Genes

“Our new tool makes possible a broad range of applications, from studying gene function and regulation to potentially correcting splicing defects in human disorders and diseases”

Researchers at the University of Toronto have harnessed a bacterial immune defence system, known as CRISPR, to efficiently and precisely control the process of RNA splicing.

The technology opens the door to new applications, including systematically interrogating the functions of parts of genes and correcting splicing deficiencies that underlie numerous diseases and disorders.

“Almost all human genes produce RNA transcripts that undergo the process of splicing, whereby coding segments, called exons, are joined together and non-coding segments, called introns, are removed and typically degraded,” said Jack Daiyang Li, first author on the study and PhD student of molecular genetics, working in the labs of U of T researchers Benjamin Blencowe and Mikko Taipale at the Donnelly Centre for Cellular and Biomolecular Research in the Temerty Faculty of Medicine.

Exons from the same gene can be mixed and matched in various combinations to produce different versions of RNA, and consequently, different proteins. This process, called alternative splicing, contributes to the diverse expression of the 20,000 human genes that encode proteins, allowing the development and functional specialization of different types of cells.

However, it is unclear what most exons or introns do and the misregulation of normal alternative splicing patterns is a frequent cause or contributing factor to various diseases, including cancers and brain disorders. In addition, there is a lack of existing methods that allow for the precise and efficient manipulation of splicing.

The new study, published in the journal Molecular Cell, describes how a catalytically deactivated version of an RNA-targeting CRISPR protein, referred to as dCasRx, was joined to more than 300 splicing factors to discover a fusion protein called dCasRx-RBM25. This protein is capable of activating or repressing alternative exons in an efficient and targeted manner.

“Our new effector protein activated alternative splicing of around 90 per cent of tested target exons,” said Li. “Importantly, it is capable of simultaneously activating and repressing different exons to examine their combined functions.”

This multi-level manipulation will facilitate the experimental testing of functional interactions between alternatively spliced variants from genes to determine their combined roles in critical developmental and disease processes.

“Our new tool makes possible a broad range of applications, from studying gene function and regulation, to potentially correcting splicing defects in human disorders and diseases,” said Blencowe, principal investigator on the study, Canada Research Chair in RNA Biology and Genomics, Banbury Chair in Medical Research and a professor of molecular genetics at the Donnelly Centre and Temerty Medicine.

“We have developed a versatile engineered splicing factor that outperforms other available tools in the targeted control of alternative exons,” said Taipale, also principal investigator on the study, Canada Research Chair in Functional Proteomics and Proteostasis, Anne and Max Tanenbaum Chair in Molecular Medicine and associate professor of molecular genetics at the Donnelly Centre and Temerty Medicine. “It is also important to note that target exons are perturbed with remarkably high specificity by this splicing factor, which alleviates concerns about possible off-target effects.”

The researchers now have a tool in hand to systematically screen alternative exons to determine their roles in cell survival, cell-type specification and gene expression.

When it comes to the clinic, the splicing tool has potential to be used to treat numerous human disorders and diseases, such as cancers, in which splicing is often disrupted.

The research was supported by the Canadian Institutes of Health Research and the Simons Foundation.

U of T researchers identify 'degrees of Kevin Bacon' gene in fruit flies

rahul.kalvapalle — Fri, 24 May 2024 20:22:51 +0000

U of T researchers identify 'degrees of Kevin Bacon' gene in fruit flies

rahul.kalvapalle Fri, 05/24/2024 - 16:22

Cutline

(photo by janeff/iStock)

Chris Sasaki

Topic

Breaking Research

Ecology & Evolutionary Biology

Faculty of Arts & Science

Genes

Genetics

Research & Innovation

U of T Mississauga

Subheadline

Researchers studied two distinct strains of fruit flies and found that one group showed different patterns of connections within their networks

A team of researchers from the University of Toronto has identified a gene in fruit flies that regulates the types of connections between flies within their “social network.”

The researchers studied groups of two distinct strains of Drosophila melanogaster fruit flies and found that one strain showed different types or patterns of connections within their networks than the other strain.

