Genomes of 240 mammalian species explain human disease risks

“In combination, the 11 articles we are now publishing in Science they provide an enormous amount of information about the function and development of mammalian genomes,” says Kerstin Lindblad-Toh, Professor of Comparative Genomics at Uppsala University and one of the two leaders of the international consortium of researchers. “In addition, we have produced data that can be used for evolutionary studies and medical research for many years.”

In a large international project run jointly by Uppsala University and the Broad Institute, more than 30 research teams have together examined and analyzed the genomes of 240 mammalian species. The results, now published in 11 articles in the journal Sciencethey show how the genomes of humans and other mammals have developed in the course of evolution.

The human genome contains approximately 20,000 genes that are the code for making all the proteins in the body. The genome also contains instructions that tell where, when, and how many proteins are made. These parts of the genome, called regulatory elements, are much more difficult to identify than the parts that give rise to proteins. However, the study of the genomes of a large number of mammals makes it possible to determine which parts of the genome are functionally important.

The hypothesis shared by the researchers behind the publications in Science It has been that if a position in the genome has been conserved through 100 million years of evolution, it is likely to have a role in all mammals. For the first time, they have been able to test this hypothesis on a large scale. By conducting a detailed survey and systematic comparison of the genomes of 240 mammals, researchers have identified regions of the human genome with previously uncharacterized function. These regions are probably regulatory elements and are important for the proper functioning of the genome. Mutations in these may play an important role in the origin of diseases or in the distinctive characteristics of mammalian species.

The researchers identified more than three million important regulatory elements in the human genome, about half of which were previously unknown. They were also able to determine that at least 10 percent of the genome is functional, ten times more than the roughly one percent that codes for proteins.

The 240 different mammals in the study vary widely in their characteristics, such as the acuity of their sense of smell or the size of their brains. The researchers were able to find regions in the genomes that cause some species to have a superior sense of smell or cause certain species to hibernate.

“It’s exciting to now have a picture of which mutations have driven the development of specific traits in these highly divergent mammals,” says Matthew Christmas, a researcher and co-author of one of the papers focusing on genome function and how it affects distinctive features. in different species.

One of the studies shows that mammals had begun to change and diverge even before Earth was hit by the asteroid that killed the dinosaurs, roughly 65 million years ago.

“Our results can also provide important information about whether mammals are at risk of extinction, depending on how much variation they have in their genome. This is information that can lay the foundation for understanding how to manage a species to help it survive,” he says. Professor Lindblad-Toh.

The new knowledge also helps researchers understand how diseases arise, by linking positions in the genome conserved by evolution with known conditions. This can be done for all species and can also be used with reference to human diseases.

“Our analyzes of 240 mammals give us a better understanding of regulatory signals in the genome. We calibrated our results to positions known to contribute to disease, and could then use these to suggest additional positions that could be prioritized for neurological traits, such as schizophrenia or immune conditions like asthma or eczema,” says Jennifer Meadows, a researcher and co-author of the second paper, which focuses on how data from the project can contribute to disease understanding.

The genome of healthy and diseased people is compared to understand which mutations lead to disease. This produces a picture of the region in the genome that may be important, but does not provide exact knowledge of which mutation causes the disease.

“A large proportion of the mutations that lead to common diseases, such as diabetes or obsessive-compulsive disorder, lie outside of genes and involve gene regulation. Our studies make it easier to identify mutations that lead to disease and understand what goes wrong,” says Lindblad-Toh.

The researchers also studied medulloblastoma cancer, which is the most common type of malignant brain tumor in children. Although modern treatments have improved the prognosis, not all children can be cured. Additionally, those who survive often experience lifelong side effects from aggressive treatment.

“In medulloblastoma patients, we found many novel mutations at evolutionarily conserved positions. We hope that analysis of these mutations lays the foundation for new diagnostics and therapies,” says Karin Forsberg-Nilsson, Professor of Stem Cell Research at Uppsala University, who led the cancer portion of the study.

This work was supported in part by the National Institutes of Health (US), the Swedish Research Council (SWE), the Knut and Alice Wallenberg Foundation (SWE), and the National Science Foundation (US).