Analytical tool predicts genes that can cause disease by producing altered proteins

July 19, 2018, Baylor College of Medicine
Credit: CC0 Public Domain

Predicting genes that can cause disease due to the production of truncated or altered proteins that take on a new or different function, rather than those that lose their function, is now possible thanks to an international team of researchers, including researchers from Baylor College of Medicine, that has developed a new analytical tool to effectively and efficiently predict such candidate genes.

The tool allowed the researchers to identify 252 candidate 'disease genes.' Some of these genes had already been studied in other labs where it was shown that they most likely cause disease by producing defective proteins, which supports the effectiveness of this novel tool. The study appears in the American Journal of Human Genetics.

"Genes can cause disease because of mutations that result in loss-of-function; that is when the gene is not producing the protein it encodes. But genes also can cause disease when mutations result in the production of a defective protein with a new function—a gain-of-function mutation—that may interfere with the function of the normal protein," said corresponding author Dr. Claudia M.B. Carvalho, assistant professor of molecular and human genetics at Baylor College of Medicine.

In 2015, Carvalho and her colleagues proposed that a gain-of-function mutation in the gene DVL1 is a common cause of dominant Robinow syndrome, a genetically heterogeneous condition for which there was no molecular explanation. They found variants of the gene DVL1 producing a protein that was defective because it was missing a piece at one end.

"These findings suggested that other genes also can cause disease, not by loss of function, but by gain of function," Carvalho said. "We wanted to know which genes might mechanistically behave in a similar manner."

"This was not an easy task," said first author Dr. Zeynep Coban-Akdemir, a bioinformatics and genetics and genomics postdoctoral associate of molecular and at Baylor. "There are computational tools to predict loss of function but not to predict genes that may cause disease through gain of function, so we started this project to do that."

The researchers began by identifying clues that a gene may cause disease by a gain-of-function mechanism.

"The clue usually is the location of the mutation in the gene. If the mutation, in this case one called premature termination codon (PTC), happens in the very end of the gene, then this usually predicts that the and messenger RNA (mRNA) will likely escape the cell's surveillance mechanisms, which then leads to the production of a defective protein and disease by gain of function," Coban-Akdemir said.

But if the PTC mutation happens either in the middle or the beginning of the gene, then this usually predicts that the surveillance mechanism will work and, therefore the mRNA will be destroyed and no will be produced by the mutated gene. In this case, disease will happen by loss of function of the gene.

"We began working with control datasets, which include the genes of large numbers of people without disease. We reasoned that if PTC mutations in a particular gene accumulated near the beginning or the middle of the gene, and not at the end, then that gene would likely be intolerant to the at the end of the gene," Coban-Akdemir said. "Genes with this characteristic became our candidates for genes that could be causing disease by a gain-of-function mechanism."

Next, the researchers looked into another database including the genes of people with diseases and investigated whether the they had previously identified were in a cohort of people with disease. The genes they identified this way can potentially cause disease by gain of function.

"The importance of this work is that there was already a way to analyze genes that caused disease because of loss of function, so here we designed and tested a tool that allows us to make predictions about which of the many genetic alterations found in patients are most likely playing a role in their by gain of function," Carvalho said. "Once we identify the , we may conduct further studies to determine ways to help the patients."

"This is an incredible example of what a fantastic benchtop experimental scientist and a terrific computational scientist can do when they put their intellects together and study the wonderful BigData generated by the Baylor College of Medicine Human Genome Sequencing Center," said senior author Dr. Jim Lupski, Cullen Professor of Molecular and Human Genetics at Baylor, principal investigator at the Baylor Hopkins Center for Mendelian Genomics and faculty with the Baylor genetics and genomics graduate training program. "I look forward to reading about work emanating from professor Carvalho and Dr. Coban-Akdemir's study for years to come."

Explore further: Mutations in gene TRAF7 are associated with a multisystem disorder

More information: American Journal of Human Genetics (2018). DOI: 10.1016/j.ajhg.2018.06.009

Related Stories

Mutations in gene TRAF7 are associated with a multisystem disorder

June 28, 2018
A group of seven patients presenting with a similar disorder of unknown origin now know of a possible genetic root of their condition. A team of researchers sequenced all the protein-coding genes in the patients' genomes ...

Mapping the genetic controllers in heart disease

July 10, 2018
Researchers have developed a 3-D map of the gene interactions that play a key role in cardiovascular disease, a study in eLife reports.

Altered gene regulation is more widespread in cancer than expected

July 10, 2018
A large-scale study provides new insights into the mechanisms that can lead to cancer. It can happen when genes mutate, but cancer also can occur when the genetic regions involved in regulating gene expression change. In ...

Intellectual disabilities caused by protein defect

September 4, 2017
Intellectual disabilities are often caused by a mutation that damages a gene, preventing the associated protein from functioning properly. However, a mutation can also change the function of a gene. As a result, the gene ...

Next generation sequencing shakes up genotype/phenotype correlation, disease discoveries

August 13, 2014
With the ability to use next generation sequencing technology, researchers have a broadened understanding of the association of genetic changes and disease causation to a much greater resolution, driving new discoveries, ...

Mutations in CWC27 result in a spectrum of developmental conditions

March 10, 2017
An international team of researchers has discovered that mutations in the human gene CWC27 result in a spectrum of clinical conditions that include retinal degeneration and problems with craniofacial and skeletal development. ...

Recommended for you

Genetic link discovered between circadian rhythms and mood disorders

August 15, 2018
Circadian rhythms are regular 24-hour variations in behaviour and activity that control many aspects of our lives, from hormone levels to sleeping and eating habits.

Ovarian cancer genetics unravelled

August 14, 2018
Patterns of genetic mutation in ovarian cancer are helping make sense of the disease, and could be used to personalise treatment in future.

New genome-editing strategy could lead to therapeutics

August 14, 2018
Researchers at UMass Medical School have developed a genome-editing strategy to correct disease-causing DNA mutations in mouse models of human genetic diseases, according to research published in the Aug. 18 edition of Nature ...

Study reveals broad 'genetic architectures' of traits and diseases

August 13, 2018
Scientists at Johns Hopkins Bloomberg School of Public Health have developed a powerful method for characterizing the broad patterns of genetic contributions to traits and diseases. The new method provides a "big picture" ...

Genetic tools uncover cause of childhood seizure disorder missed by other methods

August 13, 2018
Early childhood seizures result from a rare disease that begin in the first months of life. Researchers at University of Utah Health have developed high-tech tools to uncover the genetic cause of the most difficult to diagnose ...

Researchers predict risk for common deadly diseases from millions of genetic variants

August 13, 2018
A research team at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and Harvard Medical School reports a new kind of genome analysis that could identify large fractions of the population who have ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.