Paleogenomics: a new era for cardiology?

General cardiology

Published on May 06, 2024Reading 7 min

Deciphering ancient DNA a technical challenge above all Since the discovery of the structure of DNA by James Watson and Francis Crick in the early 1950s, it was not until the end of the 1990s that almost the entire genome human being sequenced by combining modern molecular biology and bioinformatics approaches. This was a considerable achievement that made it possible to further study the genetic relationships between different human populations. Svante Pääbo, for his part, became passionate about DNA from human remains that had disappeared for several thousand years since the mid-1980s. However, he faced a major difficulty: over time the DNA undergoes chemical modifications, strong degradation and contamination by surrounding modern DNA. It is then that he will develop new protocols with extremely strict sterility conditions in order to be able to study small fragments of ancestral genome. After successfully sequencing the DNA of an Egyptian mummy, he will then focus on Neanderthal DNA. Initially, he focused his work on the DNA of Neanderthal mitochondria – organelles present in thousands of copies in cells and which contain their own DNA. Although this is only a tiny fraction of a cell’s genetic information, for the first time he has succeeded in sequencing a region of mitochondrial DNA from a piece of bone 40,000 years old. This sequencing allows him to conclude that we, the Sapiens, are not direct descendants of Neanderthals, but rather distant cousins ​​with genetically distinct material(1). However, there is a bias: mitochondria and their DNA are transmitted only by the mother. As a result, this discovery failed to determine whether the Sapiens and Neanderthals who cohabited in Europe for thousands of years hybridized. It was only in 2010, after having succeeded in sequencing DNA, this time nuclear from extremely well preserved bones, that Pääbo and his collaborators demonstrated that there had indeed been hybridization. between Sapiens and Neanderthals. In other words, after migrating from Africa, Sapiens met Neanderthals in Eurasia with whom fertile crosses took place (2). Also in 2010, Pääbo sequenced mitochondrial DNA from a piece of phalanx found in a Siberian cave, which did not correspond to that of Sapiens or Neanderthals. This led to the discovery of a new species of hominid: Denisovan man (named after the cave where the bones were located)(3). The Denisovans occupied Asia, east of the Himalayas, while the Neanderthals were to the west of the continent. Pääbo and his team were then also able to demonstrate that, like Neanderthals, fertile crosses between Denisovans and Sapiens did take place in East Asia and Oceania. Thus, all humans of Eurasian origin have approximately 2% Neanderthal DNA, and up to 6% Denisovan DNA for populations from East Asia and Oceania. On the other hand, no ancestral genes have been found in the African genome given the fact that there was no coexistence between the different hominid species on the African continent. Ancestral genes: what for? The conservation in our genome of a small percentage of Neanderthal or Denisovan DNA, and therefore the expression of certain ancestral genes, raises the question of their roles in evolution (adaptation to the environment, resistance to diseases, reproduction, etc.). ). Thus certain haplotypes (groups of genes) with ancestral variants can confer resistance to a pathology or, on the contrary, can be associated with more severe forms. In the case of Covid-19, several studies have shown that genetic variants of a group of genes, located on chromosome 3, were associated with more severe forms of COVID-19. However, these variants have a Neanderthal origin. In South Asia, 50% of people carry at least one copy of the at-risk haplotype compared to 16% of people in Europe. The highest frequency of carriers is observed in Bangladesh, where more than half of the population (63%) has at least one copy of the Neanderthal risk haplotype, while 13% are homozygous for this haplotype. Thus, individuals of Bangladeshi origin have twice the risk of dying from Covid-19 than the general population(4). There is also an example concerning the resistance to hypoxia of Tibetan populations which is inherited from Denisovan genetic variants. Indeed, Tibetans can express a variant of the EPAS1 (endothelial PAS domain-containing protein 1) gene or also called HIF-2a (hypoxia-inducible factor-2alpha) which codes for a subunit of the HIF (hypoxia-inducible factor-2alpha) transcription factor. inducible factor). This transcription factor regulates the erythrocyte response to hypoxia by modifying the expression of erythropoietin. Thus, Tibetan populations living at an altitude of 4,000 m with the Denisovan variant have a level of red blood cells equivalent to populations living in the plains(5). Finally, sensitivity to pain is also a mechanism subject to certain variants. Studies have demonstrated the presence of Neanderthal variants of the SCN9A gene which codes for the NaV1.7 sodium channel. This sodium channel is abundantly expressed in nociceptive neurons as well as in sympathetic ganglia of the autonomic nervous system. Neanderthal variants of this channel show sodium currents that inactivate at more depolarized membrane potentials. In other words, once activated, the sodium channel remains open longer, which leads to increased signal transmission for the same stimulation. Consequently, individuals carrying these variants are more sensitive to pain(6). There are many other examples, each more surprising than the last, such as the expression of genes involved in the circadian rhythm which allow populations from northern latitudes better adaptation or even the presence of a haplotype in Mexican populations and Latin American populations associated with a 20% increase in the risk of developing type 2 diabetes. This group of genes identified in Neanderthals is present in Mexican populations with a frequency of 50%, while it is less common in East Asians and almost absent in other regions(7). From paleogenomics to cardiovascular diseases Currently, there are no studies demonstrating a direct link between the expression of Neanderthal or Denisovan variants and cardiovascular risk. However, a recent study demonstrates that the expression of a Neanderthal variant of glutathione reductase, an enzyme which limits oxidative stress, is associated with an increase in chronic inflammatory pathologies and peripheral vascular pathologies (8). Furthermore, for the Neanderthal haplotypes responsible for severe forms of Covid-19, these are mainly variants of genes involved in immunity and more particularly in the recruitment and activation of immune cells. These Neanderthal variants affect chemokine receptors (CCR9, Consequently, these different ancestral variants could contribute to the severity of coronary artery disease. Likewise, preclinical studies demonstrate that the expression of HIF-2a, this variant responsible for altitude tolerance in Tibetans, increases myocardial tolerance to ischemia and is involved in pulmonary arterial hypertension. IN PRACTICE Thus, we are all carriers of a fraction of ancestral genes, which are expressed differently depending on individuals, ethnic groups, the environment, and which condition our responses to different physiopathological contexts. Svante Pääbo’s work has opened the field to a new discipline, paleogenomics, which reveals our origins and allows us to identify genes involved in natural selection. This new discipline, combined with new high-throughput sequencing strategies, will undoubtedly contribute to the current development of personalized medicine and more particularly in the different fields of pharmacogenomics.