Tracking down microRNA candidates that can contribute to disease

November 6, 2018 by Ana María Rodríguez, Ph.d., Baylor College of Medicine
MicroRNA and mRNA visualization in differentiating C1C12 cells. Credit: Ryan Jeffs/Wikipedia

What started as Ninad Oak's side project turned out into something much larger, his doctorate thesis.

"The project started as my qualifying exam that I proposed at the end of my first year of graduate school," said Oak, a graduate student in molecular and human genetics in Dr. Sharon E. Plon's lab. "This was an off topic qualifying exam at the time, meaning the lab had not worked on this topic before."

One of the main interests of the Plon lab is predisposition, in particular looking at protein coding regions of gene variants that may be responsible for susceptibility to childhood cancers.

"I started the project thinking that we had focused on protein coding regions for a long time. But they only represent 1 percent of the genome, so I thought that by looking at the remaining 99 percent we might find variations we have been missing that might explain some undiagnosed patient cases," Oak said.

In his qualifying exam, Oak proposed to look at variations on microRNA.

"Although the amount of microRNA that is found in the cell is often studied in human disease, microRNA variations that are associated with disease are understudied," Oak said.

MicroRNAs are small non-coding RNAs that are only about 18 to 25 nucleotides long; they are much smaller than genes that code for proteins, which are thousands of nucleotides long. MicroRNAs upregulate or downregulate the expression of more than 60 percent of genes by binding to matching sequences in other's genes' RNA. One microRNA might change the level of expression of up to 200 genes at a time, therefore affecting a number of different pathways.

Disturbing the normal function of microRNAs can lead to altered expression of their target genes, and this has been associated with a wide variety of human diseases, such as cancer, cardiovascular and developmental diseases.

"When he presented this proposal, I thought it was a good idea," said Plon, who is professor of pediatrics—oncology and molecular and human genetics at Baylor and director of the Cancer Genetics Clinical and Research Programs at Texas Children's Hospital.

ADmiRE helps prioritize microRNA variation linked to disease

Oak developed a novel computational tool called ADmiRE, which stands for Annotative Database for miRNA Elements. ADmiRE extensively annotates human microRNA variants to determine which ones are likely to contribute to or cause diseases.

"There were multiple challenges when I started working on this project," Oak said. "Most datasets of genomic sequencing are of whole exome sequencing (WES), which captures only protein coding regions. So first, I looked at how well WES datasets captured microRNAs and found that they captured about 50 percent."

The second challenge was to determine how well were microRNA mutations annotated by different annotation tools that already were available. These annotation tools allow researchers to add notes of explanation or comments that provide more information about each microRNA.

"There are various annotation tools that identify where a mutation is in general in the genome, not exclusively in microRNA. I found that these tools didn't annotate microRNA accurately; they tended to favor the potential change to a protein coding gene and not the impact on microRNAs. These tools also didn't include comprehensive information that would help us interpret and prioritize the potential role of that microRNA in disease," Oak said.

Oak worked on a microRNA annotation tool that would correctly annotate all microRNA variants and then used it to analyze one of the largest publicly available WES datasets of adults (gnomAD) to establish a baseline of microRNA variation in normal human populations.

"This approach allowed us to draw conclusions about how frequently microRNAs are variable in normal datasets," Oak said. "Knowing the background variation would help us identify potential microRNA variants in disease states."

To identify microRNAs that could be associated with disease, Oak developed a metric called allele frequency percentile score that shows how frequently a microRNA varies when compared to other microRNAs in these large datasets. He then selected a group of microRNAs that were in the lower quartile, essentially highlighting those with little variation. The reasoning is that microRNAs that are highly conserved in the adult population are so because otherwise disease may follow. Those highly conserved microRNAs would be candidates for being associated with disease.

The researchers then applied this new tool to analyze mutations across 10,000 cancer cases that included 32 cancer types in the Cancer Genome Atlas PanCancerAtlas WES dataset.

"We found miR-142 mutations linked to hematologic cancers, confirming the finding made a few years ago. Also, we found microRNA mutations in miR-21, which had not been previously associated with cancer. Our analysis with ADmiRE suggests that these mutations may contribute to mechanisms involved in esophageal cancer.