The connectivity-associated gene in the first strain was then isolated. When it was swapped with the other strain, the flies exhibited the connectivity of the first strain.

Researchers named the gene after Hollywood star Kevin Bacon (photo by Theo Wargo/Getty Images)

The researchers named the gene “degrees of Kevin Bacon” (dokb), for the prolific Hollywood star of such films as Footloose and Apollo 13. Bacon’s wide-ranging connections to other actors is the subject of the parlour game called “The Six Degrees of Kevin Bacon,” which plays on the popular idea that any two people on Earth can be linked through six or fewer mutual acquaintances.

“There's been a lot of research around whether social network structure is inherited, but that question has been poorly understood,” says Rebecca Rooke, a post-doctoral fellow in the department of ecology and evolutionary biology in the Faculty of Arts & Science and lead author of the paper, published in Nature Communications. “But what we’ve now done is find the gene and proven there is a genetic component.”

The work was carried out as part of Rooke’s PhD thesis in Professor Joel Levine’s laboratory at U of T Mississauga before he moved to the department of ecology and evolutionary biology, where he is currently chair.

“This gives us a genetic perspective on the structure of a social group,” says Levine. “This is amazing because it says something important about the structure of social interactions in general and about the species-specific structure of social networks.

Post-doctoral researcher Rebecca Rooke (supplied image)

“It's exciting to be thinking about the relationship between genetics and the group in this way. It may be the first time we’ve been able to do this.”

The researchers measured the type of connection by observing and recording on video groups of a dozen male flies placed in a container. Using software previously developed by Levine and post-doctoral researcher Jon Schneider, the team tracked the distance between flies, their relative orientation and the time they spent in close proximity. Using these criteria as measures of interaction, the researchers calculated the type of connection or “betweenness centrality” of each group.

Rooke, Levine and their colleagues point out that individual organisms with high betweenness centrality within a social network can act as “gatekeepers” who play an important role in facilitating interactions within their group.

Gatekeepers can influence factors like the distribution of food or the spread of disease. They also play a role in maintaining cohesion, enhancing communication and ensuring better overall health of their group.

In humans, betweenness centrality can even affect the spread of behaviours such as smoking, drug use and divorce.

Professor Joel Levine (supplied image)

At the same time, the researchers point out that social networks are unbiased and favour neither “good” nor “bad” outcomes. For example, high betweenness centrality in a network of scientists can increase potential collaborators; on the other hand, high betweenness centrality in another group can lead to the spread of a disease like COVID-19.

“You don't get a good or a bad outcome from the structure of a network,” explains Levine. “The structure of a network could carry happiness or a disease.”

Rooke says an important next step will be to identify the overall molecular pathway that the gene and its protein are involved in “to try to understand what the protein is doing and what pathways it’s involved in – the answers to those questions will really give us a lot of insight into how these networks work.”

And while the dokb gene has only been found in flies so far, Rooke, Levine and their colleagues anticipate that similar molecular pathways between genes and social networks will be found in other species.

“For example, there's a subset of cells in the human brain whose function relates to social experience – what in the popular press might be called the ‘social brain,’” says Levine.

“Getting from the fly to the human brain – that's another line of research. But it almost has to be true that the things that we're observing in insects will be found in a more nuanced, more dispersed way in the mammalian brain.”

Big data helps autism research: U of T team identifies 18 new genes increasing risk

ullahnor — Thu, 13 Apr 2017 20:00:18 +0000

Big data helps autism research: U of T team identifies 18 new genes increasing risk

ullahnor Thu, 04/13/2017 - 16:00

Cutline

U of T researchers Stephen Scherer (left) and Ryan Huen (right) are part of the MSSNG autism genomics project (photo by Robert Teteruck/SickKids)

Jim Oldfield

Author legacy

Jim Oldfield

Topic

Artificial Intelligence

Scientists in the world’s largest autism genomics project recently identified 18 new genes that increase risk for the condition.

Some of the genes seen in participants also carry risk for heart disease, diabetes and other conditions, opening the potential for more personalized genetic counselling.

