Little Brown Bat, Myotis lucifugus. Can live up to 35 years, immune to most viruses and rarely develops cancers
Photo © Michael Durham,
Illinois Department of Natural Resources
Illinois Department of Natural Resources
Creationists routinely claim that mutation cannot produce new genetic information and that complex biological systems must have been separately designed for their allotted purposes. Yet living genomes bear little resemblance to collections of independently engineered components. Genes are duplicated, deleted, rearranged and modified; the resulting variants are tested by natural selection; and the same molecular machinery is repeatedly recruited for several different functions. A new study of bats provides a particularly revealing example of this evolutionary improvisation.
Viruses and their hosts have been engaged in evolutionary arms races for hundreds of millions of years. Viruses evolve ways to enter cells, evade immune responses and appropriate cellular machinery for their own replication, while their hosts evolve countermeasures. From a creationist perspective, this requires an intelligent designer simultaneously to design the viruses, their means of attacking their hosts and the defensive systems needed to resist them. Evolution provides the far simpler explanation: each side imposes selection on the other, with no foresight, overall plan or concern for the suffering caused along the way.
In a paper published in Nature, an international team of researchers assembled near-complete genomes for eight closely related species of Myotis bat and established primary cell lines with which to test some of the genomic findings. The comparison revealed abundant structural variation—including inversions, translocations and gene duplications—within an otherwise strongly conserved arrangement of chromosomes.
The researchers found that bats have responded differently to different classes of virus. Proteins interacting with DNA viruses showed an unusually strong signature of positive selection, whereas genes interacting with RNA viruses were especially prone to gains and losses of copies. One antiviral gene, EIF2AK2, better known as PKR, occurs in one, two or, in one lineage, three copies. The original duplication appears to have arisen near the base of the Myotis radiation, with duplicated and unduplicated forms persisting across species for tens of millions of years. This is new genetic material arising through mutation and subsequently being retained, modified or lost according to its effects—not information supplied fully formed by an external intelligence.
Nor is more necessarily better. Additional PKR copies may broaden protection against viral countermeasures, but high levels of PKR activity can also be toxic to the bat’s own cells. The persistence of different copy numbers therefore reflects an evolutionary balance between improved antiviral defence and cellular damage. It is precisely the sort of compromise expected from natural selection acting on whatever variations happen to arise, rather than the unconstrained solution expected from an omnipotent designer.
An especially interesting connection emerged between viral defence, cancer resistance and longevity. Myotis bats display extraordinary differences in lifespan despite relatively modest differences in body size, with some species living for several decades. Genes showing evidence of selection in the longer-lived lineages were disproportionately associated with immune function, ageing, DNA-damage responses and cancer-related pathways. Many of the same genes contributed to more than one of these processes—a phenomenon known as pleiotropy.
When cells from the long-lived little brown bat, Myotis lucifugus, were exposed to a chemical that causes double-strand breaks in DNA, they responded differently from cells of the other bats tested. Rather than persisting with the risky repair and continued division of badly damaged cells, they strongly activated apoptosis—programmed cell death—and suppressed pathways associated with cell growth and DNA synthesis. Destroying an irreparably damaged cell prevents it from surviving to accumulate further mutations and become cancerous, although these cell-culture findings identify a potential mechanism rather than proving by themselves how cancer is prevented in a living bat. The University of California, Berkeley News report by Robert Sanders describes this as essentially abandoning a cellular “ship” that can no longer be saved.
The overlap was not accidental background noise. Genes involved both in responses to DNA viruses and in the experimentally induced response to DNA damage occurred together significantly more often than expected by chance. The authors propose that selection imposed by viruses may therefore have helped to shape cellular mechanisms that also influence cancer suppression and longevity. An adaptation favoured in one context can have beneficial consequences in another, without either consequence having been anticipated.
Gene Duplication, Pleiotropy and the Evolutionary Arms Race. Gene duplication: raw material for evolutionary innovationWhat emerges is not a collection of systems designed independently and optimally for immunity, cancer prevention and longevity. It is a tangled evolutionary history in which mutations supplied new variants, gene duplications supplied additional genetic material, viruses imposed selection, and existing molecular pathways acquired overlapping functions. Benefits came with costs, successful variants persisted, and the accumulated results now appear in the genomes and cells of modern bats. No plan was required—and none is evident.