"At a personal level, I found this work very satisfying because I think it contributes a new technique to our lab that fills a gap in the field," Oak said. "From the scientific point of view, ADmiRE offers a new resource for researchers who have not found a genetic cause for a in protein coding genes. We have made this tool publicly available, and researchers can apply it to determine whether there is a signal in miRNA sequences. Maybe down the line this tool could be used by clinical laboratories."

"I think it is an important ," Plon said. "Mutations in microRNA have been missed for many years, but I think ADmiRE will now allow labs that have mutation data to see if these mutations that we know are important play a role in the biology of human health."

Explore further: Study shines light on gut microbiome in colon cancer

More information: Ninad Oak et al, Framework for microRNA variant annotation and prioritization using human population and disease datasets, Human Mutation (2018). DOI: 10.1002/humu.23668

Related Stories

Study shines light on gut microbiome in colon cancer

May 15, 2018
Researchers have identified a correlation between gut microbial composition and microRNA expression in human colorectal cancer, according to a recent study published in the journal mSystems. The study is the first to demonstrate ...

Study: Enhancing cancer response to radiation

December 2, 2016
OHSU researcher Sudarshan Anand, Ph.D., has a contemporary analogy to describe microRNA: "I sometimes compare MicroRNA to tweets—they're short, transient and constantly changing."

Choreographing the microRNA-target dance

January 23, 2017
Scientists face a conundrum in their quest to understand how microRNAs regulate genes and therefore how they influence human disease at the molecular level: How do these tiny RNA molecules find their partners, called messenger ...

'Treatments waiting to be discovered' inside new database

August 5, 2014
Your genes are blueprints for proteins, and molecules called microRNA can help to determine how often these genetic blueprints are manufactured into proteins. Researchers often ask what microRNA regulates a gene related to ...

MicroRNA specifically kills cancer cells with common mutation

October 3, 2016
Approximately 20 percent of all human cancers have mutations in a gene called KRAS. KRAS-mutant cancers are among the most difficult to treat, with poor survival and resistance to chemotherapy. Researchers at University of ...

Recommended for you

Progress in genetic testing of embryos stokes fears of designer babies

November 16, 2018
Recent announcements by two biotechnology companies have stoked fears that designer babies could soon be an option for those who can afford to pick and choose which features they want for their offspring. The companies, MyOme ...

From the ashes of a failed pain drug, a new therapeutic path emerges

November 16, 2018
In 2013, renowned Boston Children's Hospital pain researcher Clifford Woolf, MB, BCh, Ph.D., and chemist Kai Johnsson, Ph.D., his fellow co-founder at Quartet Medicine, believed they held the key to non-narcotic pain relief. ...

Gene editing possible for kidney disease

November 16, 2018
For the first time scientists have identified how to halt kidney disease in a life-limiting genetic condition, which may pave the way for personalised treatment in the future.

Repurposing FDA-approved drugs can help fight back breast cancer

November 16, 2018
Screening Food and Drug Administration (FDA)-approved compounds for their ability to stop cancer growth in the lab led to the finding that the drug flunarizine can slow down the growth of triple-negative breast cancer in ...

Traditional chemotherapy superior to new alternative for oropharyngeal cancers

November 16, 2018
A drug increasingly used in combination with radiotherapy to treat a type of cancer that forms in the tonsils or the base of the tongue is inferior to a previously favored option, according to a large, clinical trial led ...

New 'SLICE' tool can massively expand immune system's cancer-fighting repertoire

November 15, 2018
Immunotherapy can cure some cancers that until fairly recently were considered fatal. In addition to developing drugs that boost the immune system's cancer-fighting abilities, scientists are becoming expert at manipulating ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Anonym751719
not rated yet Nov 08, 2018
Am really grateful and thankful for what Dr.Ogun who has done for me and my family. I Was having HERPES for good three years with no solution, the diseases almost took my life and because I was unable to work and I was also loosing lots of money for medication, but one faithful day when I went online, I met lots of testimonies about this great man so I decided to give it a try and to God be the glory he did it. he cured me of my diseases and am so happy and so pleased to Write about him today. if you need his help or you also want to get cured just the way I got mine, just email him below drogungodseye@.com or Whatsapp ;+2348157755909 and get your healing. He has cure for other deadly diseases like Diabetes, Hiv/Aids, Hepatitis of all types and Cancer he can also help you with this such as (1) If you want your ex back. (2) if you always have bad dreams. (3) You want to be promoted in your office. (4) You want women/men to run after you. (5) If you want a child. et

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.