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Anti-Viral Enzyme Contributes to Mutational Mix of Hominid Genomes

NEW YORK (GenomeWeb) – An anti-viral enzyme has left clusters of mutations within hominid genomes that have likely affected their evolution, according to an international team of researchers.

Researchers from Bar-Ilan University and Cornell University scoured the human genome as well as the genomes of chimpanzees, Neanderthals, and Denisovans for mutations induced by APOBEC enzymes. In particular, they focused on the APOBEC3 enzyme, a cytosine deaminase that has undergone an expansion within primates to deal with primate-specific retroelements and viruses. It may also have introduced germline mutations, they suggested.

As they reported in Genome Research today, the researchers uncovered tens of thousands of APOBEC-induced mutations within the human genome, many of which fell within coding or regulatory regions.

"Our results are at odds with assumptions of mutational models that are at the basis of most genetic analyses, including in medical genetics, evolutionary genetics, and population genetics," co-author Alon Keinan from Cornell said in a statement.

As APOBEC3-induced mutations follow certain patterns, Keinan and his colleagues sifted through hominid genomes to search for those motifs. Through a comparative genomic analysis, they first identified mutations that occurred along the human lineage since its split from chimpanzees. After the researchers identified clusters of mutations, they looked for ones that followed APOBEC3-related motifs. From this, they found an enrichment of clustered mutations that followed the A3G-linked CCC motif.

When the researchers expanded their analysis, they uncovered evidence of A3G activity within each of the hominids — humans, Neanderthals, and Denisovans — they studied. "This is the first indication of site-directed, enzyme-induced genome evolution," Keinan and his colleagues wrote in their paper.

As mice don't share this enrichment, the researchers suggested that APOBEC-induced evolution could be primate-specific.

Since A3G acts on single-stranded DNA, the researchers suspected that transcribed regions of the genome might be more susceptible to its mutagenic effects.

Keinan and his colleagues found that that the A3G mutation set includes 1.7-fold more mutations in transcribed regions as compared to controls. They further noted that it is enriched for coding sequences as well as 5' translated regions.

About a third of the A3G-induced mutations in coding sequences led to amino acid substitutions in 31 genes within the Homo lineage, they added.

Regulatory elements like enhancers, transcription factor binding sites, and DNase I hypersensitive regions were also enriched for A3G-induced mutations, the researchers reported. However, they noted changes in the landscape of A3G activity in different regions of the genome at different evolutionary time points. This, Keinan and his colleagues said, suggests that A3G may have had a role in the evolution of functional regulatory differences among hominids.

"This novel ability of A3G to induce inherited mutations opens up a realm of possibilities for other interesting avenues of research, some with potentially novel medical implications," the researchers wrote. "While little is still known, it is of interest to understand if there are conditions that can modulate A3G activity causing mutations on heritable material. Whether there are direct functional, genetic, or environmental drivers, or it is simply a side effect of errors in the control of its compartmentalization within the cell or in its activity, are all open questions."

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