Scientists have for the first time sequenced the genetic material that codes for bats’ unique adaptations and superpowers, such as the ability to fly, to use sound to move effortlessly in complete darkness, to survive and tolerate deadly diseases, and to resist aging and cancer. The results have been reported by researchers working with the Bat1K consortium, who generated and analyzed six highly accurate bat genomes that they say are ten times more complete than any bat genome published to date.

Among the findings, the researchers identified evolution through gene expansion and loss in a family of genes, APOBEC3, which is known to play an important role in immunity to viruses in other mammals. The new insights could set the groundwork for investigating how these genetic changes—which are found in bats but not in other mammals—could help prevent the worst outcomes of viral diseases in other mammals, including humans.

A study that sequenced genomes from six widely divergent living bat species, including Phyllostomus discolor, the pale spear-nosed bat, revealed the genetics behind some bat “superpowers,” such as surviving deadly viruses and to use sound to navigate in darkness. [Brock and Sherri Fenton]

“Given these exquisite bat genomes, we can now better understand how bats tolerate viruses, slow down aging, and have evolved flight and echolocation,” said Emma Teeling, PhD, University College Dublin, co-founding director of Bat1K and senior author of the team’s published paper in Nature. “These genomes are the tools needed to identify the genetic solutions evolved in bats that ultimately could be harnessed to alleviate human aging and disease.” Bat1K is a global consortium of scientists dedicated to sequencing the genomes of every one of the 1,421 living bat species. Teeling and international colleagues reported their results in a paper titled, “Six reference-quality genomes reveal evolution of bat adaptations,” in which they concluded, “in summary, these genomes are comparable to the best reference-quality genomes that have so far been generated for any eukaryote with a gigabase-sized genome.”

With more than 1,400 species of bat species identified to date, these animals account for more than 20% of all currently living mammal species, the authors wrote. Bat species are found all around the world, and occupy many different ecological niches. “Their global success is attributed to an extraordinary suite of adaptations, including powered flight, laryngeal echolocation, vocal learning, exceptional longevity, and a unique immune system that probably enables bats to better tolerate viruses that are lethal to other mammals (such as severe acute respiratory syndrome-related coronavirus, Middle East respiratory syndrome-related coronavirus, and Ebola virus).”

Bats, therefore, represent an important model system for studying traits such as extended healthspan and enhanced disease tolerance, but in order to understand bat evolution and the molecular basis of these traits, scientists need to be able to analyze high-quality genomes. To generate these exquisite bat genomes, Teeling and colleagues used the newest technologies of the DRESDEN-concept Genome Center, a shared technology resource, to sequence the bats’ DNA, and then generated new methods to assemble the pieces into the correct order, and to identify the genes present. While previous efforts had identified genes with the potential to influence the unique biology of bats, uncovering how gene duplications contributed to this unique biology was complicated by incomplete genomes.

“Using the latest DNA sequencing technologies and new computing methods for such data, we have 96–99% of each bat genome in chromosome level reconstructions—an unprecedented quality akin to for example the current human genome reference which is the result of over a decade of intensive ‘finishing’ efforts,” commented co-senior author Eugene Myers, PhD, director of the Max Planck Institute of Molecular Cell Biology and Genetics, and the Center for Systems Biology. “As such, these bat genomes provide a superb foundation for experimentation and evolutionary studies of bats’ fascinating abilities and physiological properties.”

“More and more, we find gene duplications and losses as important processes in the evolution of new features and functions across the Tree of Life,” added evolutionary biologist and co-author Liliana M. Dávalos, PhD, professor in the department of ecology and evolution in the College of Arts and Sciences at Stony Brook University. “But, determining when genes have duplicated is difficult if the genome is incomplete, and it is even harder to figure out if genes have been lost. At extremely high quality, the new bat genomes leave no doubts about changes in important gene families that could not be discovered otherwise with lower-quality genomes.”

Species: Rhinolophus ferrumequinum (Greater horseshoe bat) [Credit: Daniel Whitby]

The team compared the bat genomes against 42 other mammals to address the question of where bats are located within the mammalian tree of life. Using novel phylogenetic methods and comprehensive molecular data sets, the team found the strongest support for bats being most closely related to a group called Ferreuungulata that consists of carnivores (which includes dogs, cats, and seals, among other species), pangolins, whales, and ungulates (hooved mammals).

To uncover genomic changes that contribute to the unique adaptations found in bats, the team systematically searched for gene differences between bats and other mammals, identifying regions of the genome that have evolved differently in bats, and the loss and gain of genes that may drive unique bat traits. “Our conservative genome-wide screens investigating gene gain, loss, and selection revealed novel candidate genes that are likely to contribute tolerance to viral infections among bats,” the team wrote. “We also uncovered genes involved in hearing that exhibit mutations specific to laryngeal-echolocating bats and ancestral patterns of selection.”

“Our genome scans revealed changes in hearing genes that may contribute to echolocation, which bats use to hunt and navigate in complete darkness,” noted co-senior author Michael Hiller, PhD, Max Planck research group Leader, the Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Institute for the Physics of Complex Systems, and the Center for Systems Biology. “Furthermore, we found expansions of antiviral genes, unique selection on immune genes, and loss of genes involved in inflammation in bats. These changes may contribute to bats’ exceptional immunity and points to their tolerance of coronaviruses.”

The investigators found evidence that bats’ ability to tolerate viruses is reflected in their genomes. The exquisite genomes revealed “fossilized viruses,” evidence of surviving past viral infections, and showed that bat genomes contained a higher diversity of these viral remnants than other species, providing a genomic record of historical tolerance to viral infection. “… we also found that bat genomes contain a high diversity of endogenized viruses,” the investigators noted. The genomes also revealed the signatures of many other genetic elements besides ancient viral insertions, including “jumping genes” or transposable elements.

Given the quality of the bat genomes the team uniquely identified and experimentally validated several noncoding regulatory regions that may govern bats’ key evolutionary innovations. “It is thanks to a series of sophisticated statistical analyses that we have started to uncover the genetics behind bats’ ‘superpowers,’ including their strong apparent abilities to tolerate and overcome RNA viruses,” said Dávalos.

“Having such complete genomes allowed us to identify regulatory regions that control gene expression that are unique to bats,” added Sonja Vernes, PhD, co-founding director Bat1K, Max Planck Institute for Psycholinguistics. “Importantly we were able to validate unique bat microRNAs in the lab to show their consequences for gene regulation “In the future, we can use these genomes to understand how regulatory regions and epigenomics contributed to the extraordinary adaptations we see in bats.”

“These genomes enable a better understanding of the molecular mechanisms that underlie the exceptional immunity and longevity of bats, allowing us to identify and validate molecular targets that ultimately could be harnessed to alleviate human aging and disease,” the authors concluded. “For example, we predict that our reference-quality bat genomes will be tools that are heavily relied upon in future studies focusing on how bats tolerate coronavirus infections. This is of particular global relevance given the current pandemic of coronavirus disease 2019 (COVID-19), and ultimately may provide solutions to increase human survivability—thus providing a better outcome for this, and future, pandemics.”

The reported study is just the beginning of the expected research. The remaining ~1,400 living bat species exhibit an incredible diversity in ecology, longevity, sensory perception, and immunology, and numerous questions still remain regarding the genomic basis of these spectacular features. Bat1K aims to answer these questions as more and more exquisite bat genomes are sequenced, further uncovering the genetic basis of bats’ rare superpowers.

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