The results of the project, named MSSNG, provide more evidence that each person’s autism is unique, meaning researchers will still need a lot more genomic data before they can sort and target the many forms of the condition. However, some families are already benefitting. The MSSNG project includes whole-genome data from more than 7,000 individuals affected by autism, and that data is stored on Google Cloud, which allows access to researchers around the world.

Professor Stephen Scherer, director of both the McLaughlin Centre at the University of Toronto and the Centre for Applied Genomics at the Hospital for Sick Children, is the senior investigator for MSSNG.

He spoke with U of T's Jim Oldfield about how the cloud is enabling a new kind of open science on autism, and what needs to happen next for big data to deliver on its potential to treat the most baffling medical conditions.

How did the MSSNG project come about?

Genome sequencing generates massive amounts of data, and the need to deal with those terabytes of information is what put us into the cloud environment.

The project came together four years ago when we decided to make all that data available. The original vision a few of us had was for truly open science, where you could type a keyword into a database, say if you’re looking for which individuals carry a gene.

We found out along the way that we need more open consent, in part because we’re dealing with clinical research data, even though it’s anonymized. So we now have a system where you apply through a data access committee. You can get anything you want in the cloud, including raw reads from the sequencers and new analytics tools we've developed. Almost 100 researchers at dozens of institutions are using the system, and we expect those numbers to grow. It’s probably one of the most open-science genetics projects right now.

Why is this technology well-suited for autism research?

We need to take this approach because autism is extremely heterogeneous in terms of how it presents clinically and the underlying genetics. There are well over 100 different forms, which is why we sometimes call them the autisms.

To subcategorize these conditions, we need big numbers and whole genomes. We calculated that to get all low hanging fruit – the highly penetrative autisms with the most common genetic variants – we’d need about 10,000 families. To find new impactful variants, including copy number variations or small insertions and deletions, some of which are in the noncoding regions of the genome, we’ll likely need up to 100,000.

Will machine learning help analyze that data?

I hope so. [U of T Professor] Brendan Frey and his group published a paper in Science a couple of years ago using MSSNG data in its early form. They used deep genomics algorithms to analyze hundreds of thousands of variants. We published a follow-up paper using his programs to look for splicing differences in autism subjects versus controls. These are some of the first papers that convincingly show non-genic regions of the genome can be involved in autism. So the short answer is we’re already using machine learning to mine the data we have, and other groups are doing it as well. We do think U of T will have a competitive advantage here.

How is MSSNG benefiting patients now?

We’ve found a total of 63 genes and mutations that increase risk for autism through this project.

That data is communicated back to families that are part of the study, through a genetic counsellor in cases where it’s relevant. Sometimes other conditions are implicated such as epilepsy, anxiety or sleep/mood disorders. In others, a formal diagnosis can help encourage earlier behavioral interventions.

A genetic profile that matches a known subtype of autism can also affect prognosis and assessment of familial recurrence risk. And we’re linking families with one another in cases where they may benefit by talking about what worked and what didn’t. In the future, this data should facilitate clinical trials based on a small number of key neurological pathways affected by the many genetic variants in autism.

What progress might we see in the next five years?

I often say autism is about 10 years behind cancer in terms of how we use genomic data. But, we’re only behind because we started later.

Some people don’t think autism should be an area of research, and some families don’t want interventions. But most want investment and research so the demand for data is very high.

If had my dream – and I think this will happen in Ontario within three years – every child with a diagnosis would have his or her genome sequenced. For about 20 per cent of families, we can now explain why autism comes about in their child. Previous technologies only looked at two per cent of the genome, the genes. Now, most leading-edge labs are studying the other 98 per cent, and whole-genome sequencing provides the fundamental road map for those experiments. We are linking all that high-quality data together and using it to decode evolution. It’s a very exciting time.

Nature Neuroscience published the recent results from MSSNG, which is a collaboration between SickKids, Autism Speaks, Verily (formerly Google Life Sciences) and researchers at the University of Toronto.

