Tyler O'Neal, Staff Editor SYSTEMS

Japanese scientists use next-generation genome sequencer, supercomputer to show the arrangements of the genome's spool-like structures affecting gene expression

Scientists at Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS) in Japan have developed a technology that produces high-resolution simulations of one of the basic units of our genomes, called the nucleosome. Their findings should help improve understanding of how changes in nucleosome folding influence the inner workings of genes.

Nucleosomes are the basic structural units of DNA packaging inside the nucleus. They are formed of DNA wrapped around a small number of histone proteins. Nucleosomes move around inside the nucleus, folding and unfolding, changing their orientations, and moving closer together or further apart. These movements affect the accessibility of various molecules to DNA, determining when and how genes turn on and off. The research group has developed a new technology to analyze the 3D positions and orientations of nucleosomes using a next-generation genome sequencer and a supercomputer. CREDIT Mindy Takamiya/Kyoto University iCeMS

"The 3D genome structure provides the physical molecular basis of gene expression processes in cells," explains iCeMS systems biologist Yuichi Taniguchi, who led the research.

To better visualize this structure, Taniguchi and colleagues developed Hi-CO, short for high-throughput chromosome conformation capture with nucleosome orientation. It builds on existing Hi-C technology by significantly improving resolution so that simulations show the 3D positions and orientations of every nucleosome analyzed in a sample.

"Being able to analyze this structure should help clarify the origins and control principles of many biological phenomena, including cell differentiation and immunity," says molecular biologist Masae Ohno, who conducted the experiments and analyses.

Hi-CO involves a month-long process in which enzymes and a variety of other molecules are used to treat an organism's genome, ultimately breaking down its DNA into millions of fragments that were close to each other due to nucleosome proximity. These fragments are then sequenced and the data is entered into a simulation program that shows the most likely orientations of each nucleosome.

Taniguchi and his team successfully tested Hi-CO on a yeast genome. They aim to next use it to analyze the genomes of other organisms while continuing to improve the technology. They also hope to use Hi-CO to study genome structures in various cell differentiation states and diseases.

Zhores supercomputer helps Russian researchers model new a method of generating gamma-ray combs

Tyler O'Neal, Staff Editor SYSTEMS

Skoltech researchers used the resources of the university's Zhores supercomputer to study a new method of generating gamma-ray combs for nuclear and X-ray photonics and spectroscopy of new materials. The paper was published in the journal Physical Review Letters.

A gamma-ray comb is a series of short bursts that, when plotted as intensity versus frequency, look as sharp and equally spaced teeth of a comb. Generating these combs at high brightness in the gamma-ray domain has been challenging because of something called ponderomotive spectral broadening - an effect that destroys the monochromaticity that allows gamma-ray sources to be used in nuclear spectroscopy, medicine, and other applications.

Sergey Rykovanov and Maksim Valialshchikov from the Skoltech High-Performance Computing and Big Data Laboratory as well as Vasily Kharin from Genity LLC offered a way to avoid this effect. To obtain the calculations needed to support this result, they used the Zhores supercomputing cluster at Skoltech.

"Our idea relies on a method that is very well known in the attosecond community--to use laser pulses with temporally varying polarization (with circular polarization in the wings and linear polarization only in the middle of the pulse) to gate emission of harmonics only to the part of the pulse where the polarization is linear," the authors write.

"Polarization gated pulses limit harmonics emission only to the region around the center of the pulse, where intensity gradients are smaller and harmonics emission efficiency is higher. Both of these lead to smaller ponderomotive broadening," Rykovanov says.

Maksim Valialshchikov adds that to run the tests necessary to confirm their results, the scientists needed a simulation with a large number of particles. "Zhores provides a large number of CPUs, and using part of them allows completing a single simulation order of magnitude faster than using a single laptop," he notes.

According to Rykovanov, the authors plan to conduct additional research regarding the impact of radiation friction and quantum effects on the visibility of gamma comb. "This will allow us to move towards the experimental observation of the proposed effect in the nearest future," he says.

The authors say their proposed method can be used in photonuclear experiments as well as nonlinear quantum electrodynamics experiments planned at DESY, the German particle accelerator research center, and SLAC National Accelerator Laboratory in the US.

Unprecedented data sharing driving new rare disease diagnoses in Europe

Tyler O'Neal, Staff Editor SYSTEMS

Results are just the 'tip of the iceberg', according to researchers

Rare disease experts detail the first results of an unprecedented collaboration to diagnose people living with unsolved cases of rare diseases across Europe. The findings are published today in a series of six papers in the European Journal of Human Genetics.

In the main publication, an international consortium, known as Solve-RD, explains how the periodic reanalysis of genomic and phenotypic information from people living with a rare disease can boost the chance of diagnosis when combined with data sharing across European borders on a massive scale. Using this new approach, a preliminary reanalysis of data from 8,393 individuals resulted in 255 new diagnoses, some with atypical manifestations of known diseases. Sergi Beltran and Leslie Matalonga pictured in front of a supercomputer and servers that hosts the RD-Connect GPAP platform. The platform is located at the CNAG-CRG facilities in the Parc Cientific de Barcelona.

A complementary study describes the method in more detail and four accompanying case studies showcase the advantages of the approach. In one case study, researchers used the method to identify a new genetic form of pontocerebellar hypoplasia type 1 (PCH1), a genetic disease that affects the development of the brain. PCH1 is normally linked to mutations in four known genes. The researchers used the method to identify a new variant in a fifth gene.

In another case study, researchers used the method on an individual with a complex neurodevelopmental disorder and found the disease was caused by a new genetic variant in mitochondrial DNA. This went previously undetected because the patient did not present typical symptoms of a mitochondrial disorder. The diagnosis will help tailor treatment for the individual and inform their family members on the possibility of passing it on to future generations.

Key to the reanalysis of unsolved cases is the RD-Connect Genome-Phenome Analysis Platform, which is developed, hosted, and coordinated by the Centro Nacional de Analisis Genomico (CNAG-CRG), part of the Centre for Genomic Regulation (CRG), based in Barcelona.

Recognized officially by the International Rare Diseases Research Consortium and funded by the EU, Spanish and Catalan governments, the RD-Connect GPAP provides authorized clinicians and researchers with secure and controlled access to pseudonymized genomic data and clinical information from patients with rare diseases. The platform enables the secure, fast, and cost-effective automated re-analysis of the thousands of undiagnosed patients and relatives entering the Solve-RD project.

According to Sergi Beltran, co-leader of Solve-RD data analysis and Head of the Bioinformatics Unit at CNAG-CRG, "Solve-RD has shown that it is possible to securely share large amounts of genomics data internationally for the benefit of the patients. The work we are publishing today is just the tip of the iceberg since many more patients are being diagnosed thanks to the innovative methods developed and applied within Solve-RD".

An estimated 30 million people in Europe are affected by a rare disease during their lifetime. More than 70% of rare diseases have a genetic cause. However, around 50% of patients with a rare disease remain undiagnosed even in advanced expert clinical settings that use techniques such as genome sequencing.

At the same time, scientists around the world are finding an average of 250 new gene-disease associations and 9,200 variant-disease associations per year. As scientific understanding expands, reanalyzing data periodically can help people receive a diagnosis.

The consortium, which consists of more than 300 researchers and clinicians in fifteen countries and collectively sees more than 270,000 rare disease patients each year, aims to eventually diagnose more than 19,000 unsolved cases of rare diseases with an unknown molecular cause. Their preliminary findings are an important first step for developing a European-wide system to facilitate the diagnosis of rare diseases, which can be a long and arduous process.