From the two-gram bumblebee bat to whales weighing many tons, the more than 6,000 species of mammal on the planet – including humans – are highly divergent. Over the past 100 million years, they have adapted to nearly every environment on Earth. Now, an international collaboration of scientists with the Zoonomia Project – the largest comparative mammalian genomics resource in the world – has cataloged the diversity in the genomes of 240 mammalian species, representing over 80% of mammalian families. Their findings across 11 papers in this issue of Science 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 Zoonomia Project is an international effort in which researchers sequenced a range of mammal genomes and then aligned them – a massive computational task. Using the alignment, the researchers identified regions of the genomes, sometimes just single letters of DNA, that are most conserved, or unchanged, across mammalian species and millions of years of evolution — regions that they hypothesized were biologically important. These regions – while they don’t give rise to proteins – may contain instructions that direct where, when, and how much protein is produced. Mutations in these regions could play an important role in the origin of diseases or in the distinctive features of mammal species, the authors hypothesized.
Through their analyses, the researchers tested this hypothesis and were also able to ascertain that at least 10% of the human genome is functional, ten times as much as the approximately one per cent 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 this data and approach 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 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.
***A related embargoed news briefing was held at 11:00 a.m. U.S. ET on Tuesday, 25 April, 2023, as a Zoom Webinar. Recordings of the briefing can be found here.***
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