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16/08/2016 - Press release

Catalogue described of genetic mutations, their frequency and arrangement on the DNA

This is the first detailed analysis of the presence and distribution of genetic mutations in more than 67,000 people

An international project, The Exome Aggregation Consortium (ExAC), involving researchers from the IMIM (Hospital del Mar Medical Research Institute) as the only Spanish participant, has analysed the DNA that encodes proteins in 60,706 individuals from different ethnic groups and has presented the international scientific community with a catalogue that contains the mutations identified, their frequency and their arrangement on the DNA. The study has been published in the journal Nature and involved the analysis of ten times more individuals than in any previous study.

DNA is the molecule within our cells that contains the information for making proteins, in the form of a sequence of four letters or bases [adenine (A), guanine (G ), thymine (T) and cytosine (C)]. In recent years we have developed technologies to sequence, i.e., read the order of these bases in a person's DNA. Changing one of these bases can sometimes alter the protein that the cell makes and lead to illness. For this reason, it is important to know what the normal sequence of bases in DNA is, the frequency of mutations (changes in the sequence of these bases), and where these changes take place, by making a catalogue and map of DNA mutations in humans.

"The ExAC project involved sequencing the protein-encoding DNA of 60,706 people. Up to this point there was a map of genetic variability in human DNA taken from two studies that had analysed 6503 and 2504 individuals, respectively. In this study almost ten times the number of people were tested", explains Roberto Elosua, coordinator of the Cardiovascular Epidemiology and Genetics group at the IMIM. The researcher goes on to say that "Almost 7.5 million mutations have been identified, approximately half of which present in a single person and 99% of which occur in less than 1% of the population. That's why we drew up a map of rare mutations that may be useful in the study of patients suffering rare hereditary diseases."

To study genetic diseases a patient's DNA is usually sequenced. A common problem is determining which of the mutations identified in the DNA analysed is that causing the disease in the particular patient. Elosua explains that "In this study we saw that certain variants believed to cause a disease are very common in the population, and are therefore unlikely to actually be the cause of this genetic illness. It has been estimated that, on average, each individual is a carrier of at least 54 genetic variants which were considered to cause disease".

In this paper the researchers have also described the fact that genetic variants are not randomly distributed throughout the DNA, and it has been possible to identify 3230 genes that have almost no rare genetic variants, those which cause disease, meaning these genes may be important in the survival or reproductive ability of our species. Interestingly, only 28% of these genes have been previously associated with illness.

The study has also enabled the identification of around 180,000 genetic variants that cause a loss of function in the protein that is produced. On average, each individual carries about 120 of these mutations that cause function loss. By analysing the presence of these variants we are able to identify people who have protein alterations and assess the impact this loss of protein function has on health.  

The researchers have made this catalogue of human mutations available to the international scientific community in order to move forward in our understanding of the genetic basis of disease and help improve the health of individuals.

Reference article:

Analysis of protein-coding genetic variation in 60,706 humans”. ExAC Consortium. Nature 2016.

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