April 12, 2016

Primate evolution moves into the fast lane

The pace of evolution typically is measured in millions of years, as random mutations accumulate over generations. Researchers at Cornell and Bar-Ilan universities have uncovered a new mechanism for mutation in primates that is rare but rapid, site-specific and aggressive.

The novel process is triggered by a member of the APOBEC family of virus-fighting enzymes. APOBECs in primate cells – including those of chimpanzees, Neanderthals and modern humans – mount a vigorous defense against viruses, bombarding the viral genome with clusters of mutations to thwart the infection. However, having a mutation-based defense is risky for cells, since “friendly fire” could wreak havoc on the genome as well.

Alon Keinan, associate professor of biological statistics and computational biology at Cornell, collaborated with Erez Levanon at Bar-Ilan University in Israel to find the signature of past mutations in humans and our closest relatives. Their paper was published April 7 in the journal Genome Research.

They focused on the APOBEC3 enzyme since it has expanded into several subtypes during primate evolution, each with a recognizable mutational signature. The researchers discovered evidence of a new mechanism for primate evolution that causes fast and complex changes to genes in a single generation and can be passed on to offspring.

They knew the enzyme recognizes a specific motif in DNA and targets only one of the DNA bases for mutation. Another telltale sign: multiple mutations occurring close together. Using conservative criteria, they identified thousands of such instances unique to primate genomes and, as negative control, did not identify any in other vertebrates such as mice that lack many of the APOBEC3 genes.

“What is appealing is that it’s an accelerated evolutionary mechanism that could generate a large change in a gene in a single generation,” said Levanon. “The beauty of this, in an evolutionary sense, is that it’s an aggressive mechanism that creates clusters of mutations in parts of the genome that affect traits, which could have a more complex effect on function immediately.”

The enzyme’s preference for regions of the genome that code for proteins or affect gene regulation is a vestige of their primary function in viral defense. Many viruses are composed of single stranded DNA or RNA, and DNA being actively used as a template for proteins is temporarily single stranded and unwound from the double helix. To the enzyme, they look the same.

The mutations they have produced have not been scrubbed from the gene pool by natural selection, raising the question of a possible role for this and related enzymes in primate evolution.

“These events potentially mutate dozens of DNA bases in a small region less than the size of a gene. It is reasonable to think that most of these mega-mutations will be deleterious and will disappear in evolutionary time, but we do see a large number that survived,” said Keinan. “Importantly, those that survived are overrepresented in functionally important parts of the genome, which suggests that some of these mutations have been maintained by natural selection because they conferred an advantage.”

The study was funded by the European Research Council, the I-CORE Program of the Planning and Budgeting Committee in Israel, and the U.S. National Institutes of Health.

Amanda Garris is executive editor of PeriodiCALS magazine.