A new study on alcohol abuse could help us finally reveal secrets to fight genetic diseases

The human genome project has not kept up with the hype in the fight against the disease, but a new study on alcohol abuse could change that.

It's been almost 20 years since Bill Clinton joined Tony Blair to announce the first rough sequencing of the human genome in June 2000. The president rushed against the White House audience:

We are more and more impressed by the complexity, beauty and wonder of the most divine and most sacred gift of God. Thanks to this new and profound knowledge, humanity is about to acquire a new and immense healing power.

This has not happened yet, though. We have identified the genetic basis for some rare diseases, such as this cognitive impairment, but our understanding of the major diseases, including cancer, heart disease and diabetes, seems hardly better than at the beginning of the century. The good news is that there may finally be a way forward – but first, the story so far.

The human genome is the collection of DNA that contains the recipe of what we are as individuals. Sequencing has certainly had benefits. We have determined the actual number of genes it contains, as well as their structure and function. All of these were considered essential to understand our sensitivity to all genetic diseases, from cancer to insomnia.

This created big surprises. Because of our intellectual superiority over other mammals, geneticists thought we needed at least 100,000 genes to listen to Bach or discern fine wines. But it turned out that all mammals, from mice to humans, share the same suite of about 20,000 genes. After digesting this discovery, at least, an opportunity arose: fewer genes meant easier search for genetic mutations causing disease – all the more so as it turned out that genes do not constituted only 2% of the genome.

The stone of stumbling

Geneticists have attempted to exploit the revelations about the genome by conducting studies exploring thousands of tiny genetic modifications in hundreds of thousands of patients with different diseases to compare their results to those of healthy people. This allowed them to correlate DNA genetic modifications achieved in an unimaginable way before June 2000. Thus, one has much better understood the "genetic architecture" of a large number of DNAs. Conditions ranging from cancer to schizophrenia through addiction.

However, after the publication of the first thousands of studies, geneticists were horrified to discover that 98% of the virus-associated changes they had identified in the genome did not occur in the genes. Instead, the vast majority of disease-related changes occur in 98% of the genome that is not made up of genes – known as the "junk food genome" because little of it. between them had the most blurred notion of what he was or how to study it.

At this point, a white knight appeared in the form of 440 scientists from around the world known as the ENCODE consortium. ENCODE, headquartered in Stanford, spent about US $ 400 million to prepare a much vaunted "Encyclopedia of the Human Genome", gathering huge amounts of data to understand what was happening in the genome of junk food.

Among the various litigious claims, the consortium later proclaimed that at least 10% of the human genome was made up of genetic switches called activators that turn genes on and off. But if this seemed to be the way to overcome genetic diseases, difficulties soon became apparent.

Scientists have suggested that these complex DNA sequences evolve continuously at high speed, implying that they are not as important as genes. They can also be unique to individual species rather than common to many. At the same time as discoveries that activators appeared to be transient and ephemeral in the genome, it was beginning to resemble our ability to quickly understand the human genome, which may have been overexpressed.

An alternative approach

Some geneticists, including myself, are questioning this wisdom. This is related to the way scientists have identified activators up to now: where we can recognize genes very clearly using a three-letter code system, ENCODE has identified activators using biochemical marker tests – just like the studies that then posed difficulties with these switches.

However, there is not enough evidence to say that the "enhancer markers" in these tests accurately identify all the enhancers in the genome. More fundamentally, the use of markers assumes that activators behave in a uniform manner. If they are active only in specific cells at specific times, biochemical marker tests will not always be accurate because they can not reflect the activity of all the amplifiers in very specific regions in which they are active. If this is the case, amplifiers could be conserved in the genomes of many more species than suggested by previous biochemical markers studies.

To test this idea, the Universities of Aberdeen and Edinburgh collaborated to identify the genetic causes of anxiety and alcohol abuse, which kills 7.7% of men and 2.6% of women in world. To do this, we studied mice – because they too can be prone to alcoholism when exposed to alcohol.

There is a gene called GAL that produces a small neuropeptide called galanin, which affects the consumption of alcohol. However, we knew that when you compare people who drink a lot to those who do not drink, you do not see any differences in the LAG gene. By studying the mice, we identified what appeared to be an activator that activated this gene in specific regions of their brains.

We compared the genome sequences of 100 animal species, including humans, mice and birds, and found the same presumed activator on the genome, at about the same position, some distance from the gene. The evolutionary branches of birds and humans being separated some 310 million years ago, the fact that this entity has survived makes it extremely likely that it is at the center of the abuse. d & # 39; alcohol.

To test this, we used a new gene editing technology to remove the amplifier in the mouse. Indeed, we found that our modified gene mice drank significantly less than normal mice after a week of alcohol exposure. They also became less anxious – although only men. With the help of human genetics studies conducted at the University of Edinburgh, we found that in humans the same activator plays an important role in controlling mood and mood. alcohol consumption.

This is the first time that anyone demonstrates that the same activator controls alcohol consumption and mood in a large number of species. This suggests that activators with important functions can be detected in the human genome by looking at how far they exist in different species. Far from being the transient and ephemeral entities suggested by biochemical marker studies, our work demonstrates that activators are essential for driving the expression of specific genes in specific cells where they play an important role in maintaining health.

I think that functional studies on activators like the one we have conducted will be the key to truly fulfilling the promises of this eventful day in June 2000. We will then be able to appreciate the functional consequences of the changes associated with the disease identified by previous studies of the genome.