The genetic make-up of humans and chimpanzees is 98 to 99 per cent the same. So why do we differ? In recent years, researchers have shown that gene expression - i.e. when, where and how strongly genes are transcribed - is largely responsible for our different development over the course of evolution.
Researchers from Professor Norbert Hübner's ‘Genetics and Genomics of Cardiovascular Diseases’ research group and the ‘Pluripotent Stem Cells’ technology platform led by Dr Sebastian Diecke at the Max Delbrück Center have now revealed just how surprisingly different gene expression is in the hearts of humans and other primates. The study in ‘Nature Cardiovascular Research’ provides information on the adaptation mechanisms that regulate genes that distinguish our heart from those of our closest evolutionary relatives. It also shows that research results obtained on animal hearts cannot be easily transferred to human hearts.
‘We were particularly surprised by how much gene regulation in the human heart differs from that of other primates,’ says first author Dr Jorge Ruiz-Orera. Anatomically, the hearts of most mammals are similar. ‘But we have undergone many unique evolutionary innovations in terms of gene regulation or translation into proteins,’ he adds.
The scientists discovered hundreds of genes and microproteins - these are tiny proteins previously identified in human organs, but whose function was largely a mystery. These microproteins are present in the human heart but absent in the hearts of other primates, rats or mice. ‘Many of these human genes and microproteins are also abnormally expressed in heart failure. This suggests that they play an important role in heart function and heart disease and are potential targets for therapies,’ explains Ruiz-Orera.
Comparison of gene transcription and translation
The team analysed heart tissue from chimpanzees and macaques, which came from the Dutch biobank of Dr Ivanela Kondova at the Biomedical Primate Research Centre in Rijswijk. In addition, they analysed stored heart tissue from humans, rats and mice, which they had already used in previous research.
Using RNA sequencing, the researchers first mapped and quantified the RNA molecules of the heart tissue. This provided a comprehensive overview of gene expression in different primary species. To specifically identify the RNA regions that are translated into proteins, the researchers used Ribo-seq, a ribosome profiling technique that sequences the RNA fragments that were actively translated in each cell. This provided information about which genes produce functional proteins. By integrating data from these technologies, the team created the most comprehensive resource to date on gene and protein activity in human and non-human primate hearts.
Specific microproteins - which are encoded by small snippets of DNA called open reading frames (ORFs) - are formed or translated in unique ways in human heart cells at different stages of development. This suggests that some of these genetic elements have evolved to meet the requirements of the human heart, Ruiz-Orera explains. (ORFs do not have the classic characteristics of protein-coding genes and are therefore not classified as genes).
‘The energy requirements of our hearts are different from those of smaller primates such as macaques, which have much faster heart rates,’ he explains. ‘This difference appears to be reflected in the regulation of genes related to energy production in the heart. These evolutionary adaptations may also be related to our upright gait, lifestyle and diet.’
The team identified a total of over 1,000 species-specific adaptations in the genome, including 551 genes and 504 microprotein coding regions that are unique to the human heart. Among them were 76 genes that occur in humans as well as in other primates and mammals, but have evolved to be expressed in the heart only in the human species.
Significance for heart disease and animal testing
The researchers showed that some of the genes and microproteins that are specific to humans are dysregulated in diseases such as dilated cardiomyopathy. They may therefore play a role in the development of heart disease and could serve as targets for new treatments.
The study also raises important questions about the use of animals such as mice to study the genetics of human heart disease. ‘Our results suggest that the differences between species can sometimes lead to misleading results,’ says Ruiz-Orera. ‘There are many genes that are active in the human heart but not in the hearts of other species.’
In humans, for example, the SGLT1 gene is active in the heart. In non-human primates, rats and mice, however, this is only the case in the kidneys. Inhibitors of SGLT1 and SGLT2 have been shown to alleviate heart failure, although their exact role in the heart is still a mystery, says Ruiz-Orera. However, since it is not active in the hearts of other species, researchers can learn little when testing such therapies in animal models. ‘It's important to consider the evolutionary context in medical research,’ he adds.
Original publication: Evolution of translational control and the emergence of genes and open reading frames in human and non-human primate hearts. Jorge Ruiz-Orera, Duncan Miller, Johannes Greiner, et al., Nature Cardiovascular Research, 2024
Source: press release MDC
