USC researcher uses mammal DNA to zoom into the human genome with unprecedented resolution

“Why do humans have disease if they went through millions of years of evolution?” It’s a question Steven Gazal, PhD, assistant professor of population and public health sciences at the Keck School of Medicine of USC, hopes to answer.

Gazal is part of an international team of researchers who have become the first to precisely identify base pairs of the human genome that remained consistent over millions of years of mammalian evolution, and which play a crucial role in human disease. The findings were published in a special Zoonomia edition of Science.

Gazal and his team analyzed the genomes of 240 mammals, including humans, zooming in with unprecedented resolution to compare DNA. They were able to identify base pairs that were “constrained” – meaning they remained generally consistent – across mammal species over the course of evolution. Individuals born with mutations on these genes may not have been as successful within their species or were otherwise not likely to pass down the genetic variation. “We were able to identify where gene mutations are not tolerated in evolution, and we demonstrated that these mutations are significant when it comes to disease,” explains Gazal.

The team found that 3.3% of bases in the human genome are "significantly constrained," including 57.6% of the coding bases that determine amino acid position, meaning these bases had unusually few variants across species in the dataset. The most constrained base pairs in mammals were over seven times more likely to be causal for human disease and complex trait, and over 11 times more likely when researchers looked at the most constrained base pairs in primates alone.

The dataset was provided by the Zoonomia consortium, which according to the project website, "is applying advances in DNA sequencing technologies to understand how genomes generate the tremendous wealth of animal diversity.” Gazal gives credit to Zoonomia for making this type of data available to researchers and anticipates it will be widely used by human geneticists. “It’s a cheap resource to generate, as opposed to datasets generated in human genetic studies,” says Gazal. 

His team’s findings are a significant step forward, as Gazal notes, "we do not understand 99% of the human genome, so it is fundamental to understand which part has been constrained by evolution and is likely to have an impact on human phenotypes.” Their discoveries and methods could become crucial tools for further research.

The next step for Gazal and his team is to repeat the process with a primate-only dataset. By restricting the subjects, they hope to focus on functions of DNA that appeared more recently in human evolution. “We expect this to be even more useful in determining information on human disease,” says Gazal.