“Why do humans get sick if they have gone through millions of years of evolution?” It’s a question Stephen Ghazal, PhD, assistant professor of population sciences and public health at USC’s Keck School of Medicine, hopes to answer.
Gazelle is part of an international team of researchers who have become the first to pinpoint base pairs from the human genome that have remained constant over millions of years of mammalian evolution, and which play a critical role in human disease. The results have been published in private Zoonomia edition of Sciences.
Ghazal and his team analyzed the genomes of 240 mammals, including humans, zooming in with unprecedented resolution for a DNA comparison. They were able to identify base pairs that were ‘restricted’ – meaning they remained generally consistent – across mammalian species over the course of evolution. Individuals born with mutations on these genes may not be successful within their own species or are not likely to pass on genetic variation. “We’ve been able to identify places in development where genetic mutations are not tolerated, and we’ve shown that these mutations are important when it comes to disease,” explains Ghazal.
The team found that 3.3% of the bases in the human genome are “significantly restricted,” including 57.6% of the coding bases that specify the position of amino acids, meaning these bases have unusually few variants across species in the dataset. The most restrictive base pairs in mammals were seven times more likely to be causative of human disease and complex traits, and over 11 times more likely when the researchers looked at the most restrictive base pairs in primates alone.
The dataset was provided by the Zoonomia consortium, which according to the project’s website, “applies advances in DNA sequencing technologies to understand how genomes generate an enormous wealth of animal diversity.” Gazal gives credit to Zoonomia for making this kind of data available to researchers and expects it to be widely used by human geneticists. “It’s an inexpensive resource, unlike the datasets created in human genetic studies,” says Ghazal.
His team’s findings are an important step forward, notes Ghazal, “We don’t understand 99% of the human genome, so it’s key to understand which part was evolutionarily restricted and likely to have an impact on human phenotypes.” Their discoveries and methods can become crucial tools for further research.
The next step for Gazelle and his team is to repeat the process using a primate-only dataset. By restricting the subjects, they hope to focus on DNA functions that have emerged recently in human evolution. “We expect this to be more useful in quantifying information about human disease,” says Ghazal.