The next blockbuster? U of T startup Protagenic Therapeutics goes public on U.S. stock market

ullahnor — Fri, 10 Mar 2017 19:38:53 +0000

The next blockbuster? U of T startup Protagenic Therapeutics goes public on U.S. stock market

ullahnor Fri, 03/10/2017 - 14:38

Cutline

Protagenic Therapeutics comes from research done at David Lovejoy's lab. From left to right, Dr. David Hogg, Professor David Lovejoy, master's students Mia Husic and Ola Michalec and PhD researcher Andrea D'Aquila (photo by Johnny Guatto)

Jennifer Robinson

Author legacy

Jennifer Robinson

Topic

Breaking Research

Health

Prozac

Protagenic Therapeutics

Innovations & Partnerships Office

Subheadline

Company fuelled by ongoing discoveries at U of T

The fortuitous discovery of an ancient gene, which made the leap from bacteria to animals hundreds of millions of years ago, could be the next billion-dollar breakthrough in the antidepressant market.

Bigger than Prozac? Maybe.

A game-changer in the industry if approved? Absolutely, says David Lovejoy, a U of T neuroendocrinology professor.

The company, Protagenic Therapeutics, founded on research conducted in Lovejoy's lab at the Ramsay Wright building, took a leap forward by getting listed on the New York-based OTCQB stock exchange, considered a stepping stone to the NASDAQ.

“This is an entirely new gene, a new process and a paradigm shift in terms of how we look at drugs to relate to stress-associated pathology like depression, anxiety, addictions, post-traumatic stress disorder and even some of the more psychotic conditions like bipolar and schizophrenia,” Lovejoy explains.

“This could lead to an entirely novel approach to treat addiction.”

And, he says U of T was the source of all the research behind the hormonal drugs tied to this gene.

Thirteen years ago, Lovejoy and his team of student researchers were looking for a family of four genes tied to the stress response in animals when they identified a novel but related gene that was “special.”

“As soon as we had the gene, I went to the University of Toronto Innovations Office [now Innovations & Partnership Office (IPO)] . . . and they got very excited,” says Lovejoy of the Faculty of Arts & Science. As the son of an engineer and businessman, early on he was instilled with the importance of ensuring his research had a practical outlook.

U of T encouraged and supported him in the creation of a company, which eventually located its headquarters in New York City with “a very enthusiastic investor.” A Canadian subsidiary is located in Toronto.

“They were absolutely fantastic,” Lovejoy says of IPO. “They got us involved with a number of people and introduced us to business development officers . . . Had I not received that support, we would have never gone forward.”

So how does an ancient gene impact our emotional states in this fast-paced modern world?

During the process of evolution, Lovejoy’s “special” gene became important for the normal function of brain cells in humans. Protagenic’s natural hormone drugs are based on a small protein encoded by this gene, located on the X chromosome.

When stressed, cells are starved for nutrients. He describes the response as similar to when we have bills piling up and not enough money in our bank accounts to pay.

“If someone hands you a cheque for a $100,000, you don’t have that stress. That’s what this hormone does,” he says. “It protects the cells and turns on their ability to utilize nutrients against neurodegeneration and stressors, but it’s completely natural . . .

“This hormone is so important in humans there are virtually four identical copies of it. It’s the only hormone that is that well conserved. It’s that important. It predates insulin, and yet it does a lot of the same things that insulin does.”

At this time, Protagenic Therapeutics is well into its preclinical work and is expected to start phase 1 clinical trials later this year or early next year for use in treating depression, anxiety and addiction, Lovejoy says. If deemed safe and approved by the U.S. Food & Drug Administration, their product could be on the market in as little as six years.

Going public will help fund these trials, which can take tens of millions of dollars and years to complete. But he says his company has two important advantages: they have a drug that is different, i.e. not in competition with previously approved offerings, and the drug comes from natural hormones “that the body is already prepared to deal with.”

The experience of creating a startup and launching the company publicly has been an exciting ride, Lovejoy says, adding he’s open to talking to fellow academics about taking the plunge.

