From sequencing DNA to sequencing life

Whoever invented the term Next-Generation Sequencing (NGS) wasn’t making things easy for whoever has to name its successor – what would you call the next next generation of sequencing technology? The field continues to develop at a rapid pace, says Wei Chen, who heads the Genomics platform at the Berlin Institute for Medical Systems Biology (BIMSB). Over the past two years or so, he says, the most significant changes in sequencing have sprung from economics rather than engineering, so there’s still time to think of a name.

Rapidly falling costs have brought genome-wide studies within the reach of many more groups, Wei Chen says, enabling scientists to approach the core facility with a wider range of questions. One concerns the variation found in individuals, or in diseased tissues such as tumors – crucial for zooming in from the level of a species to that of a single person, and an essential step along the path toward “personalized medicine.” Genome-wide association studies (GWAS) are now exposing subtle new connections between hereditary variations, an individual’s likelihood of developing particular diseases, and likely responses to a specific therapeutic regime.

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Wei Chen, Wei Sun and Claudia Quedenau in the BIMSB Genomics core facility. Photo: David Ausserhofer / MDC

 

Sequencing projects continue to reveal new mechanisms underlying devastating diseases. In 2014, in a project carried out with Joachim Will’s group in the Division of Pediatric Cardiology at the Charité, Sebastian Fröhler and other members of Wei’s group carried out an analysis of members of a family including two children affected by a disease called Long-QT syndrome. This rare hereditary disease alters the rhythm of the heartbeat, is accompanied by a range of cognitive and physical disorders, and can lead to sudden death. A screen of genes known to be involved in the syndrome had failed to reveal a typical mutation. The BIMSB group used whole-exome sequencing – analyzing all protein-encoding regions of the genome – to search for another molecule that might be involved. They discovered a new mutation in a gene called CACNA1C, which encodes a calcium ion channel, helping to refine the diagnosis and opening new avenues for treatment.

Deep sequencing methods have also been giving researchers a much closer look at complete transcriptomes, revealing a huge range of RNA molecules produced by cells that go far beyond protein-encoding messenger RNAs. The facility has helped characterize populations of microRNAs that play an important role in regulating the flow of information from genes to proteins during embryonic development and other processes. Their methods are also providing insights into many other species of molecules such as long-noncoding RNAs (lncRNAs) , whose functions are not yet clear.

Additionally, powerful new combinations of sequencing and biochemical methods are also providing a deeper look at epigenetic characteristics of cells involved both basic biological processes and disease. The differentiation of most stem cells into specialized types, for example, is accompanied by certain types of changes that are now accessible to sequencing. The same is true of tissues affected by a range of pathologies.

Particular sequences – or proteins such as histones that are associated with them – may acquire chemical tags such as methyl groups, which often change the activation status of nearby genes. These changes can be detected on a genome-wide scale, either through chemical methods that expose DNA sequences that have been methylated, or antibodies that target specific changes in histones and can then be pulled down for an analysis of nearby sequences. The latter method is being used in an enormous national project called the German Epigenome Consortium, which aims to characterize epigenetic features of basic human biology and diseases.

Such innovations have turned the sequencing of DNA and RNAs into tools that can now be used to explore new aspects of the biology of humans and other organisms. Many more applications will surely be developed in the near future, Wei Chen says. Combined with falling costs, this is giving scientists an enormous new palette of tools to investigate new fundamental and health-related aspects of the biological questions they have been pursuing for many years.

Link to the homepage of Wei Chen’s group:

https://www.mdc-berlin.de/18619167/en/research/core_facilities/genomics_platform

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