Genetic Engineering & Biotechnology News

OCT15 2017

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10 | OCTOBER 15, 2017 | GENengnews.com | Genetic Engineering & Biotechnology News "Over the past two years, we have been working on a new project, in which we looked at a smaller number of individuals but in a much more comprehensive way with respect to structural variation, using orthogonal genomic technologies, including long-read technologies. We are finding so much more structural variation," adds Dr. Lee. Many structural variants occur in parts of the genome that have tandem repeats sur- rounding them, and this partly explains the difficulties in annotating them. "Short reads have significant limitations in terms of what they are able to find," says Dr. Lee. Long-read technologies, as well as technologies such as strand-seq and optical mapping, provide information on a larger scale and are ideally positioned to identify and characterize structural variants in chro- mosomal regions that were much more chal- lenging to identify and analyze in the past. A better insight into the structural complexity of the CNVs may shed light on their func- tional relevance. "Once our results are re- leased, people will be able to use the infor- mation to go into their gene or region of in- terest and delve into the functional aspects in much more detail than we will be doing with the scope of the current study," says Dr. Lee. Paralleling the growing interest in under- standing chromatin structure-function rela- tionship, a topic of interest in recent years has been to interrogate the way in which structural variants can change chromatin structure locally. "We are just starting to scrape the surface of how structural varia- tion changes may cause a local change in chromatin structure and how that alters the expression of a gene nearby and leads to a phenotype, and a lot more work is needed to look at this," says Dr. Lee. Evolution and Links to the Microbiome "We have always been proponents of the involvement of copy number variants in shaping human phenotype, disease, and evo- lution, but that is a very hard thing to test," says Omer Gokcumen, Ph.D., assistant pro- fessor of biological sciences at State Univer- sity of New York at Buffalo. Most inter-indi- vidual genomic variation, when the number of base pairs is considered, is generated by CNVs. "The problem is that the mechanisms that create these copy number variants as compared to single nucleotide variants are different," says Dr. Gokcumen. CNV may be created through repair errors from non- homologous recombination, other types of recombination errors, or gene conversions. "This leads to differences in where they oc- cur in the genome and, also, to differences in their size, and generates many subcategories of copy number variants, with potentially different implications in disease and type of disease," says Dr. Gokcumen. Salivary MUC7, an abundant human protein encoded by the mucin-7 gene, is a good example of such variation in the types of functional CNVs and a primary focus in Dr. Gokcumen's lab. The mucin-7 gene car- ries 69-base-pair subexonic repeats that oc- cur in various copy numbers among individ- uals. These repeats, which affect protein size, encode for densely O-glycosylated proline-, threonine-, and serine-rich (PTS) tandem re- peat domains. The protease-resistant glycan regions provide binding sites for microbes. "The 1000 Genomes Project, which is the ultimate and most accurate database that we have right now, is completely miss- ing the copy number variation in this gene there because it is so hard to discover them with shorts reads," says Dr. Gokcumen. To capture the PTS-repeat CNV in mucin-7, Dr. Gokcumen and colleagues genotyped 251 random samples from the 1000 Ge- nomes Project and revealed that CNV in this gene occurred independently in at least two branches of the human phylogenetic tree. Subsequently, an analysis of more than 2,500 genomes revealed that MUC7 sub- exonic CNVs fell into eight divergent hap- lotype clusters. Two haplogroups had the 5 PTS-repeat allele and the others harbored the 6 PTS-repeat allele. The gene in a group of genomes from sub-Saharan Africa was very different from the versions that were found in other humans. Three independent studies have previous- ly associated CNV in PTS repeats of MUC7 with asthma susceptibility. 1–3 However, one of the shortcomings with the studies was Drug Discovery R By simultaneously quantifying and qualifying nucleic acid samples in parallel, the Fragment Analyzer™ is transforming sample prep analysis for the world's leading genomic research institutions. 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More at AATI-US.COM Single Cell Genomics DNA, RNA, cancer, heterogeneity, homogeneity, cell signaling, high throughput , automation, sensitivity, rapid advancement, isolation, cell sorting, SNP, CNV, metagenomics, 6pg DNA, 10pg RNA, 6 billion base pairs, phenotype, function, epigenetics, molecular profiling, clonal expansion, stem cells, CTC, microbial ecology, cellular lineage, regulatory networks, 30,000 genes, cell profiling, sequencing Single Cell Genomics DNA, RNA, cancer, heterogeneity, homogeneity, cell signaling, high throughput , automation, sensitivity, rapid advancement, isolation, cell sorting, SNP, CNV, metagenomics, 6pg DNA, 10pg RNA, 6 billion base pairs, phenotype, function, epigenetics, molecular profiling, clonal expansion, stem cells, CTC, microbial ecology, cellular lineage, regulatory networks, 30,000 genes, cell profiling, sequencing Single Cell Genomics DNA, RNA, cancer, heterogeneity, homogeneity, cell signaling, high throughput , automation, sensitivity, rapid advancement, isolation, cell sorting, SNP, CNV, metagenomics, 6pg DNA, 10pg RNA, 6 billion base pairs, phenotype, function, epigenetics, molecular profiling, clonal expansion, stem cells, CTC, microbial ecology, cellular lineage, regulatory networks, 30,000 genes, cell profiling, sequencing Single Cell Genomics DNA, RNA, cancer, heterogeneity, homogeneity, cell signaling, high throughput , automation, sensitivity, rapid advancement, isolation, cell sorting, SNP, CNV, metagenomics, 6pg DNA, 10pg RNA, 6 billion base pairs, phenotype, function, epigenetics, molecular profiling, clonal expansion, stem cells, CTC, microbial ecology, cellular lineage, regulatory networks, 30,000 genes, cell profiling, sequencing JUST RIGHT FOR SINGLE CELL GENOMICS While some changes introduced by copy number variations may have no phenotypic consequences, others underlie disease, explain evolutionary processes, or impact the response to medication. Copy Number Variation Continued from page 8

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