An individual’s complete genome sequencing and genome-wide association studies (GWAS), which look at a large number of subjects, are the foundation for the development of precision medicine. Their potential is far from being fully exploited.
In Italy, a two-day congress in Aosta took stock of 5000genomi @ VdA, a project launched two years ago that led to the creation of a Center for Personalized, Preventive and Predictive Medicine (CMP3VdA) coordinated by the Italian Institute of Technology , supported by European and regional funds and by numerous public and private research partners. Divided into two departments, Medical Genomics and Computational Genomics, the center has over 450 square meters of laboratories whose construction has recently been completed.
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“What makes it unique at national and European level is the integration between the research activities related to genomic sequencing and the hospitals and the Aosta Valley health system” explains the co-coordinator of the project. Stefano GustincichHead of the LifeTech Technologies for Life Sciences area of the Italian Institute of Technology in Genoa, who talks about “setting up a real aircraft carrier” made up of infrastructures, experimental protocols, sample collection, bioinformatics analysis and, to follow, interpretation of the results.
“Whole genome sequencing aims at identifying new potentially pathogenic variants, informing the clinical discussion in a growing number of pathologies in real time,” he explains. Manuela Vecchicoordinator of the medical genomics team of 5000genomes @ VdA.
The five sub-projects
The project concerns, in fact, the mapping of the genome of healthy individuals in the Valle d’Aosta Region with neurological, neurodegenerative and neurodevelopmental, oncological and organ transplant-susceptible diseases to conduct studies of association between genes and the risk of developing disease. .
In particular, its five main sub-projects foresee the recruitment of 2,000 patients with Alzheimer’s or Parkinson’s in order to identify genomic variants known to cause neurodegenerative diseases or an increased risk of developing them; 800 cancer patients to develop a new personalized genomic panel for genetic alterations incidence in the Valle d’Aosta population; of 400 children and adults with autism spectrum disorders and other cognitive disorders. Furthermore, in the case of transplants, about 200 patients of the Piedmont – Valle d’Aosta Regional Transplant Center who have undergone or are awaiting an organ transplant will be analyzed, to identify genomic variants associated with diseases that made the transplant necessary: “The pathology that causes organ failure such as to require transplantation remains elusive in 20% of cases and can be attributed to monogenic causes in about 30% of the remaining patients who have a diagnosis,” explains Vecchi.
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“Knowing the clinical history of the patients, we also aim to identify genetic profiles associated with rejection and help in assessing the dosage and efficacy of post-transplant drugs, such as immunosuppressive therapy.” The experimental protocols for this part have been approved and a good number of cancer patients have already been recruited.
Finally, the last sub-project will concern population genomics, sequence 500 healthy subjects and serve as a control group, but not only. In fact, “it is important to study the genome of a population as it provides knowledge on the origins and history of the population itself and – explains Vecchi – on the possible existence of particular genetic traits capable of exposing them to the risk of developing certain diseases”.
Nanopore sequencing
In addition to the latest generation sequencer, Illumina NovaSeq 6000, the team from Valle d’Aosta will have at its disposal an innovative technology, Oxford Nanopore Technologies (ONT), developed in England, of which at the moment there are few examples in Italy, and which “in five years is destined to become the method of choice for sequencing “predicts Gustincich.
Compared to Illumina, which works on fragments of 150-400 nucleotides, Nanopore in a single reading reaches as many as 30-50 thousand bases: the DNA or RNA molecule is passed through a nanometric pore and the current perturbation caused from each base it allows to reconstruct their order. “This gives an overview of large sections of the genome and, on the one hand, reduces the possibility of errors that creep in when assembling the various fragments for the reconstruction of the entire sequence; on the other, it allows a more accurate study of the so-called junk DNA, not coding but with crucial regulatory functions, characterized by repeated sequences that are very difficult to place “explains Gustincich. “In addition, the method also identifies any changes in the reading of the RNA that translate into alterations in the expression of proteins, the so-called epitrriptomic alterations”.
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In addition to infrastructures, Nanopore requires computational resources such as sophisticated signal analysis, high computing capacity and data storage and interpretation. Furthermore, in collaboration with the regional territorial bodies, on the occasion of the centenary of the Gran Paradiso National Park, this method will reconstruct the reference genome of the Valle d’Aosta Ibex with which the genomes mapped with Illumina will be compared.
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Future developments
There is no knowledge to be applied in the clinical setting without data. “Genomics is experiencing its golden age,” explains Vecchi. “On this, oncology has led the way and is at least a decade ahead of neurology. But because of the lesser knowledge in this discipline, we could expect a huge impact in the short term.” In addition to launching large programs of complete genome sequencing of the entire Italian population, “the real revolution in knowledge could come from a prospective-retrospective study, promoted by the national health system, which would require the mapping of subjects at birth, to investigate in the course of life correlations between variants and polymorphisms and the development of pathologies also in the light of the lifestyles adopted “, comments Vecchi, who in any case recalls the importance of discussing the ethical implications relating to the collection but above all to the use of such information. Often, in fact, behind these great efforts to create databases there are commercial interests of consortia or even individual companies, as in the Icelandic case of DeCode Genetics, purchased ten years ago by the American biotech Amgen.
The other countries
The next country is the United Kingdom. The “100,000 Genomes Project”, which ended in 2018, led to the mapping of the entire genome of cancer patients or patients with rare diseases: the first analyzes on 4 thousand people show that the mapping leads to a new diagnosis in 25% of cases and in 14% these cases are variations that would not have been identified with other methods. Furthermore, an analysis of 12 thousand complete sequences, published in the journal Science, shows that the method has allowed to find a real “treasure” of clues on the causes of cancer: genetic mutations that provide a history of damage and repair processes. occurred in each individual case.
The discoveries on cancer
The analysis also led to the identification of 58 new mutational cancer signatures. In addition, during the Research Summit on May 4, says Vecchi, “Genomics England announced the entry into the clinical routine of complete mapping for cancer patients or patients diagnosed with rare disease, often children with important symptoms that, in the absence of a timely intervention is destined to quickly fail “.
This virtuous model of collaboration between the National Research Agency and the British NHS is not the only one. Other examples are “Sweden, where a collaboration between hospital and university allows for complete sequencing for rare diseases and in 40% of cases a molecular diagnosis has been reached”. Then there is Qatar, which aims to become the “Iceland of the Middle East”, as stated by the emir who finances the Qatar Genome Sequencing initiative, which has led to the sequencing of one in ten Qataris and will reach 30% in the next four years. And Italy must quickly catch up with projects aimed at genomics and big data.