It’s an idea with growing interest on campus. In the years since he created his company, the number of faculty research-based startups and inventions has skyrocketed at the University of Toronto.

From 2011-2015, IPO reported 837 inventions, 244 patent applications and 89 research-based startups. Those with licensing agreements with U of T — like Protagenic Therapeutics — have generated $49 million in revenue.

“The interaction of Protagenic Therapeutics, the University of Toronto, our department of Cell and Systems Biology and our IP people has been instrumental in our success,” he says. “My grad students and a number of my undergrad students are gaining training in understanding the commercialization process. Indeed, some of them are named as co-inventors on patents.

“I think we’ve achieved a seamless transition between academia, patent protection and commercialization.”

Andrea D’Aquila, a PhD student in Prof. Lovejoy’s lab, agrees.

“Few academic laboratories provide experiences with both academia and industry,” she said. “I have been able to publish in academic journals, as well as being named as a co-inventor on patent applications. As a scientist-in-training, it’s one of the best experiences to understand both sides of the coin in discovery and development.”

Jennifer Fraser, IPO’s current director, adds that the university is proud to have been a part of the project.

“ We knew it would be several years before a product would make it to market, but we were able to identify a unique investor,” Fraser says. “Dr. Lovejoy’s passion came through in our discussions with them. That made all the difference.”

U of T researcher part of international study uncovering new schizophrenia risk genes

ullahnor — Fri, 25 Nov 2016 15:12:07 +0000

U of T researcher part of international study uncovering new schizophrenia risk genes

ullahnor Fri, 11/25/2016 - 10:12

Cutline

Christian Marshall, assistant professor in U of T's Faculty of Medicine and associate director in genome diagnostics at the Hospital for Sick Children (photo courtesy of SickKids)

Caitlin Johannesson

Author legacy

Caitlin Johannesson

Topic

Canadian and international scientists have uncovered six new schizophrenia risk genes in the largest study of its kind.

The results of the international Psychiatric Genomics Consortium CNV working group are published in the Nov. 21 advance online edition of Nature Genetics. They further support the important role genes play in susceptibility to schizophrenia, and may be helpful in early diagnosis.

The team built a standardized pipeline to analyze the genes of individuals with schizophrenia as well as healthy controls using microarrays (technology which uses a microchip to determine if a genome has either missing or duplicated pieces of DNA). Researchers reported that individuals with schizophrenia tended to carry more genetic alterations than those in the control group, and these rare genomic copy variations or CNVs tended to affect genes in the synapse (the junction between two nerve cells).

“This study represents a milestone. Because of the systematic analysis in a large number of individuals with schizophrenia we were able to implicate several new genes, many of which are in the same biological pathways found in the brain,” says the first author of the paper Christian Marshall, assistant professor in U of T's department of laboratory medicine and pathology and associate director in genome diagnostics and The Centre for Applied Genomics at The Hospital for Sick Children (SickKids). “Making the connection between these common pathways can lead to development of targeted therapies for schizophrenia and other psychiatric conditions.”

The study included over 40,000 people and more than 170 scientists and clinicians from across North America and Europe.

Schizophrenia is diagnosed in one in 100 people and is a chronic and severe psychiatric condition that affects how a person thinks, feels and behaves with onset in late teens or early adulthood. Previous studies of genomic copy number variation (CNV), which are duplications and deletions in the genes, have established an important role for rare genetic variants in the etiology of schizophrenia, but many studies are underpowered to robustly confirm these genetic associations.

Like many mental illnesses you can’t just take an x-ray or simple blood test to confirm a diagnosis, says Marshall, who is part of U of T's Faculty of Medicine. With this research, clinicians have genetic tools to help find more definitive answers as to whether a patient carries the risk genes for schizophrenia. The hope is this standardized pipeline will also accelerate discoveries for other conditions.

The team was co-led by U of T Professor Stephen Scherer, senior scientist and director of the Centre for Applied Genomics at SickKids and the McLaughlin Centre at the University of Toronto and Jonathan Sebat, director of Beyster Center for Psychiatric Genomics and professor in the department of psychiatry at the University of California San Diego's School of Medicine.

