Nav: Home

Powerful new genomics method can be used to reveal the causes of rare genetic diseases

October 10, 2019

LA JOLLA, CA - A team led by a scientist at Scripps Research has invented a new genomics technique for tracking down the causes of rare genetic diseases.

The technique, which the researchers report in Science, makes use of the fact that people inherit two copies or "alleles" of virtually every gene, one from the mother and one from the father. The new method compares activity levels of maternal and paternal alleles across the genome and detects when the activity of an allele lies far enough outside the normal range to be a plausible cause of disease.

The researchers demonstrated their technique by using it to reveal disease-causing genes in patients with rare muscular dystrophies.

"Adding this method to our toolkit should allow us to detect the causes of rare genetic diseases for some of the cases in which standard methods fail," says study first author Pejman Mohammadi, PhD, an assistant professor in the Department of Integrative Structural and Computational Biology at Scripps Research.

Mohammadi began working on the project as a postdoctoral research associate in the Lappalainen lab at the New York Genome Center and Columbia University. After joining Scripps Research in 2018, he continued the research collaboratively with Lappalainen lab.

The team was focused on finding a better way to identify rare genetic diseases that emerge early in life and can be significantly debilitating or even life-threatening. Standard methods of sequencing genes and their transcripts--applied to the affected person and family members--usually can reveal the cause, but only if the disease-driving gene mutations are obvious ones that result in missing or severely truncated proteins.

At least half of rare genetic diseases have more subtle causes that effectively can't be detected using standard methods, Mohammadi says. For example, a mutation may affect a region of DNA that isn't itself a gene but is involved in regulating the activity of a gene--and the resulting dysregulation of that gene's activity can lead to disease.

The method developed by Mohammadi and his colleagues uses gene transcription data to detect differences in the activity levels of maternal and paternal alleles. Many rare genetic diseases result from DNA mutations affecting a single allele of a gene. Comparing the activity of maternal and paternal alleles, which share the same molecular environment in the same cells in the same person, is a more sensitive approach than comparing one person's gene activity to another's--since any two people will differ in many other confounding factors that affect gene activity besides their genetic backgrounds.

"Even if you had an identical twin, the fact that the twin ate a burger this morning and you didn't would create differences between you in the activity levels of many genes," Mohammadi says.

To help gauge when an allele's activity is truly abnormal, the method includes a calculation, from publicly available gene transcription data, of the normal, healthy range of differences in maternal versus paternal allele activity--for every gene.

The method, called ANEVA-DOT (analysis of expression variation--dosage outlier test), can be used to identify a handful of genes in each individual with apparently abnormal expression levels in one allele.

"It might tell you there are 10 or 20 genes with allele activity levels that are way off, and you can then follow up to determine which of those is causing the disease--but compared with other methods, it cuts down dramatically the number of genes you have to analyze in that way," Mohammadi says.

He and his colleagues demonstrated the ANEVA-DOT method by applying it to a group of patients with muscular dystrophy-type genetic diseases. They successfully detected the disease-linked genes in cases where there was already a diagnosis and an expected major imbalance in allele activity. In many of the undiagnosed cases, the ANEVA-DOT technique uncovered a short list of plausible disease-linked, muscle-related genes. In one case that was resolved by the time the researchers submitted their paper, a suspect gene uncovered by ANEVA-DOT was confirmed as the disease gene.

The scientists now are using ANEVA-DOT to help a San Diego children's hospital diagnose genetic disease in newborns.
-end-
The study's authors, in addition to Pejman Mohammadi, were Stephane Castel, Jonah Einson, Paul Hoffman, and Tuuli Lappalainen, of Columbia University and the New York Genome Center; Beryl Cummings and Daniel MacArthur of Massachusetts General Hospital and the Broad Institute of MIT and Harvard; Christina Sousa of Scripps Research; Sandra Donkervoort, Payam Mohassel, Reghan Foley, and Carsten Bonnemann of the National Institute of Neurological Disorders and Stroke; Zhuoxun Jiang and Hae Kyung Im of the University of Chicago; and Heather Wheeler of Loyola University Chicago.

The research was funded by the National Institutes of Health (UL1TR002550, UL1TR001114, K99HG009916, R01MH106842, UM1HG008901, R01GM122924, R01MH107666, P30DK020595, R15HG009569, and UM1 HG008900).

Scripps Research Institute

Related Genome Articles:

Deciphering the walnut genome
New research could provide a major boost to the state's growing $1.6 billion walnut industry by making it easier to breed walnut trees better equipped to combat the soil-borne pathogens that now plague many of California's 4,800 growers.
Illuminating the genome
Development of a new molecular visualisation method, RNA-guided endonuclease -- in situ labelling (RGEN-ISL) for the CRISPR/Cas9-mediated labelling of genomic sequences in nuclei and chromosomes.
A genome under influence
References form the basis of our comprehension of the world: they enable us to measure the height of our children or the efficiency of a drug.
How a virus destabilizes the genome
New insights into how Kaposi's sarcoma-associated herpesvirus (KSHV) induces genome instability and promotes cell proliferation could lead to the development of novel antiviral therapies for KSHV-associated cancers, according to a study published Sept.
Better genome editing
Reich Group researchers develop a more efficient and precise method of in-cell genome editing.
Unlocking the genome
A team led by Prof. Stein Aerts (VIB-KU Leuven) uncovers how access to relevant DNA regions is orchestrated in epithelial cells.
Why do we need one pair of genome?
Scientists have unraveled how the cell replication process destabilizes when it has more, or less, than a pair of chromosome sets, each of which is called a genome -- a major step toward understanding chromosome instability in cancer cells.
A new genome for regeneration research
The first complete genome assembly of planarian flatworm reveals a treasure trove on the function and evolution of genes.
Decoding the Axolotl genome
The sequencing of the largest genome to date lays the foundation for novel insights into tissue regeneration.
The Down's syndrome 'super genome'
Only 20 percent of foetuses with trisomy 21 reach full term.
More Genome News and Genome Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#541 Wayfinding
These days when we want to know where we are or how to get where we want to go, most of us will pull out a smart phone with a built-in GPS and map app. Some of us old timers might still use an old school paper map from time to time. But we didn't always used to lean so heavily on maps and technology, and in some remote places of the world some people still navigate and wayfind their way without the aid of these tools... and in some cases do better without them. This week, host Rachelle Saunders...
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.