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In genetics, all that glitters is not gold

In 2010, Sonia Vallabh was working as an attorney in a US law firm when her mother died due to a rare disease known as fatal familial insomnia. The pathology is a prion disease that has been observed in some 100 patients around the world. Forty of them live in Spain, almost half of them in the Basque Country. The disorder, characterized by symptoms such as insomnia, ataxia and dementia, develops when a genetic mutation causes proteins to take on shapes different from that of the normal molecule. As a result, they clump together and accumulate in the central nervous system. The area most affected by the toxicity of this protein is the thalamus, which plays a role in numerous physiological functions, including the regulation of sleep.

Both Sonia and her mother had the D178N mutation. To Sonia, just 26 years old at the time, it seemed like a death sentence. But the attorney decided to resign from the law firm where she was working and start studying biology, with the aim of discovering the real origin of the disease. Because in genetics, everything that glitters is not gold, at least according to the results recently published in Nature by the Exome Aggregation Consortium (ExAC).

The study has brought to light the most extensive catalog of human genetic variation applied to clinical research performed to the present date. The team of scientists, led by MIT’s Broad Institute, has analyzed the exomes of more than 90,000 people, although after performing the processing, quality control and filtering of the data, they have released the conclusions of 60,706 individual exomes. The DNA sequences, from the fraction of the genome responsible for coding the proteins, were from individuals from different population groups of Europe, Africa, south-east Asia and Latin America. As has occurred in other studies related with genomics, researchers collected significantly fewer exomes of individuals from the Middle East and Central Asia. 

Multiple alignment of DNA sequences

Source: Shaury Nash (Flickr)

The consortium analyzed over 7.4 million genetic variants. Given the large sample of exomes they had, they were able to conduct an in-depth study on the variants that appear very infrequently in the aforementioned populations. As explained in the Nature article, the database created surpasses by one order of magnitude the information that had been available up to now on exomes and genetic variants. Further, the researchers state that the density of these genetic variants is not uniform across the entire genome. Rather, the observation of these variants depends on factors such as the properties of the mutations and selection pressures. The vast quantity of exomes analyzed, in any event, has allowed them to detect the recurrence frequencies of rare variants in the populations, which they have called mutational recurrence.

After completing her biology studies, Sonia Vallabh joined the group of Daniel MacArthur, one of the directors of ExAC. One of the objectives of the team was related with the obsession the former lawyer had had in mind since her mother’s death: to determine whether the D178N mutation bore any relation with fatal familial insomnia, as appeared to be the case. Having access to such a massive amount of information, the team was able to explore the roots of many rare diseases of genetic origin, including the disorder that Vallabh’s mother had suffered. The results, however, were truly alarming. 

Some of the results published by the ExAC consortium, one of the main findings is that many of the reportedly pathogenic variants found in ExAC are at too high a frequency to be consistent with disease prevalence and penetrance.

Source: Monkol Lel et al. (Nature)

Some of the genetic mutations that had been considered pathogenic in the past were actually found to be benign. The ExAC researchers analyzed the presence of 192 genetic variants in the exome of the participants and found evidence that, in a majority of cases, these changes could have been erroneously interpreted. Their conclusions, published in Nature, indicated that only nine of these variants could be potentially pathogenic, as a large proportion of the rest were in the exome of healthy individuals. The clinical implications of the study will have a great impact, as many of these genetic variants, previously associated with the appearance of Mendelian disorders, guide the diagnosis and treatment of these pathologies. This initial catalog of 60,000 exomes, which will be doubled by year-end, spurred a recent editorial in Nature in which the scientific community was urged to rethink the relationship between genes and diseases.

It is possible that many of these genetic variants have been identified as causes of a disease without sufficient scientific evidence to support such a claim. This conclusion opens the door to a radical revision of the studies performed up to the present thanks to DNA sequencing and genomic analysis. ExAC, the largest catalog of human genetic variants, is also a very powerful tool in the area of clinical research. Unfortunately for Vallabh, the analysis of the mutation she carries has 100% penetrance, as the researchers did not find this variant in healthy patients, as did occur in other cases, such as the M232R mutation or the variant V2101, previously associated with the appearance of prion diseases. The scientist will continue searching among millions of data in the coming years to expand the catalog presented by the ExAC, and know whether or not the mutation she carries causes fatal familial insomnia. This is a true battle against time that can change the application of genomics in biomedicine.