Genes can be duplicated by errors during DNA replication or chromosome recombination. Initially, this produces an additional copy of existing genetic information. Because one copy can continue performing the original function, the other is freer to accumulate mutations. It may eventually acquire a modified function, divide the original function with its partner, remain as an additional functional copy or deteriorate into a non-functional pseudogene.
Duplication followed by mutation therefore provides a well-understood mechanism by which genomes acquire additional genetic information. No foresight is involved: duplications occur without regard to whether they will be useful, and natural selection determines which variants persist.
The antiviral gene EIF2AK2, usually known as PKR, illustrates this process in Myotis bats. PKR detects double-stranded RNA, a feature associated with many viral infections, and responds by inhibiting protein production within the cell, thereby obstructing viral replication. An ancestral duplication produced a second PKR copy early in the evolution of Myotis. Bats now carry different combinations of one, two or, in one lineage, three copies, while the duplicated and unduplicated forms have persisted across species for tens of millions of years.
Host and virus: an evolutionary arms race
Viruses depend on host cells for their reproduction, so they evolve mechanisms that exploit cellular proteins and disable antiviral defences. Hosts, in turn, benefit from mutations that prevent this exploitation or restore their defences. Each successful adaptation on one side changes the selective environment confronting the other:
- A host defence restricts viral replication.
- Viral variants capable of evading that defence leave more descendants.
- Those viruses impose stronger selection on the host population.
- Host variants better able to resist the new viral strategy become more common.
This continuing cycle is often called a Red Queen arms race: both parties must continue evolving merely to maintain their relative positions. It has no intended destination and does not necessarily produce perfection. It produces whatever works well enough under the immediate circumstances.
The different PKR copies in bats may make it harder for a virus to disable the entire defence with a single countermeasure. However, PKR also suppresses the bat cell’s own protein production, and excessive activity can damage or kill the cell. Additional copies therefore entail a trade-off between broader antiviral protection and increased cellular toxicity. This is characteristic of evolution by natural selection, which must modify existing components and balance competing costs and benefits.
Pleiotropy: one genetic change, several effects
Genes seldom perform isolated tasks. Their products participate in interacting cellular networks, so a mutation affecting one process can also affect apparently unrelated traits. This is known as pleiotropy.
In these bats, many genes involved in interactions with DNA viruses also participate in the control of inflammation, cell division, cellular senescence, DNA-damage responses and programmed cell death. Selection favouring more effective antiviral defence could therefore alter cancer resistance and longevity at the same time. Where one genetic change produces beneficial effects on several traits, the result may be described as agonistic pleiotropy. Where a benefit in one context is accompanied by a cost in another—as with antiviral activity and cellular toxicity—the result is an evolutionary trade-off.
Consequently, bat immunity, cancer resistance and longevity need not have evolved as three separately designed systems. They can emerge from the modification and reuse of overlapping molecular pathways subjected to different selective pressures over millions of years.
Host–pathogen conflicts and the biological compromises they produce are discussed more fully in my book, Unintelligently Designed Arms Races: How Nature Refutes Intelligent Design. Such arms races make little sense as the work of a benevolent, intelligent designer supposedly responsible for both the attack and the defence, but they are an inevitable consequence of mutation, competition and natural selection.
Clues to longevity may reside in the genomes of long-lived bats
An abundance of genes that interact with viruses helps bats stay healthy despite huge viral loads. UC Berkeley scientists are finding that these same genes play a role in longevity
The secret to a long life may lie in the genomes of the longest-lived mammals for their size: bats.
That idea captivated Juan Manuel Vazquez when he was a graduate student at the University of Chicago, but at the time he couldn’t find any good, published information on bat genomes to provide clues. Once he became a UC Berkeley postdoctoral fellow in 2020, however, he unleashed his passion and began scouring the Western U.S. for bat species that could provide tissue samples and DNA to sequence.
Enlisting the help of Berkeley undergraduates, he traveled around the West erecting mist nets over streams, ponds and rivers at night to capture, biopsy and release as many species of bats as he could. He focused on those in the genus Myotis, which contains the bat with the longest lifetime — a Brandt’s myotis, Myotis brandtii. One individual was banded in Europe and recaptured 50 years later.
