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Archive - Apr 22, 2017

Statistical Analysis of Cancer Patient Data, Looking for Mutations Shared by Similar Domains in Different Proteins, Reveals Thousands of Rare Mutations Linked with Cancer; Researchers Coin New Term “Oncodomain”

Scientists have identified thousands of previously ignored genetic mutations that, although rare, likely contribute to cancer growth. The findings, which could help pave the way to new treatments, were published online on April 20, 2017 in the open-access journals PLOS Computational Biology. The article is titled “Oncodomains: A Protein Domain-Centric Framework for Analyzing Rare Variants in Tumor Samples.” Cancer arises when genetic mutations in a cell cause abnormal growth that leads to a tumor. Some cancer drugs exploit this to attack tumor cells by targeting proteins that are mutated from their usual form because of mutations in the genes that encode them. However, only a fraction of all the mutations that contribute significantly to cancer have been identified. Thomas Peterson, Ph.D., at the University of Maryland, and colleagues developed a new statistical analysis approach that uses genetic data from cancer patients to find cancer-causing mutations. Unlike previous studies that focused on mutations in individual genes, the new approach addresses similar mutations shared by families of related proteins. Specifically, the new method focuses on mutations in sub-components of proteins known as protein domains. Even though different genes encode them, different proteins can share common protein domains. The new strategy draws on existing knowledge of protein domain structure and function to pinpoint locations within protein domains where mutations are more likely to be found in tumors. Using this new approach, the researchers identified thousands of rare tumor mutations that occur in the same domain location as mutations found in other proteins in other tumors-- suggesting that they are likely to be involved in cancer.

Atomic-Level Motion in Proteins May Drive Bacteria's Ability to Evade Immune System Defenses

A study from Indiana University (IU) has found evidence that extremely small changes in how atoms move in bacterial proteins can play a big role in how these microorganisms function and evolve. The research, recently published online on March 27, 2017 in PNAS, is a major departure from prevailing views about the evolution of new functions in organisms, which regarded a protein's shape, or "structure," as the most important factor in controlling its activity. The PNAS article is titled “Entropy Redistribution Controls Allostery in a Metalloregulatory Protein.” "This study gives us a significant answer to the following question: How do different organisms evolve different functions with proteins whose structures all look essentially the same?" said Dr. David Giedroc (photo), Lilly Chemistry Alumni Professor in the IU Bloomington College of Arts and Sciences' Department of Chemistry, who is senior author on the study. "We've found evidence that atomic motions in proteins play a major role in impacting their function." The study also provides new insights into how microorganisms respond to their host's efforts to limit bacterial infection. Serious bacterial infections in people include severe health-care-associated infections and tuberculosis, both of which have grown increasingly common over the past decade due to rising drug resistance in bacteria. Approximately 480,000 people worldwide develop multidrug-resistant (MDR) tuberculosis each year, for example, according to the Centers for Disease Control and Prevention (CDC). "What we've shown is atomic-level motional disorder -- or entropy -- can impact gene transcription to affect the function of proteins in major ways, and that these motions can be 'tuned' evolutionarily," said Dr. Daiana A. Capdevila, a postdoctoral researcher in Dr. Giedroc's lab, who is first author on the study.

Scientists Use CRISPR Editing to Restore Visual Function in Two Mouse Models of Retinitis Pigmentosa

Using the gene-editing tool CRISPR/Cas9, researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health, with colleagues in China, have reprogrammed mutated rod photoreceptors to become functioning cone photoreceptors, reversing cellular degeneration and restoring visual function in two mouse models of retinitis pigmentosa. The findings are published in the April 21 advance online issue of Cell Research. Retinitis pigmentosa (RP) is a group of inherited vision disorders caused by numerous mutations in more than 60 genes. The mutations affect the eyes' photoreceptors, specialized cells in the retina that sense and convert light images into electrical signals sent to the brain. There are two types: rod cells that function for night vision and peripheral vision, and cone cells that provide central vision (visual acuity) and discern color. The human retina typically contains 120 million rod cells and 6 million cone cells. In RP, which affects approximately 100,000 Americans and 1 in 4,000 persons worldwide, rod-specific genetic mutations cause rod photoreceptor cells to dysfunction and degenerate over time. Initial symptoms are loss of peripheral and night vision, followed by diminished visual acuity and color perception as cone cells also begin to fail and die. There is no treatment for RP. The eventual result may be legal blindness. In their published research, a team led by senior author Kang Zhang, M.D., Ph.D., Chief of Ohthalmic Genetics, Founding Director of the Institute for Genomic Medicine and Co-Director of Biomaterials and Tissue Engineering at the Institute of Engineering in Medicine, both at UC San Diego School of Medicine, used CRISPR/Cas9 to deactivate a master switch gene called Nrl and a downstream transcription factor called Nr2e3.

Serendipitous Finding Leads to Promising Mouse Model for Severe Genetic Disorder Known As NGY1 Deficiency

Researchers from the RIKEN Global Research Cluster in Japan have developed a potential mouse model for the genetic disorder known as an NGLY1 deficiency. Published online on April 20, 2017 in the journal PLOS Genetics, the study describes how a complete knockout of the Ngly1 gene in mice leads to death just before birth, which can be partially rescued by a second knockout of another gene called Engase. When related genes in the mice used for making the knockouts are variable, the doubled-deletion mice survive and have symptoms that are analogous to humans with NGLY1-deficiency, indicating that these mice could be useful for testing potential therapies. NGLY1-deficiency is a relatively newly discovered genetic disorder, with the first patient identified in 2012. The symptoms are severe, and include delayed development, disordered movement, low muscle tone and strength, and the inability to produce tears. Understanding how lack of NGLY1 leads to these symptoms is critical when considering targets for therapeutic interventions, and creating useful animal models of the disease is therefore equally important. The RIKEN team has already had some success studying the consequences of Ngly1 deficiency in cultured animal cells. The Ngly1 gene codes for an enzyme that helps remove sugar chains from proteins that are scheduled for degradation. Their research showed that when Ngly1 was absent, sugars normally removed by Ngly1 were improperly removed by another enzyme called ENGase. Knocking out the ENGase gene led to normal protein degradation. The open-access PLOS Genetis article is titled “Lethality of Mice Bearing a Knockout of the Ngly1-Gene Is Partially Rescued by the Additional Deletion of the Engase Gene.”