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Dutch Startup Gen-X Offers Functional Genome Annotation Services

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SAN FRANCISCO (GenomeWeb) – Startup Gen-X, which spun out of the Netherlands Cancer Institute in 2017, is offering services for functional genome annotation using its survey of regulatory elements (SuRE) technology.

SuRE is a method for characterizing regulatory elements by transfecting barcoded plasmid libraries containing millions of random DNA fragments into cells. Transcripts of the barcodes are only produced if the inserted DNA fragment contains a transcription start site, allowing for both active promoters and enhancers to be identified.

Joris van Arensbergen, the company's CEO, began developing SuRE when he was a postdoctoral researcher in Bas van Steensel's lab at the Netherlands Cancer Institute. The team first described the technology in a Nature Biotechnology publication in 2017 and van Arensbergen spun out Gen-X soon after. But it wasn't until this year that he began focusing on the startup full time. The company now has the three employees, two of which are part-time, and van Arensbergen anticipates having around four full-time positions by the end of the year. The company is funded solely through its service revenues. Van Arensbergen declined to disclose the cost of it services, noting that price is dependent on the scope of the project and so varies between customers.

He said that the goal of developing the SuRE technology was to enable the high-throughput identification of regulatory elements. "High-throughput technologies like RNA-seq and ChIP-seq give a genome-wide picture of where RNAs are produced and where proteins bind," he said. "But these are descriptive assays, not functional [ones]." The gold standard functional methods are still very low throughput. "We wanted to close the gap between high-throughput methods that are purely descriptive and the functional assays that are low throughput."

The SuRE assay involves first building a plasmid library that contains hundreds of millions of random DNA elements, each linked to a unique 20-bp barcode. Each DNA element is about 300 bp in length, with unique start and end positions. One library will give about 30-fold coverage of a human genome. The library is then transfected into cells and the DNA elements that contain promoters or enhancers will transcribe the downstream barcode. The transcribed barcodes are then isolated from the other mRNA and sequenced, which gives a genome-wide quantitative profile of the promoter and enhancer activity.

In a Nature Genetics study published last month, the Netherlands Cancer Institute team described how such an assay could be applied to identify SNPs that impact regulatory activity.

In that study, the researchers demonstrated how the technology could be applied. For instance, the team combined SuRE with a GWAS that identified more than 6,700 "lead" SNPs associated with at least one of 36 blood-related traits. Such lead SNPs are not necessarily causal and are typically accompanied by more than 150 other SNPs, any of which could be the causal one, van Arensbergen said.

Overlaying SuRE data helped to focus in on potentially causal SNPs. For instance, he said, SuRE pointed to one SNP in particular that was within 100 kilobases of 11 lead SNPs associated with red blood cell traits like hemoglobin concentration. That SNP sits 11 kilobases upstream of a gene responsible for inhibiting red blood cell production in mice, suggesting that it may play a role in regulating red blood cell production by affecting the expression of that gene.

Van Arensbergen said that combining SuRE with GWAS and eQTL studies will be one application of the technology. "When you look at GWAS and eQTL studies, 95 percent of disease- and trait-associated variants are identified in noncoding parts of the genome," he said. But, researchers tend to focus on the 5 percent that are in coding regions, since those are the ones they can understand and better interpret. In addition, he said, GWAS and eQTL studies are "low resolution," identifying huge blocks of DNA that often contain hundreds of variants. "So you're stuck with the problem of having hundreds of SNPs without knowing which is causal," he said. "But with this assay, you can look at those noncoding variants and see if any of them affect regulatory activity." Such regulatory variants are also thought to play a big role in impacting disease and traits.

While other technologies have also been developed to study regulatory elements, including ChIP-seq and ATAC-seq, van Arensbergen says that the SuRE technology is different in that it provides a more direct readout of promoter and enhancer activity. ATAC-seq identifies regions of chromatin that are open, which can indicate a potential regulatory element, but the method does not measure the DNA in isolation, so it's not clear whether the regulatory activity is due to the underlying sequence or another factor such as the 3D architecture of the chromatin or a distal enhancer.

The company is offering the SuRE technology as a service and van Arensbergen said that initial interest has been primarily from companies developing gene therapies. The technology is particularly suitable for research in gene therapy because it enables a genome-wide profile of promoters and enhancers and can be done in different cell types and under different conditions. For instance, van Arensbergen said, "a researcher can stimulate a blood cell line with a steroid and then identify those elements that become active on stimulus." He noted that Gen-X is currently working with a gene therapy company focused on arthritis that is looking to identify elements that can be used to regulate expression of a therapeutic gene.

A second major application will be in basic research for pharmaceutical or agricultural companies looking to identify genetic targets. For example, Gen-X is currently involved in a research project to screen patients with monogenic diabetes. The patients already had exome sequencing, which failed to identify a mutation responsible for their condition. Gen-X will apply its SuRE technology to screen these patients for noncoding mutations that could potentially explain their condition. In another project, for a consortium of agricultural companies, Gen-X will use the SuRE technology to functionally annotate the tomato genome.

Longer term, van Arensbergen said the company would be interested in continuing to pursue projects such as the diabetes study to annotate the genomes of patient cohorts for which a genetic cause is suspected but for whom a causal mutation has not been identified by exome or whole-genome sequencing. Ultimately, its service could become as a complement to diagnostic sequencing that yields a negative result.

In addition, while Gen-X is currently focused on providing the technology as a service, van Arensbergen said that there could be the possibility of developing products. He did not think that the company would develop the SuRE assay into a kit, but instead it might develop specific promoters or enhancers for gene therapy strategies. However, he noted that this was not in the firm's near-term plans.

The main focus will be to broaden the number of customers, especially within the gene therapy space, and to further develop the bioinformatics for functional annotation of the genome. 

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