Read about Professor Scherer's research on autism

The Psychiatric Genomics Consortium began in early 2007, and it includes over 800 investigators from 38 countries. The PGC is the largest consortium and the largest biological experiment in the history of psychiatry. Core funding for the Psychiatric Genomics Consortium is from the US National Institute of Mental Health.

Caitlin Johannesson is a senior communications specialist with SickKids

Bad genes aren’t always bad news say U of T researchers

lavende4 — Fri, 04 Nov 2016 18:23:33 +0000

Bad genes aren’t always bad news say U of T researchers

lavende4 Fri, 11/04/2016 - 14:23

Cutline

Arrays of mutant yeast strains in a Petri dish. The faster the cells grow, the bigger the size of colonies.

Jovana Drinjakovic

Author legacy

Jovana Drinjakovic

Topic

We usually think of mutations as errors in our genes that will make us sick. But not all errors are bad, and some can even cancel out or suppress the fallout of those mutations known to cause disease. While little has been known about this process – called genetic suppression – that will soon change as University of Toronto researchers uncover the general rules behind it.

Teams led by Professors Brenda Andrews, Charles Boone and Frederick Roth of the Donnelly Centre and the department of molecular genetics, in collaboration with Chad Myers of the University of Minnesota Twin Cities, have compiled the first comprehensive set of suppressive mutations in a cell, as reported in the latest issue of Science. The four researchers are members of the genetic networks program of the Canadian Institute for Advanced Research. Their findings could help explain how suppressive mutations combine with disease-causing mutations to soften the blow or even prevent disease.

This curious bit of biology has only come to light as more healthy people have had their genomes sequenced. Among them are a few extremely lucky folks who remain healthy despite carrying catastrophic mutations that cause debilitating disorders, such as Cystic Fibrosis or Fanconi anemia.

How could this be?

“We don’t really understand why some people with damaging mutations get the disease and some don’t. Some of this could be due to environment, but a lot of could be due to the presence of other mutations that are suppressing the effects of the first mutation,” said Roth, who is also a senior scientist at Sinai Health System’s Lunenfeld-Tanenbaum Research Institute.

Imagine being stuck in a room with a broken thermostat and it’s getting too hot. To cool down, you could fix the thermostat – or you could just break a window. Genetic suppression essentially “breaks the window” to keep cells healthy despite damaging mutations. And it opens a new way of understanding, and maybe even treating, genetic disorders.

“If we know the genes in which these suppressive mutations occur, then we can understand how they relate to the disease-causing genes and that may guide future drug development,” said Jolanda van Leeuwen, a postdoctoral fellow in the Boone lab and one of the scientists who spearheaded the work.

But finding these mutations is not easy; it’s a proverbial needle in the haystack. A suppressive mutation could, in theory, be any one of the hundreds of thousands of misspellings in the DNA, scattered across the 20,000 human genes, which make every genome unique. To test them all would be impractical.

“A study like this has never been done on a global scale. And since it is not possible to do these experiments in humans, we used yeast as a model organism, in which we can know exactly how mutations affect the cell’s health,” said Van Leeuwen. With only 6,000 genes, yeast cells are a simpler version of our own, yet the same basic rules of genetics apply to both. Also, it’s relatively easy to remove any gene from yeast cells in order to study the most severe case of a mutation, where the gene function is completely gone.

The teams took a two-pronged approach. On the one hand, they analyzed all published data on known suppressive relationships between yeast genes. While informative, these results were inevitably skewed towards the most popular genes – the ones that scientists have already studied in detail. Which is why Van Leeuwen and colleagues also carried out an unbiased analysis by measuring how well the cells grew when they carried a damaging mutation on its own, or in combination with another mutation. Because harmful mutations slow down cell growth, any improvement in growth rate was thanks to the suppressive mutation in a second gene. These experiments revealed hundreds of suppressor mutations for the known damaging mutations.

