Research Roundup: Gene Function, Autoimmune Diseases, Genes for Schizophrenia and More
There are plenty of great scientific research stories out this week. Here’s a look at just a few of them.
A Possible New Framework for Studying Gene Function
Since the completion of the Human Genome Project in 2003, science’s understanding of how genes interact to cause disease has grown dramatically. But it’s also heightened the complexity of how to interpret genetic and genomic data. Researchers with the University of Toronto have published a potential framework for studying gene function as part of a network in the journal Cell.
Michael Costanzo, Senior Research Associate in Charles Boone’s laboratory at the University of Toronto, stated, “It would be a simpler problem if one particular mutation resulted in Disease X all of the time, but that’s often not the case. To understand the effect of combinations of variants is really difficult. We suspect it’s particular sets of mutations that really impact what the disease outcome is going to be in a personal genome. How genes interact with each other is important and, given our current understanding of gene-gene interactions, it’s not a problem that’s easily solved by reading individual genome sequences.”
The research team used its work in large-scale analyses in model systems, such as budding yeast, which included mapping a global genetic network, can translate to other systems. They also focused on “how a global genetic network not only annotates gene function but also provides new insights into the genotype-to-phenotype relationship.”
Are Genetic Risk Scores Valuable?
Researchers at the UCL Genetics Institute in London published research in the Annals of Human Genetics questioning the value and reliability of genome-wide polygenic scores, or GPS. This type of information combines data from thousands of genetic markers. Each of those markers has a minimal effect on their own, but the analysis is supposed to produce an overall disease risk assessment based on the entire genetic background.
“I think it’s a real problem that these tests are being promoted so enthusiastically, sometimes based on claims which simply don’t stand up under examination,” stated David Curtis, the study author. “I don’t see that they’re ready for clinical use yet and frankly I doubt that they ever will be.”
How Autoimmune Diseases are Related to Each Other
Researchers with the Karolinska Institute in Stockholm, Sweden, utilized the largest twin registry in the world to evaluate seven autoimmune diseases. They found that the risk of developing diseases is mostly inherited, but some of the diseases are more closely related than others. They are presenting their work at ENDO 2019, the Endocrine Society’s annual meeting in New Orleans, La.
They utilized data on 116,320 twins from the Swedish Twin Registry. They found that Addison’s disease, celiac disease (gluten intolerance) and type 1 diabetes are strongly influenced by “genes with heritability greater than 85 percent.” However, environmental factors contribute to Hashimoto’s hypothyroidism, Graves’ disease, and atrophic gastritis much more. “Our results indicate that Addison’s disease and vitiligo often overlap with other disorders, whereas celiac disease more rarely associates with the other diseases,” stated Jakob Skov, the study’s lead investigator and a PhD student at the Karolinska Institute.
He also stated, “These results contribute to our understanding of what causes autoimmunity and how autoimmune diseases are related. We examined the risk of acquiring not only one specific disease, but any one in a cluster of conditions. The findings may be helpful in patient education and autoimmune risk counselling.”
More Than 400 Gene Linked to Schizophrenia Development
Researchers at the Icahn School of Medicine at Mount Sinai have identified 413 gene associations with schizophrenia across 13 regions of the brain. They published their work in the journal Nature Genetics.
The study involved more than 100,000 people, 40,299 with schizophrenia and 62,264 matched controls. The research group used genome-wide association studies with transcriptomic imputation to identify schizophrenia-associated disease with tissue-level resolution. They found that genes associated with schizophrenia are expressed through development, including specific stages of pregnancy, and others during adolescence and adulthood. They also found that different regions of the brain have different risks for the disease, with most in the dorsolateral prefrontal cortex.
“Our new predictor models gave us unprecedented power to study predicted gene expression in schizophrenia, and to identify new risk genes associated with the disease,” stated Laura Huckins, Assistant Professor of Genetics and Genomic Sciences, and Psychiatry at Mount Sinai. “In particular, it was fascinating to see schizophrenia risk genes expressed throughout development, including in early pregnancy.”
The Role of Zombie Cells in Diabetes
Researchers at Mayo Clinic have found that senescent cells, sometimes called Zombie Cells (because it sounds cool), when removed from the fat tissue in obese mice resulted in a decrease of the severity of diabetes. In addition, some of the causes or consequences of the disease seemed to disappear as well. They published their research in the journal Aging Cell.
“Our findings show that senescent cells are a cause of obesity-related inflammation and metabolic dysfunction, and that senolytic drugs hold promise as a treatment of these conditions and their complications, which include diabetes,” stated James Kirkland, senior author of the study. Kirkland is director of the Robert and Arlene Kogod Center on Aging at Mayo Clinic.
Using genetically modified mice and normal mice, the team removed zombie cells by causing genetically-mediated cell death and by using a combination of senolytic drugs. These drugs selectively kill senescent—essentially inactive—cells, but not normal cells. As a result, glucose levels decreased and insulin sensitivity improved. Inflammatory factors also decreased.
How the Ebola Virus Attaches to Cells
Although it’s getting fewer headlines than other outbreaks, the Democratic Republic of Congo is struggling with another Ebola outbreak that has killed more than 1,000 people. Although there are no specific cures, researchers with Lehigh University have identified the mechanisms the Ebola virus uses to attach to the cells it infiltrates. This may lead to potential treatments, preventatives, or have broad usefulness in viral research. The work was published in Scientific Reports.
Researchers know that Ebola uses a natural process called micropinocytosis, a way cells clean up their surroundings by internalizing the cell debris around it. Cell surface proteins act as receptors, which allow immune cells to recognize the cellular debris and internalize it. The Ebola virus interacts with specific proteins, T-cell immunoglobulin and mucin domain (TIM) to get inside the cell. Once inside, the Ebola virus membrane fuses to the endosome formed around it and releases its genetic materials into the cell.
“Viral RNA further hijacks the cell mechanism to make proteins and replicate themselves inside,” stated Frank Zhang, associate professor of bioengineering and mechanical engineering at Lehigh. “They then bud off the membrane to form a new virus while the healthy host cell dies.”
The researchers used single-molecule force spectroscopy to quantify the specific interaction forces between the TIM proteins and the Ebola virus. They also showed that the TIM-Ebola virus interactions are mechanically comparable to adhesion molecule-ligand interactions.