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BeyondSeq Report Summary

Project ID: 634890
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - BeyondSeq (Genomic diagnostics beyond the sequence)

Reporting period: 2015-05-01 to 2016-10-31

Summary of the context and overall objectives of the project

Accurate diagnosis is a prerequisite for efficient health care. Ideally, if signs of pathogenesis could be detected before or at early stages of disease onset, then effective intervention and treatment may be administered. Many disease states are associate with genomic aberrations such as specific genetic mutations, epigenetic modifications or DNA damage lesions. Characterization of such aberrations at early stage relies on ultra-sensitive genomic analysis that is only partially addressed by the current available technologies. Diagnostics based on cytogenetic approaches provides information on the single-chromosome level but suffers from low resolution and low throughput. In contrast, next generation sequencing (NGS) based diagnostics provides single base resolution and high throughput but suffers from short reads that prevents the analysis of large genomic aberrations, as well as being prone to bias due to PCR-amplification and erasure of epigenetic information.
The ground-breaking goal of this research proposal is to establish a robust set of diagnostic assays via single-molecule, genetic/epigenetic profiling of native chromosomal DNA. A successful accomplishment of this goal will allow the characterization of genomic aberrations otherwise hidden by ensemble averaging. Dissemination and commercialization of the developed technologies will open new horizons in biomedical diagnostics and personalized medicine.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The beyondSeq project has fostered exciting new collaborations between the member teams. these collaborations already yielded joint publications and several others are currently in the pipeline. During the first period of the project we have developed a new DNA labeling strategy for mapping of specific sequence motifs that will allow DNA mapping and bar-coding. Reagents and protocols have been circulated among the teams in order to establish a commercialization ready kit for general use.
In addition, instrumentation and devices for deposition and imaging of individual DNA molecules have been developed and tested by several partner groups. The new devices comprise a critical step towards realization of the project aims to create a compete toolbox for single molecule characterization. Additional promising advances in this front are microfluidic sorting and size selection of DNA and advanced solid state nano-pore devices combined with optical detection. This working period has also shown first results in the context of advanced genetic and epigenetic testing. specific labeling schemes have been developed for the identification of disease related genetic mutations on individual chromosome segments as well as for diagnosis of cancer by epigenetic bio-markers. Finally, we have invested efforts to promote single-molecule assays related to antibiotic resistance in bacteria and have shown promising results for analysis and mapping of bacterial resistance plasmids.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This research project aims to establish a robust experimental toolbox for genetic and epigenetic profiling of unamplified genomic DNA molecules. We focus on emerging DNA mapping technologies and their transition from lab to clinic with the potential to dramatically expand diagnostic capabilities based on genomic information.
Successful accomplishment of this proposal is expected to significantly promote the state-of-the-art within several key areas of both basic life science research and medical sciences. The proposed toolbox and resulting assays will open new diagnosis and prognosis avenues and may lead to exciting new discoveries that will broadly impact the genetics and epigenetics research communities by providing unprecedented potential for studying the genomic aspects of pathogenesis.
We specifically address three types of challenges to current genomic-based diagnostics:
(i) Loss of relevant information such as DNA damage, rare mutations or epigenetic marks following PCR amplification.
(ii) Limitations in resolving long-range variations in genomic layout, preventing large scale screens (including DNA repeats, structural variations and copy number variations).
(iii) Limitations imposed by the sample such as low sample amounts (micro biopsy) or inhomogeneous/ highly variable samples (bacterial cultures)
Within the scope of this proposal we aim to deliver a set of diagnostic tools in the form of fully functional assays that demonstrate the utility of our single-molecule approach and provide concrete solutions for pressing biomedical diagnostic challenges. The general concepts and methods developed in this project will open new avenues for the future development of additional innovative diagnostic tools.

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