The Zoonomia Project is an international collaboration that seeks to discover the genomic basis of shared and specialized traits in mammals. The project, led by Uppsala University and the Broad Institute, has surveyed and analyzed the genomes of 240 different mammals. The results, now published in 11 articles in Science, show how the genomes of humans and other mammals have developed over the course of evolution. The research shows which regions have important functions in mammals, which genetic changes have led to specific characteristics in different species, and which mutations can cause disease.

“In combination, the 11 articles we are now publishing in Science provide an enormous amount of information about the function and development of mammalian genomes,” said Kerstin Lindblad-Toh, PhD, professor in comparative genomics at Uppsala University, the director of Science for Life Laboratory Uppsala, and the scientific director of vertebrate genome biology at the Broad Institute. “Moreover, we have produced data that can be used for studies of evolution and medical research for many years to come.”

The project is the largest comparative mammalian genomics resource in the world. The work has cataloged the diversity in the genomes of 240 mammalian species, representing over 80% of mammalian families. Their findings pinpoint parts of the human genome that have remained unchanged after millions of years of evolution, providing information that may shed light on human health and disease. The authors’ work also reveals how certain uncommon mammalian traits—like the ability to hibernate—came to be. They say these analyses, and the breadth of questions they answer, only show a fraction of what is possible with this data for understanding both genome evolution and human disease.

The sequencing and aligning of the genomes was a massive computational task. Using the alignment, the researchers were also able to ascertain that at least 10% of the human genome is functional, ten times as much as the approximately 1% that codes for proteins. The findings further revealed genetic variants likely to play causal roles in rare and common human diseases, including cancer. In one paper in the package, researchers studying patients with medulloblastoma identified mutations in evolutionarily conserved positions of the human genome they believe could be causing brain tumors to grow faster or to resist treatment. The results show how using these data and approaches in disease studies could make it easier to find genetic changes that increase disease risk.

In other papers in the package, the researchers pinpointed parts of the genome linked to a few exceptional traits in the mammalian world, such as extraordinary brain size, superior sense of smell, and the ability to hibernate during the winter. The authors use the genomes to confirm that an estimate of effective population size and diversity can help predict risk in species that are hard to monitor and sample.

Another study in the package shows that mammals had begun to change and diverge even before the Earth was hit by the asteroid that killed the dinosaurs, approximately 65 million years ago. A different study examined more than 10,000 genetic deletions specific to humans using both Zoonomia data and experimental analysis and linked some of them to the function of neurons. Other Zoonomia papers in the package uncovered a genetic explanation for why a famous sled dog from the 1920s named Balto was able to survive the harsh landscape of Alaska; discovered human-specific changes to genome organization; used machine learning to identify regions of the genome associated with brain size; described the evolution of regulatory sequences in the human genome; focused on sequences of DNA that move around the genome; discovered that species with smaller populations historically are at higher risk of extinction today; and compared genes between nearly 500 species of mammals.

The special issue is accompanied by two Perspectives that provide further insights into the Zoonomia Project’s approach, findings, and future impacts.

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