Scientists closer to pointing out genes responsible for diseases

August 19, 2016

160 genetic mutations are harmless

Researchers have more than 3,000 genes discovered in which some mutations are very likely to play a role in diseases. They also found more than 160 genetic mutations that were previously labelled as hereditary diseases, but in fact harmless. These findings help researchers to determine whether genetic mutations in patients are responsible for the disease.

"Researchers and clinicians should be able to identify which changes in the DNA are significant," so said DR. Jane Gibson of the University of Southampton, not involved in the research. "Is a particular change also found in healthy people? This helps to set priorities in genetic changes and narrow down the likely cause of the disease in their patients. "

Value for money

This new research is based on DNA-regions encoding information to make proteins. These regions contain most of the genetic variations which are known serious to cause rare diseases such as muscular dystrophy, "says Daniel MacArthur, senior author of the research at the Broad Institute of MIT and Harvard." By focusing on these regions we really get value for money regarding the understanding of the genetic causes of serious diseases. "

The research is the result of an international cooperation, entitled exac, where data from all over the world were combined, so as to produce the largest catalogue ever of variations in the protein-coding regions of DNA with the data of more than 60,706 persons.

More than half is only seen once

The scientists discovered about 7.5 million genetic variations in the database. "More than half of this, we see only once in 60,000 people. That's an incredibly rare frequency, "said MacArthur, adding that most of the mutations identified had never been seen before.

Besides the fact that it shows a huge variation in humans, this finding implicates something very important. "This extremely rare variants are probably those involved in serious diseases like muscular dystrophy," said MacArthur.

The research also showed that there are 3,230 genes that have less genetic variations to inactivate the gene than expected, which means that many of those genes are likely to be involved in essential processes in the cell. That means, as the researchers say, that disruptive genetic mutations in these genes are likely to produce adverse effects - although such an effect in more than 70% of these genes are yet unknown. "We know some of the genes in the list already where gene disruptions that cause severe childhood onset diseases," MacArthur said.

Surprising discoveries

The team was also able to dismiss more than 160 genetic variants that had been wrongly associated with inherited disorders. "Startling discoveries like this provide us with a better understanding of how the human genome works and how various changes may or may not affect our health," says Gibson.

While the database Exac has been free for clinical use since the end of 2014, the new research, published in the journal Nature, is the first analysis of this data. By using the database to find out how generic a genetic variation of a patient is, researchers hope to be able to screen the future mutations that cause disease. "If a particular genetic variation occurs in one in 6,000 people, it may not be a complete causal variation that occurs in one in a 100,000," said MacArthur.

It is not so rare

Ewan Birney, co-director of the European Bioinformatics Institute in Cambridge, said the Exac database is extremely important. "Previously, there would be a sense that if you had breast cancer, and you had a rare mutation in genes known as BRCA1 or BRCA2, then perhaps that rare mutation was the reason you got breast cancer, Now we can say, yes it is rare, but not so rare, so probably doesn’t cause breast cancer."

In another study by researchers at the Royal Brompton Hospital and the University of Oxford scientists described how they used the Exac database to disprove the number of linked genetic mutations to cardiomyopathy, a disease of the heart muscle which 500 people in the UK suffer and one of the most common causes of sudden death in young people in good health.

The researchers show with a publication in the journal Genetics in Medicine how genetic information from nearly 8,000 patients has been compared to the genetic variations found in the Exac database. The team found that 40 of the 48 genes that were previously linked to one form of cardiomyopathy, and a third of the genes linked to a different form were probably not the cause of the disease.

Your family is also at risk

In addition to increasing the accuracy of the diagnosis, the results are also likely to be very valuable for the testing of family members of those who are diagnosed with a hereditary disease. " When a mutation is identified you can cascade it around the family and you can say to other family members you are also at risk,," said Birney.

Although the Exac database shows genetic information of various ethnicities such as Latino, Asian and African, there are populations including those of Central Asia that are missing from the database. “For Europeans now we have this database that really helps to screen out what ends up being benign mutations,” said Birney. “We need that now for all populations.”