PAIRS / VARIANT KNOWN DISEASES CAUSED BY STRUCTURAL VARIANTS SCHIZOPHRENIA Deletion, Duplication CARNEY COMPLEX Deletion HEREDITARY BREAST & OVARIAN CANCER Deletion, Insertion POOR DRUG METABOLISM Duplication CHRONIC MYELOID LEUKEMIA Translocation NEUROFIBROMATOSIS Insertion SNV INDELS www.pacb.com/sv + 1,000' s MORE KNOWN… …AND MANY TO BE DISCOVERED > 20,000 STRUCTURAL VARIANTS IN A HUMAN GENOME For Research Use Only. Not for use in diagnostic procedures. PN: INF100-091817 Structural variants (SVs) represent approximately 60 percent of all human genomic variation, yet Illumina short-read sequencers do not reliably find them. PacBio uses long-read sequencing to reveal SVs in hopes of boosting the diagnostic yield from genetic testing. (Infographic Courtesy of Pacific Biosciences)

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