A mapping expedition to the exome



The IMIM Research Group on Epidemiology and Cardiovascular Genetics, coordinated by Roberto Elosua, took part this year in the Exome Aggregation Consortium (ExAC), the largest international project to date to study the presence and distribution of genetic mutations. The new map of genetic variability that this project is drawing up is a leap comparable to that of the move from traditional maps to satellite cartography, as it multiplies tenfold the number of individuals analyzed in previous studies. The participating centers have managed to include more than 67,000 people from all over the world, representative of the general population, of whom 800 are from the IMIM REGICOR (Girona Heart Register) study.


The final goal of the Exome Aggregation Consortium is to provide a description of where variations in the sequence of letters in the genes are found in order to determine which ones can be considered to condition whether or not a person suffers from a specific disease.


The exome under study

The final goal of this genetic cartography is to provide a description of where variations in the sequence of letters in the genes are found in order to determine which ones can be considered to condition whether or not a person suffers from a specific disease. ExAC does not study the complete genome (an impossible task given the 3 billion letters of which it is composed); it studies the exome, which represents 2% of this sequence and is responsible for coding the proteins that perform or fail to perform their functions in the body and is considered the backbone of the genome. In this way, we reduce the impossible number of letters to 60 million and we can identify the presence of variations in the sequence of letter. Furthermore, we can determine the frequency with which these variations appear in the population. Genetic variations that present in less than 1% of the population are considered rare variants (or mutations) and are those that are linked to rare genetic diseases (which depend on a single gene or small group of genes).


New coordinates for locating the source of diseases

This new genetic map - a real catalog of genetic mutations in the human species - makes it possible to identify 7.5 million rare variants. We have also seen that each of us approximately 3.5 million of these mutations at key points, which are probably what makes us different from each other, even though we share 99% of the genome with each other. The good news is that a large part of these variants have no implications for our health. There are also mutations that, to date, were thought to cause certain diseases but we now know do not, as they are so frequent in the population that the average person could carry at least 54 of these variations and not suffer from the diseases they were thought to have caused. This does not mean that people who have these diseases do have the mutations, but other conditioning factors are probably needed before the mutations are activated.

Another unexpected finding of the study is that genetic variants do not appear to be distributed randomly throughout the DNA. A total of 3230 genes have been found with almost no mutations. It is surprising that they are stable and immutable and, according to Roberto Elosua, this may indicate that they are not important enough to life or to reproduction for variants to exist. Curiously, only 28% of these genes have previously been linked to a disease.

The new map of mutations has also made it possible to identify some 180,000 genetic variants that cause loss of function in the protein manufactured. Each person appears to carry an average of 120 of these mutations that lead to errors.


At the service of explorers

The information obtained in the ExAC project is human heritage; it is available on line and can be consulted by the entire scientific community easily and quickly by means of the Exome Browser of the ExAC Broadinstitute.

While genetic cartography is still in its infancy, this first stage of exploring and describing mutations, with their location and frequency, is decisive. It facilitates research and diagnosis of the nearly 4700 hereditary diseases that we know about and which depend on a single gene, such as hemophilia, familial hypercholesteremia, and Huntingdon disease. It also opens the way to researchers who need to know whether their genetic findings regarding a disease are mutations or not and whether they can be considered to be a potential cause. Just like a map tells us whether we are going in the right direction.



Reference article

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





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