In a new paper appearing this week in the journal Nature, Vazquez and colleagues report the first analysis of eight Myotis genomes and the discovery of a close link between the animal’s longevity and its immune system — longer-lived bats had higher levels of cancer-fighting genes.
A tiny Myotis thysanodes or fringed Myotis.Elise Lauterbur
The findings suggest that an immune system able to mount an overwhelming attack against infectious organisms and cancer may be integral to a long lifespan. The overlap between genes involved in aging and those involved in fighting disease also means that understanding one will help scientists understand the other.
Bats evolved to live for a long time without getting diseases, which suggests that we don’t necessarily need to look at diseases of aging and diseases of infection as completely separate fields. We can look at these bats and try to understand how, in the same way you can improve your immune system to fight off viruses, maybe you can improve your immune system so it doesn’t decline in old age. Or maybe bats can help us find ways to fight off tumors so our immune system doesn’t get tired, and that can also help us deal with other stresses of life and not exhaust our immunity.
Juan Manuel Vazquez, first author.
Department of Integrative Biology
University of California, Berkeley
Berkeley, CA, USA.
For the study, Vazquez cultured cells he biopsied from the wings of the bats. (He currently has cell cultures from 259 individuals representing 32 species.) When he treated cultured bat cells with toxic chemicals, he found an unusual response: for the longest-lived bat in his sample, the widespread little brown bat (Myotis lucifugus), the toxin didn’t trigger activation of genes for DNA repair proteins, but rather up-regulated genes promoting cell death.
We found the literal opposite of what we expected if you treat the bats with a lethal dose of this chemical. The longest-lived bat in North America decides ‘I can’t save this ship’ and immediately switches gears to prioritize killing off the cells that are damaged. The elephant, another cancer-resistant species that is long-lived, has the exact same strategy — if you can’t save the cell, kill the cell.
Juan Manuel Vazquez.
The discovery is a heads-up that clues to longevity can be gleaned from understanding the different ways animals deal with disease, said Peter Sudmant, a Berkeley associate professor of integrative biology who studies the genes involved in aging and longevity.
By looking across the diversity of life and the remarkable longevities of different species, we hope we can better understand the interplay between DNA damage and the immune system to enable us to have full and healthy life spans. If you start looking at long-lived species like elephants, whales and bats, you start finding ways that nature has actually already resolved a lot of these problems in human health.
Juan Manuel Vazquez.
Longevity, an active lifestyle and an immune system on high alert
The bat lifestyle has been a big success since the group arose about 60 million years ago. Bats now comprise 20% of all mammalian species, live on all continents except Antarctica and occupy a wide range of ecological niches. Of the known 1,511 species, about 139 are in the Myotis genus, which is known for bats exhibiting an extreme range of lifespans. While Brandt’s myotis bats can live half a century, the black Myotis — Myotis nigricans, of South and Central America — lives a mere seven years. This is as if our close relative, Homo neanderthalensis, lived nine times longer than modern Homo sapiens, Vazquez said.
Despite bats’ evolutionary success, scientists were surprised to find that their immune systems are hyperactive, working overtime to suppress damaging inflammation from constant viral infections without actually becoming sick. As a result, healthy bats can host an amazing variety of viruses, some of which, like the cause of COVID-19, can spill over into human populations.
A team of researchers taking tissue samples from bats captured for study and subsequently released.Juan Manuel Vazquez
Some researchers have linked bats’ robust immune systems to their very active lifestyle. Vazquez likens bats’ nighttime patrols for bugs to running several ultramarathons every day.
Bats have evolved this incredible fitness capacity, this incredible ability to deal with disease and this incredible ability to be able to prevent cancer. That means that, by understanding how bats have evolved to do all these things that other mammals haven’t, we can find completely new and unexpected ways of dealing with the normal things that cause human diseases.
Juan Manuel Vazquez.
The new study provides tantalizing clues. Vazquez found that whenever he identified a bat gene linked to lifespan, his collaborator, Elise Lauterbur, then at the University of Arizona, had identified the same gene as one involved in the bat’s interaction with viruses.
