Over the past 100 million years, mammals have adapted to nearly every environment on Earth. Scientists with the Zoonomia Project have been cataloging the diversity in mammalian genomes by comparing DNA sequences from 240 living species, from the two-gram bumblebee bat to giant whales, from the aardvark and the African savanna elephant to the yellow-spotted rock hyrax and the zebu. Their findings across 11 papers in the new issue of the journal 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.
Scientists with the Zoonomia Project offer a vast quantity of insights into the workings and progress of mammalian genomes. Image credit: Victoria Regen.
The Zoonomia Project is an international effort in which the researchers sequenced a range of mammal genomes and then aligned them — a massive computational task.
Using the alignment, they 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.
Through their analyses, the authors tested this hypothesis and were also able to ascertain that at least 10% of the human genome is functional, 10 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 special issue, scientists 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.
Their results show how using these 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.
They 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 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; and used machine learning to identify regions of the genome associated with brain size.
They also 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.
“We’re very enthusiastic about sequencing mammalian species,” said Professor Kerstin Lindblad-Toh, a researcher at Uppsala University and the scientific director of vertebrate genome biology at the Broad Institute.
“And we’re excited to see how we and other researchers can work with these data in new ways to understand both genome evolution and human disease.”
