Bat Genomes Link Viral Defense, DNA Repair and Longevity Through Shared Evolutionary Pathways

A small snip of wing tissue, taken without killing the bat, was the starting point for one of the more detailed looks yet at why some bats live for decades, shrug off infections and seem unusually resistant to cancer. From those biopsies, an international team led by researchers at the University of Vermont and Penn State University built near-complete genomes and primary cell lines for eight closely related Myotis bat species.

The assemblies were thorough. Using long-read sequencing and Hi-C scaffolding, the team placed about 98.6 percent of nucleotides into 22 to 23 chromosome scaffolds per species. Each genome held about 20,869 protein-coding genes with counterparts in other mammals. Chromosome arrangements were fairly stable, but each genome carried roughly 6,813 to 8,013 structural variants compared with Myotis myotis, most shorter than 10,000 DNA bases: inversions, duplications and translocations. Copy-number changes mattered most, because an extra gene copy can later take on a different job. As Elise Lauterbur of the University of Vermont put it, you potentially end up with two things you are good at instead of one.

The researchers then looked at proteins that interact with viruses and found a split. In Myotis and other bats, proteins that interact with DNA viruses were strongly enriched for positive selection, meaning their sequences changed under evolutionary pressure. Proteins that interact with RNA viruses did not show that genome-wide pattern. Instead, those genes were significantly more likely to have expanded or contracted in number along the Myotis family tree. The team checked the positive-selection result against 47 publicly available genomes from non-Myotis bats, and comparisons with several other mammal groups suggested the bat pattern was unusual.

One example was PKR, an immune and stress-response protein found across mammals. Myotis genomes contained one, two or three copies. The ancestral form, PKR2, appears to have been joined by a duplicate, PKR1, near the root of the Myotis lineage, and both duplicated and non-duplicated arrangements persisted for tens of millions of years. Yet functional tests did not show that two copies simply meant stronger defense. Expressed together, PKR1 and PKR2 produced an intermediate shutdown of protein translation, and tests with two RNA viruses showed no stronger restriction from the pair. Large doses of PKR also reduced cell viability, suggesting a balance between fighting viruses and harming the bat's own cells.

On lifespan, the team compared changes across an evolutionary tree of more than 1,000 mammals. Bats showed some of the largest and fastest lifespan shifts despite relatively small changes in body size. Myotis brandtii and Myotis lucifugus, the little brown bat, ranked in the 99th percentile for rapid lifespan increases relative to their ancestors; Myotis myotis ranked in the 93rd and Myotis grisescens in the 92nd. Many genes under selection belonged to immunity, cancer and aging pathways, and cancer-related pathways were especially enriched in lineages with some of the biggest lifespan gains. In M. lucifugus, 35 of 65 genes in one high-fidelity DNA double-strand break repair pathway showed evidence of selection, as did 21 of 37 in another related pathway.

Cell experiments pointed the same way. The team exposed primary skin cells from five bat species to neocarzinostatin, a compound that causes double-stranded DNA breaks. At low doses, M. lucifugus was the only species whose cells lost viability after 24 hours and showed increased apoptosis, the programmed process by which cells eliminate themselves. At high doses, its cells lost the most viability and showed the highest apoptosis. Six hours after treatment, genes that halt the cell cycle and promote cell death grew more active, while genes for division, growth and DNA synthesis declined. Some of the strongest damage responses overlapped with genes tied to DNA-virus interactions, and the link held even when the analysis was limited to genes under positive selection in M. lucifugus.

"Pathogen adaption, longevity, and cancer resistance—they are fundamentally linked," Lauterbur said, adding that many genes that adapted to viruses in bats also function in longevity and cancer resistance. The findings do not trace these traits to a single gene; they point to overlapping changes in immune defense, structural variation, DNA repair and cell-death pathways. They also caution against assuming an extra immune gene means better protection.

For human medicine, the work remains exploratory: it identifies pathways worth studying, not treatments. The nonlethal biopsy method may make long-term studies easier, and the findings are published in the journal Nature.