Comparing the human genome with that of hypothetical ancestral mammals that lived 100 million years ago could hold the key to uncovering DNA segments involved in the development of diseases like cancer and schizophrenia, which are challenging to detect using current methods. This is one of the promises of the Zoonomia Project, an international collaboration of over 30 laboratories from various institutions and countries, led by researchers from the University of Uppsala in Sweden and the Broad Institute in the US. Their initial findings were published Thursday, April 27, in a special edition of Science with 11 articles dedicated to the evolution of placental mammals — a group that excludes animals such as the platypus and kangaroo.
Drawing upon previously unexplored data on 241 species, covering nearly all mammal families, the project is working to reconstruct the evolutionary history of mammals while also gaining insights useful in developing new methods of treating and diagnosing diseases. Another goal of the project is to unravel the genetic mechanisms that distinguish species and identify species at greatest risk of extinction, which can help to inform conservation priorities.
Mônica Imbuzeiro / Wikimedia CommonsAmazon river dolphins are specially adapted for life in waterMônica Imbuzeiro / Wikimedia Commons
“Analyzing genome evolution over time allows us to pinpoint segments unchanged across species and segments changed in some species,” explained Elinor Karlsson, a professor of bioinformatics at the Broad Institute and the University of Massachusetts, and one of the project coordinators, in an interview with Pesquisa FAPESP. The project’s chosen name, Zoonomia, pays homage to Erasmus Darwin (1731–1803), the grandfather of Charles Darwin and author of the 1794 book Zoonomia; or the Laws of Organic Life.
Karlsson notes that it is typically the genes — the better studied 1% of the genome — that undergo mutations, which are more readily interpretable due to their functional effects. These DNA alterations lead to specific changes in proteins, which can either have detrimental effects or contribute to heightened genetic diversity within populations, potentially even resulting in the emergence of new species.
“Segments that change less are responsible for regulating genes to produce more for less proteins,” explains Karlsson. “If a particular genome region has remained unchanged for 100 million years, it likely serves a vital function in mammals.” Mutations can also be associated with diseases. The researchers have determined that 9% of the genome plays regulatory roles, while the remaining 90% still harbors unknown functions.
Clodomiro Esteves Junior / Wikimedia CommonsCapybara: the world’s largest rodent, with amphibious habitsClodomiro Esteves Junior / Wikimedia Commons
According to Karlsson, gene regulation plays an important role in complex disorders such as schizophrenia, which cannot be diagnosed based on the presence of a single causative gene and may take time to manifest throughout an individual’s life. “In these diseases, genome regulation changes during an individual’s development, affecting the production of proteins and giving rise to the disorder.” The researchers speculate that a portion of this regulation may influence poorly studied phenomena, such as embryonic and brain development.
Currently, the most common approach to studying complex diseases involves comparing the genomes of individuals with and without the condition to identify regions that are exclusive to the affected individuals. According to Karlsson, the problem with this approach is that it deals with large DNA segments including both genes and regulatory regions.
“The genome holds an immense amount of information, so analyzing each of these segments is costly and time-consuming, and you risk wasting time on nonessential areas,” she notes. The evolutionary approach could offer a pathway — or a shortcut — to identifying the DNA segments that are relevant for health.
Desmodus / Wikimedia CommonsBats…Desmodus / Wikimedia Commons
Last month, Karlsson and her colleagues decided to host the fifth Zoonomia conference in Manaus, in the heart of the Amazon rainforest, instead of in a beach city as was their tradition. “For the first time, I had the chance to personally encounter animals like sloths, monkeys, and dolphins that I had previously only seen as DNA sequences on a computer screen.”
One of the articles in the special issue of Science explores the evolution of placental mammals, concluding that the group began to diversify before the extinction of dinosaurs. “Placental mammals emerged over 100 million years ago when the continents were still interconnected,” explains Eduardo Eizirik, a professor of biology at the Pontifical Catholic University of Rio Grande do Sul (PUC-RS) and one of the authors of the paper.
