Now a new study using bioinformatics, led by scientists at the Buck Institute for Age Research, reports the ability to predict the molecular cause of many inherited genetic diseases. These predictions involve tens of thousands of genetic disease-causing mutations and have led to the creation of a web-based tool available to academic researchers who study disease. The research is due to be published online in the February 9, 2010 edition of Human Mutation.
“We now have a quantitative model of function using bioinformatic methods that can predict things like the stability of the protein and how its stability is disrupted when a mutation occurs,” said Buck Institute faculty member Sean Mooney, PhD, who led the research team. “Traditionally people have used a very time consuming process based on evolutionary information about protein structure to predict molecular activity,” Mooney said, “I think we’re the first group to really quantitatively describe the universe of molecular functions that cause human genetic disease.”
The research was done in the contexts of inherited single gene diseases, complex diseases such as cardiovascular and developmental disorders and mutations in cancerous tumors. The study focused on amino acid substitutions (AAS), which are genetically driven changes in proteins that can give rise to disease, and utilized a series of complex mathematical algorithms to predict activity stemming from the mutations.
As a first step, researchers used available databases of known sites of protein function and built mathematical algorithms to predict new sites of protein function said Mooney. They then applied the algorithms to proteins that have disease-associated mutations assigned to them and looked for statistical co-occurrences of mutations that fell in or near those functional sites. Because the computer algorithms are imperfect, researchers compared that information against a data set of neutral AAS, ones that don’t cause human disease, said Mooney. “We looked for statistical differences between the percentage of mutations that fell into the same functional site from both non-disease and disease-associated AAS and looked to see if there was a statistically significant enrichment or depletion of protein activity based on the type of AAS . That data was used to hypothesize the molecular mechanism of genetic disease,” said Mooney.
Mooney says 40,000 AAS were analyzed which represents one of the most comprehensive studies of mutations. Describing the results, he used the analogy of a car as a protein -- a big molecular machine. “We are predicting how this machine will break down,” said Mooney. “We’ve known the car isn’t working properly because it has some defect; now we can hypothesize that the symptom stems from a broken water pump.”
The web tool, designed to enhance the functional profiling of novel AAS, has been made available at http://www..mutdb.org/profile. Mooney identified three different areas of research that could be furthered by use of the tool. Scientists who manage databases of clinically observed mutations for research purposes could develop hypotheses about what those mutations are causing on a molecular level; they may also be able to use the tool to correlate molecular activity to the clinical severity or subtype of a disease. Mooney says cancer researchers re-sequencing tumors could use the tool to identify mutations that drive the progression of the malignancy. He also expects non-clinical researchers who work with mutations in proteins to use the tool to gain insight into what is causing the mutations. “We are happy to collaborate with scientists, to share data and help them better identify hypotheses about the specific mutations they might be interested in,” said Mooney.
The project involved collaborations with several organizations. Scientists from Cardiff University in the UK supplied the Human Gene Mutation Database (http://www.hgmd.org). Researchers at the Indiana University School of Informatics and Computing helped develop the statistical methods for measuring enrichment and depletion of the mutations. Scientists at the National Center for Biomedical Ontology at Stanford University mapped the disease names and provided a standard vocabulary for the work. Researchers at the Department of Biological Sciences at the University of Maryland collected the genetic data from the National Library of Medicine and formatted them for this study. All the analysis was done by scientists at the Buck Institute and Cardiff University.Contributors to this work:
Kris Rebillot | Newswise Science News
Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden
The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
22.09.2017 | Life Sciences
22.09.2017 | Medical Engineering
22.09.2017 | Physics and Astronomy