There is way more overlap than you would expect just by random chance between the genes that are associated with longevity and genes that are associated with viral interactions.
Juan Manuel Vazquez.
Another surprise was that Myotis bats have an enhanced abundance of genes that make proteins that interact with DNA viruses — viruses, like herpes, that encode their genes using DNA. These proteins can either promote infection or protect against it, such as by boosting expression of the antiviral hormone interferon.
DNA viral interacting proteins were strongly enriched for selection in bats in contrast to most other mammals, where there is a very strong enrichment for selection for both DNA and RNA viral interacting proteins.
Assistant Professor Peter H. Sudmant, corresponding author.
Department of Integrative Biology
University of California, Berkeley
Berkeley, CA, USA.
Humans and other primates, on the other hand, tend to have more genes for proteins that interact with RNA viruses, like COVID and HIV, than DNA viruses.
This mismatch between bats and humans may be why viruses spilling over from bats into humans and causing zoonotic disease have wreaked such havoc in recent years.
Humans and bats are badly suited to each other. That is one of the reasons why we have to be careful working with bats — it’s a two-way street for zoonoses. We don’t want to give the bat something and we don’t want to get something from the bat. That mismatch is definitely something we should look into more.
Juan Manuel Vazquez.
While Vazquez continues to investigate the genetic control of longevity in cell culture in his new faculty position at Pennsylvania State University, Sudmant is more interested in the immune responses of these cells.One thing that I’m really excited about is the trade-off between how a bat protects itself by producing proteins that attack the genomes of viruses but also protects its own genome from being attacked by those proteins.
Assistant Professor Peter H. Sudmant.
He currently has cell cultures from many species of primate in which he is studying the genetic basis of longevity and how that’s related to DNA repair genes.
In addition to Vazquez, Sudmant and Lauterbur, now at the University of Vermont, other co-authors of the paper include Lucie Etienne of the École Normale Supérieure in Lyon, France, and David Enard of the University of Arizona in Tucson. The work was funded by the National Institutes of Health and the National Science Foundation.
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This was not research in which evolution was added afterwards as a speculative explanation for results obtained independently of it. The theory of evolution was central to the design of the study, to the questions the researchers asked and to the methods they used to answer them. Without common descent, mutation and natural selection, the eight bat genomes would have been little more than catalogues of similarities and differences.
Evolutionary theory allowed the researchers to construct a phylogeny, distinguish ancestral features from recent changes, reconstruct where gene duplications and losses occurred, and identify branches on which particular genes had experienced positive selection. It enabled them to test whether changes in lifespan coincided with selection acting on immune, cancer and DNA-damage pathways. Even the discovery that duplicated and unduplicated forms of *PKR* have persisted across several species for tens of millions of years depends upon understanding those species as descendants of shared ancestors.
The laboratory experiments then gave functional meaning to that evolutionary history. The unusual response of Myotis lucifugus cells to severe DNA damage was not interpreted as an isolated piece of biological machinery installed for the purpose of preventing cancer. It was examined in the context of genes already identified through comparative genomics as products of viral selection, revealing how antiviral defence, programmed cell death, cancer suppression and longevity may have evolved together through pleiotropy.
Intelligent design contributes nothing comparable. It does not predict which genes should have been duplicated, why some bats retain the duplicates while others do not, why DNA- and RNA-virus interactions produced different genomic responses, or why greater antiviral protection should carry the cost of increased cellular toxicity. Nor does it explain why a designer would create viruses capable of attacking bats and then equip bats with imperfect and potentially harmful countermeasures. “The designer chose to do it that way” can accommodate every conceivable observation precisely because it predicts none of them.
Evolution, by contrast, explains both the adaptations and their limitations. Random mutations and structural changes supplied variation; viruses, cancer and other environmental pressures determined which variants were more likely to persist; and natural selection modified existing molecular networks without foresight or any requirement to produce an optimal result. The same theory that creationists dismiss made the research possible and transformed its observations into a coherent, testable account of how bat immunity, cancer resistance and longevity arose. It was not merely supported by the findings: it was the indispensable scientific framework through which those findings could be discovered and understood.
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