Genome for $ 100? New DNA sequencers could change the game in biology, medicine science

For DNA sequencing, this is “the year of the big change,” said Michael Snyder, a systems biologist at Stanford University. Consistency is crucial in areas from basic biology to virology to human evolution, and its importance continues to grow. Clinicians insist on using it for early detection of cancer and other diseases, and biologists are finding more and more ways to use genomics to study individual cells. But for years, most sequences relied on machines from a single company, Illumina.

Last week, however, a young company called Ultima Genomics said at a meeting in Orlando, Florida, that with new twists in existing technology, it could provide human genomes for $ 100 apiece, one-fifth of the current price. Several other companies also promised faster and cheaper sequencing at the same meeting, Advances in Genome Biology and Technology. This year, major patents defending Illumina’s sequencing technology will expire, paving the way for more competition, including from Chinese company MGI, which last week announced it would start selling its machines in the United States this summer. “We may be on the brink of the next sequencing revolution,” said Beth Shapiro, an evolutionary biologist at the University of California, Santa Cruz (UCSC).

Most sequencing companies, including Illumina, which controls 80% of the global market, depend on “synthesis sequencing”. The DNA to be deciphered is divided into single strands, which are usually cut into short pieces and mounted on a surface – often a tiny grain – in a container called a flow cell. Each single thread fragment serves as a template to guide thread synthesis with complementary bases delivered one by one to the pearl channels. As each added base is changed to glow, the camera can record where it is attached – and hence the identity of the corresponding base on the original thread. The steps are repeated until the new DNA strand is completed.

Ultima streamlined the process by spraying billions of DNA-laden pearls on round dessert-sized silicon wafers. The nozzles above each wafer gently spray bases and other reagents, which are spread thinly and evenly over the substrate as it rotates, reducing the amount of these expensive materials required. Instead of moving back and forth under the camera, the disc spirals, similar to how a CD is played, which speeds up imaging. This is “smart engineering.” [that] avoids very complex plumbing, ”said Mark Akesson, a molecular biologist at UCSC. A neural network program quickly converts image data into a sequence.

The chemistry of the sequence is also different. Only a few bases carry fluorescent labels, which reduces costs. In addition, the bases lack the usual stop signal, which ensures that no additional bases will be locked. Without these “terminators”, the growing chain can sometimes add several bases at once, speeding up the process. “Many of these innovations are used elsewhere, but they seem to have come together very well here,” said Jay Shendure, a geneticist and technology developer at the University of Washington (UW) in Seattle.

Ultima CEO Gilad Almogi and his colleagues demonstrated the technology’s potential in four pre-printed photos published in late May on bioRxiv. In one, they and their colleagues at the Broad Institute of Massachusetts Institute of Technology and Harvard used their machine to sequence more than 224 already sequenced human genomes and found that their results were the same as their previous work. Three other studies show that the technology can assess a cell’s repertoire of expressed genes, the effects of mutations and epigenetics – chemical modifications of DNA that affect gene activity.

Until now, the cost has limited such unicellular research, making research difficult. But Snyder found that Ultima’s cheap approach allowed him to sequence multiple colon cancer cells to document how a modification of DNA, methylation, changes with the development of colon cancer.

In another prepress, Joshua Levin and his colleagues at the Broad Institute tested the ability of Ultima technology to identify active genes in individual blood cells, as shown by RNA transcripts of the genes. The team found that Ultima’s machine identified these genes as well as Illumina’s. And he added: “This changes the game because of the lower price.”

Florence Chardon, a UW genomics student who modifies DNA with the CRISPR genome editor, is excited about the prospect. “The cheaper [sequencing] the more accessible this type of research is for more laboratories and more people, ”she says.

But Lior Pachter, a computational biologist at the California Institute of Technology, has reservations about the new technology. He and graduate student A. Sina Booeshaghi examined one of the most active genes in blood cells from Levin’s team, a possible biomarker for cancer, also known to produce a protein that athletes sometimes inject to increase their performance illegally. Ultima technology sometimes misses the active gene, Patchter said. “The error rate was very high and productivity was very low.”

The gene has a stretch in which the same base is repeated eight times, and Ultima acknowledges that long repetitions can undermine the accuracy of its readings. Searching elsewhere in the Ultima sequence, Patchter finds errors when a base is repeated only three times. He notes that the human genome contains at least 1.4 million of these so-called homopolymers. However, he says, “Some applications don’t need perfect sequences.”

Patchter and others also oppose the advertised $ 100 price tag. This figure covers only reagents, not labor, pre- and post-sequencing steps, and initial costs for an unpublished machine. Even if the $ 100 figure is real, it may not be unique: other companies are also promising $ 100 for the human genome.

One is MGI, a subsidiary of Chinese sequencing giant BGI. MGI technology is similar to that of Illumina, but increases accuracy by adding four bases at once while sequencing DNA. To track which bases are involved, he uses antibodies that are brighter and cheaper than fluorescent dyes. Illumina also promised lower costs and presented new chemicals at the meeting to increase accuracy and flexibility.

To realize this bargain, Ultima and MGI require filling their sequencers to capacity with hundreds of genomes. But high-throughput sequencing is “not always good for clinical practice, even if it’s good economics,” says Greg Elgar, a genomics biologist at Genomics England, because sometimes a doctor only needs to analyze the genome of one or more people. Other companies with new flow cells and chemistry can economically sequence a small number of genomes. At last week’s meeting, Element Biosciences CEO Molly He announced that the company was already supplying desktop sequencers that could sequence three human genomes at once, at a cost of $ 560 each. Another company, Singular Genomics, also promises desktop technology that doesn’t require high bandwidth to save costs.

These machines, like those from Illumina, MGI and Ultima, all decipher short fragments of DNA. But over the past seven years, two companies, Pacific Biosciences and Oxford Nanopore Technologies, have worked on sequencing “long readings,” thousands of bases that leave fewer partial sequences to fit into a complete genome. Technology “can sequence the natural DNA molecule in all its glory,” says Elgar. They struggle with low accuracy and high cost, but he says they are on track to become practical tools.

You still don’t count the sequencing giant Illumina. His scientists “probably kept a few cards in their back pockets” to maintain their strong market position, said Albert Villela, a bioinformer and genomics consultant in Cambridge, England. Nevertheless, Illumina faces unprecedented competition, he added. “It is time to look [DNA sequencing] a landscape with fresh eyes. ”

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