Newsmakers: Basic research findings by Johns Hopkins scientists focus on gene sequencing, hearing loss and a brain disorder

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Yes, Scientists Have Sequenced the Entire Human Genome, But They’re Not Done Yet

The human genome, from end to end, has been sequenced, meaning scientists worldwide have identified most of the nearly 20,000 protein-coding genes. However, an international group of scientists notes there’s more work to be done. The scientists point out that even though we have nearly converged on the identities of the 20,000 genes, the genes can be cut and spliced to create approximately 100,000 proteins, and gene experts are far from agreement on what those 100,000 proteins are.

The group, which convened last fall at Cold Spring Harbor Laboratory in New York, has now published a guide for prioritizing the next steps in the effort to complete the human gene “catalog.”

“Many scientists have been working on efforts to fully understand the human genome, and it’s much more difficult and complex than we thought,” says Steven Salzberg, Ph.D., Bloomberg Distinguished Professor of Biomedical Engineering, Computer Science, and Biostatistics at The Johns Hopkins University. “We have provided a state of the human gene catalog and a guide on what’s needed to complete it.”

Salzberg, along with Johns Hopkins biomedical engineer and associate professor Mihaela Pertea, Ph.D., M.S., M.S.E., postdoctoral researcher Ales Varabyou and 19 other scientists, offered perspectives on the human gene catalog Oct. 4 in the journal Nature.

The scientists say that while the final list of protein coding genes is nearly complete, scientists have not yet fully cataloged the variety of ways that a gene can be cut, or spliced, resulting in “isoforms” of proteins that are slightly different. Some protein isoforms will not affect the protein’s function but some may be different enough to result in increased risk for a particular trait, condition or illness.

To complete the catalog, the scientists propose a comprehensive look at how each gene is expressed into functional and nonfunctional proteins and the three-dimensional shape of those proteins.

The scientists also propose a focus on cataloging non-coding RNA genes. RNA is the genetic material that is transcribed by DNA and follows a molecular path to making proteins. Instead of proteins, non-coding RNA genes encode other types of molecular material that performs a cellular function.

Finally, the international group emphasizes the importance of enhancing commonly used databases of gene variations that cause illness and disease, improving clinical laboratory standards for annotating DNA sequencing results and developing new technology to enable more effective and precise methods to match the wide array of proteins with their gene products.

When It Comes to Hearing, the Left and Right Sides of the Brain Work Together, Mouse Research Shows

Johns Hopkins-led research has revealed an extensive network of connections between the right and left sides of the brain when mice are exposed to different sounds. The researchers also found that some areas of the brain are specialized to recognize certain sounds, such as “calls” from the animals. Further, the researchers also found that deaf mice had far fewer right and left brain connections, suggesting that the brain needs to “hear” and process sound during early ages to spur development of left-right brain connections.

The findings, say the researchers, may eventually help scientists pinpoint the time period when such brain connections and specialization form, and offer potential insights into how to restore hearing loss.

“The auditory system is a collection of parts, which need to be connected properly,” says Johns Hopkins neuroengineer Patrick Kanold, Ph.D., a professor of biomedical engineering. “Using a novel microscope that enabled us to see both brain hemispheres at the same time, we found that some of those connections are between the right and left brain hemispheres, allowing functional specialization. When the brain does not get the right inputs, for example in hearing loss, these brain connections are missing. This obviously is an issue if we hope to restore hearing at a later age.”

In efforts to find new ways to restore hearing, Kanold’s team will continue its work to identify the specific time period when brain connections form in response to sound and how to restore abnormal connections. The team is also continuing research to understand how the brain adapts to and modulates sound processing to filter out distracting signals, such as its recent work indicating that the brain’s frontal cortex provides specific signals to the auditory system during behaviors that might help in this filtering process.

New Mouse Models May Help Scientists Find Therapies for Brain Development Disorder

For more than 25 years, Richard Huganir, Ph.D., Bloomberg Distinguished Professor of Neuroscience and Psychological and Brain Sciences and director of the Solomon H. Snyder Department of Neuroscience, at the Johns Hopkins University School of Medicine, has studied the protein SYNGAP1 that is now known to be linked to a group of neurodevelopmental disorders that are usually diagnosed during early childhood. Working with biotechnology companies to find new therapies for the conditions, his team at Johns Hopkins Medicine reports it has developed new mouse models that more accurately represent genetic mutations in people who have SYNGAP1-related disorders.

The new collection of mouse models, now available to scientists developing treatments, have several variations in the SYNGAP1 gene, which were discovered to cause conditions marked by seizures, cognitive impairment, social deficits and sleep disturbances.

The SYNGAP1 gene, found also in humans, makes proteins that regulate synapses, the space between two neurons where they trade chemical and molecular messages. When SYNGAP1 is mutated, as in the case of SYNGAP1-related disorders in people, neurons make less of the protein in the synapse, and learning and memory are impaired.

In other mouse models, called “knock-out” models, the SYNGAP1 gene is removed entirely. Huganir says both the knock-out models and the new versions — “knock-in” models, which carry a variety of SYNGAP1 mutations linked to the disorders — will be helpful in finding therapies that boost SYNGAP1 protein production.

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