Researchers at Australia's Garvan Institute of Medical Research have developed a new technology based on synthetic human genome sequences, which they have dubbed “Sequins” and describe as synthetic mirror DNA sequences that reflect the human genome. The new technology is described in two linked studies—“Spliced synthetic genes as internal controls in RNA sequencing experiments” and “Representing genetic variation with synthetic DNA standards”—published recently in Nature Methods. The researchers are hopeful that this intuitive new technology will become useful for better genome mapping and analysis, in both analytical and clinical laboratories.
The human genome is riddled with complexity, yet fundamentally simple, containing only four DNA “letters” (A, C, G, and T) that constitute more than 6 billion DNA bases. While an individual’s genome can be sequenced relatively cheaply and quickly, the subsequent analysis of the human genome is a much deeper and more complicated problem.
"Human genome sequencing is transforming biomedical research and healthcare," explained senior study author Tim Mercer, Ph.D., who led the development of sequins and is a lab head at Garvan's Genomics and Epigenetics Division. “And as genome sequencing is being increasingly used to diagnose disease, it is more important than ever that researchers and clinicians understand the accuracy of the genomic data they are looking at."
Dr. Mercer and his team came up with the idea of adding sequins to a patient's DNA sample during sequencing. These sequins (or sequencing spike-ins) then act as internal standards, helping researchers analyze the large data files that are generated during genomic sequencing.
"Sequins are, essentially, mirror images of natural DNA sequences,” Dr. Mercer noted. “Like us, the genome has a 'handedness', and just as our right hand differs from our left hand, sequins differ from natural genome sequences. So sequins behave just like natural genome sequences, but they can be easily recognized as synthetic."
When sequins are added to a sequencing reaction as internal controls, they provide the means with which to assess the sensitivity and accuracy of genome sequencing.
"A whole series of steps, first in the lab and then on the computer, are required to sequence a person's genome or the genes that are expressed in different cells,” Dr. Mercer remarked. “Sequins are with the person's DNA every step of the way: responding just as real DNA does at each step, yet unmistakably different from that real DNA. This allows a scientist to assess, and optimize these different steps."
Since sequins are added to each sample, they can provide a sample-by-sample assessment—an analysis that has not previously been possible.
The Garvan researchers believe that clinical diagnostics is an area in which using sequins should lead to improvements—for example in cancer diagnosis.
"Sequins are the first technology to allow diagnostic statistics to be applied to each individual genome sequencing test," Dr. Mercer stated, "and we anticipate that their use will improve the reliability and sensitivity of genetic disease diagnosis."
Moreover, the use of sequins may also make it possible to directly compare genomic data from research institutes and sequencing centers worldwide.
"Sequins bring DNA sequencing to clinical standard, and will be an essential platform for genomic research and medicine," said co-author John Mattick, Ph.D., executive director at the Garvan Institute.
Since all genomes, from bacteria to human, have handedness, sequins can be similarly designed for any organism, or for almost any next-generation sequencing platform, making the potential applications of sequins almost limitless. And the best part for researchers is that the sequin technology is freely available.
"We invite academics to get in touch, and we can send them some Sequins for their genome research,” Dr. Mercer said. “We're keen to get this technology out into other labs, in Australia and worldwide."
"This is another important step in advancing Garvan's mission to bring genomics to the clinic," said Dr. Mattick.