Genetic Engineering & Biotechnology News

OCT15 2017

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Genetic Engineering & Biotechnology News | GENengnews.com | OCTOBER 15, 2017 | 11 that it was determined that individual single nucleotide polymorphisms do not accurately predict the copy number state, making ge- nome-wide association studies unable to ac- curately predict repeat numbers. To address this challenge, Dr. Gokcumen and colleagues identified several single nucleotide poly- morphisms that tag independently evolved PTS-repeat alleles and found combinations that predicted the copy number status. This analysis revealed that the number of subex- onic repeats in mucin-7 was not associated with asthma, but discovered a correlation between haplotypic variation in this gene and oral microbiome composition. "Where we are heading is not necessarily individual copy number variants any longer, but more a haplotype-level understanding of genetic contribution," says Dr. Gokcumen. Individual variants may change the func- tion of multiple genes in a manner that is shaped by other variants somewhere else in the genome. "On top of that and even fur- ther up, we have a large contribution from the transcriptome and microbiome, and now the question becomes how a copy number variant and the associated single nucleotide polymorphisms are behaving given a par- ticular diet, under a particular microbiome composition, or under a specific immune pathogenic pressure, rather than just making a simple association," says Dr. Gokcumen. CNVs in Genitourinary Malignancies "We looked at several genitourinary ma- lignancies in The Cancer Genome Atlas," says Mark W. Ball, M.D., clinical fellow in urologic oncology at the National Cancer Institute. In a recent analysis of datasets for several genitourinary malignancies from The Cancer Genome Atlas, conducted at the Johns Hopkins University School of Medi- cine, Dr. Ball and colleagues examined the correlation between somatic mutations and CNVs with pathological features and surviv- al outcomes. "We did not find this for every malignancy, but the overall trend was that a higher rate of copy number variation was as- sociated with advanced pathological features and worse survival outcomes," says Dr. Ball. One of the limitations in understanding the involvement of CNVs in genitourinary malignancies is the scarcity of data. "Previ- ously, we did not really have a lot of data, and currently The Cancer Genome Atlas is all that we have," says Dr. Ball. Even then, much less data are available as compared to other malignancies, such as colorectal cancers, for which copy number changes have been studied to a much greater extent. "There is a push and an enthusiasm on mul- tiple fronts towards an era of personalized medicine, and if we perform more sequenc- ing and copy number variation assays we will gain a lot of understanding of how these endpoints, which are currently mostly theo- retical, translate into picking a treatment strategy for a patient," says Dr. Ball. Cytochromes and Medication Metabolism "We have been using the Pacific Biosci- ences long-read third-generation sequenc- ing platform to interrogate genomic regions that would typically not be accessible using short-read technologies," says Stuart Scott, Ph.D., associate professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai. A key focus in Dr. Scott's lab is CYP2D6, a highly polymor- phic gene that encodes a cytochrome P450 involved in the metabolism of approximate- ly a quarter of all common medications. Pre- dicting CYP2D6 metabolizer status requires knowledge of both the copy number and the sequence of each allele, because duplication of a functional copy will lead to an increased amount of an active enzyme, but duplica- tion of a non-functional allele will still not be functional. Using short-read sequencing to interro- gate the CYP2D6 gene is challenging due to the high sequence homology between CYP2D6 and its neighboring pseudogenes. Consequently, Dr. Scott and colleagues de- veloped a single-molecule real-time (SMRT) sequencing assay, which allowed for full gene characterization and the discovery of dupli- cated and novel alleles. "For samples that had more than two copies, we would also amplify and barcode the duplicated region and sequence it," says Dr. Scott. The size of the gene, approximately 5 kb, allowed se- quencing of the entire gene in one long mul- tiplexed read. "On the analytical side, which is the genetic testing side, we need to be able to generate high-resolution sequencing data for these difficult-to-interrogate regions and genes, and have high confidence in the data that we derive from sequencing," says Dr. Scott. On the clinical utility side, an impor- tant consideration is to identify whether any therapeutic recommendations or changes can be made for an individual, based on the results. "It is critical to determine whether these changes would lead to any therapeutic benefits, and that is currently very highly de- bated," says Dr. Scott. References available online. Drug Discovery VIAFLO II ASSIST VOYAGER II Adjustable Tip Spacing Pipette Motorized tip spacing enables parallel transfers of multiple samples between labware of different sizes and formats. The tip spacing can be changed by the simple push of a button, no manual adjustments or two handed operations are needed. 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