Importantly, regardless of the approach, the data point to the same conclusion. To find suppressor genes, we often don’t need to look far from the genes with damaging mutations. These genes tend to have similar roles in the cell – either because their protein products are physically located in the same place, or because they work in the same molecular pathway.

“We’ve uncovered fundamental principles of genetic suppression and show that damaging mutations and their suppressors are generally found in genes that are functionally related. Instead of looking for a needle in the haystack, we can now narrow down our focus when searching for suppressors of genetic disorders in humans. We’ve gone from a search area spanning 20,000 genes to hundreds, or even dozens. That’s a big step forward,” said Boone.

Why bad genes don't always lead to bad diseases

sgupta — Thu, 16 Jul 2015 15:53:11 +0000

Why bad genes don't always lead to bad diseases sgupta Thu, 07/16/2015 - 11:53

Cutline

Professor Andy Fraser of U of T's Donnelly Centre hopes his study will help doctors better predict and lessen the “severity of genetic diseases”

Jovana Drinjakovic

Author legacy

Jovana Drinjakovic

Topic

Subheadline

“We hope that this will eventually lead to new therapies,” says Professor Andy Fraser, “a new way to tackle these life-threatening conditions”

That two people with the same disease-causing mutation do not get sick to the same extent has been puzzling scientists for decades.

Now Professor Andy Fraser and his team have uncovered a key part of what makes every patient different.

“We have shown how genetic background – that is, the unique set of DNA letters present in any person’s genome – influences the severity of any genetic disease,” says Fraser, a professor in the University of Toronto’s Donnelly Centre for Cellular & Biomolecular Research.

The finding advances our ability to predict how severe any inherited genetic diseases will be in each affected person, a key insight into human disease.

Their study is published today in Cell, a leading biomedical journal.

The onset and severity of genetic diseases can vary widely. For example, people who carry mutations in a gene called CFTR will go on to develop cystic fibrosis (CF), a lung disease where mucus build-up makes breathing difficult and leads to life-threatening infections. But while some patients are diagnosed as newborns, others do not show any signs of the disease until adulthood.

Predicting disease severity is critical because often the uncertainty can be almost as frightening as the diagnosis.

“At present we can tell little more than that someone will get a genetic disease, but cannot tell them how bad this might be. This is a bit like telling someone that they will have a car crash but not whether this will be a mild bump or a major crash. Changing this uncertainty helps patients greatly and also lets doctors focus on those likely to be most severely affected,” says Fraser, who is also a professor in the department of molecular genetics.

Disease-causing mutations mainly strike at a gene’s function – they change the order of DNA letters so that a gene’s product, that is, protein, ends up faulty and unable to do its job in a cell.

Genetic background influences how much protein gets made, finely tuning genes like dimmer switches. This means that every person ends up having their own unique amount of thousands of different proteins.

If a person carries a disease-causing mutation, the resulting faulty protein will lead to a disease. Fraser’s team found that if the levels of that faulty protein just happen to drop below a threshold, that’s when things start to get worse as the effect of the mutation becomes more severe.

This important insight into human disease came from a powerful experimental organism – a lowly worm.

“Worms are the only animals in which we could do this massive scale of experiments to investigate how genetic background affects the severity of genetic disorders,” says Fraser.

Following initial experiments that saw a quarter of million worms scrutinized for the effects of genetic mutations, the data were then validated in human cells with the same take-home message: the severity of a disorder is a combination between the fault in the protein and its amount in each individual.

(Above: the worm known as Caenorhabditis elegans has been a powerful tool for uncovering basic rules of genetics in all organisms, including humans)

Of the three billion DNA letters that make up human genome, an astonishing three million are different between any two people. This genetic variation is great for our lives, underpinning our looks, talents and social interaction. But there is also a more sinister side to this hodgepodge of DNA, as it determines what disease we get and how bad they might turn out to be.

“Now for the first time we can begin to predict disease severity for each affected person by measuring their unique personal gene activity,” says Fraser. “We hope that this will eventually lead to new therapies aimed at turning down the severity of genetic diseases, a new way to tackle these life-threatening conditions.”

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