Nortondefeis / Wikimedia Commons… sloths…Nortondefeis / Wikimedia Commons
Small, mouse-like animals freely roamed the planet until they were gradually separated by the drifting apart of North America from Eurasia in the Northern Hemisphere, and South America from Africa and India in the Southern Hemisphere. “Once isolated, the populations followed their own evolutionary paths, giving rise to the major groups that exist today, such as primates, rodents, carnivores, bats, and others,” suggests Eizirik.
Approximately 20 million years later, major continental flooding occurred as a result of global warming and a substantial rise in sea levels. This further intensified the process by dividing Africa into two parts and transforming large landmasses in the Americas into islands.
To compare the genomes, the researchers aligned the DNA sequences of all 241 species and then compared each letter — each base, in technical terms — to document the differences. “It’s like creating an enormous table with 2.3 billion columns and 240 rows, where we input the letter that appears in the genome of each species,” Eizirik explains.
The task was especially challenging due to the potential structural changes that can occur in species’ genomes over time. For this reason, the genome had to be initially fragmented, and the equivalent regions of each species identified.
Since the mutation rate of DNA over time can be estimated, these evolutionary trees also provide clues into the era when ancestral animals existed. The data was intersected with the known ages of 37 mammal fossils to perform molecular dating and make necessary adjustments.
Around 66 million years ago, the major mammalian groups, now separated and freed from predation and competition with dinosaurs, underwent further waves of diversification as they adapted to different environments, giving rise to groups as diverse as bats, elephants, and whales. “The diversification occurred rapidly, over a span of just a few million years, particularly in groups like bats and rodents,” Eizirik explains. Each of the original groups underwent diversification, filling the ecological voids left behind by the large reptiles.
Understanding genomes can also aid in identifying species that are threatened with extinction, supporting conservation efforts. The genome holds valuable information that can be used to indirectly estimate the size of species populations over time.
Luc Viatour / Wikimedia Commons… and squirrel monkeys have adapted for flight and tree dwellingLuc Viatour / Wikimedia Commons
Smaller populations tend to exhibit lower genetic variability, which hampers their ability to adapt to environmental changes. For instance, among Brazilian felines, margays historically had smaller populations compared to ocelots, resulting in reduced levels of genetic diversity today, an aspect that is taken into account in vulnerability assessments.
“The challenge in reconstructing the evolution of living organisms based on the genome lies in its sheer magnitude as well as the fact that not all segments tell the same story,” notes biologist Cristina Miyaki from the University of São Paulo, who was not involved in the study. She explains that conserved segments and segments that have undergone changes through evolution may tell different narratives despite belonging to the same genome. “The authors worked around this issue not only by using large amounts of data but also by conducting multiple analyses to test the extent to which the proposed phylogenetic trees [diagrams representing evolutionary relationships] accurately reflected these data,” she says.
Bo Mertz / Wikimedia Commons… and a small rodent, reminiscent of the animals that survived the dinosaursBo Mertz / Wikimedia Commons
The studies as part of the Zoonomia Project were made possible by technological advancements that, over a span of 20 years, have reduced the time it takes for sequencing machines to read a genome from 15 years to just a few hours. Sophisticated computational techniques for analyzing evolutionary patterns have also played a vital role.
With their study on mammal evolution, Eizirik and colleagues have substantiated a hypothesis they have been pursuing since 2001, when they demonstrated in a Nature article that placental mammals began diversifying before the extinction of the dinosaurs. With the vast amount of data now available and advancements in computational analytics, the group was able to test its initial theory — and it held up. “Only this time, the amount of information supporting the theory is hundreds of thousands of times greater.”
Scientific articles
FOLEY, N. M. A genomic timescale for placental mammal evolution. Science. vol. 380, no. eabl8189. apr. 28, 2023.
MURPHY, W. J. et al. Molecular phylogenetics and the origins of placental mammals. Nature. vol. 409, pp. 614–18. feb. 1, 2001.
