SWIFT EVOLUTION OF IMMUNITY AND CANCER GENES IN BATS

 

Bats, the second largest order (Chiroptera) of mammals, are known for their adaptation which includes powered flight, laryngeal echolocation, unusual longevity, and low rates of cancer. Through the years it has also been understood that bats are hosts of several viruses and have played a major role in emerging zoonotic viruses that include Marburg virus, Nipah virus, and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), either by direct human contact or via bridge hosts. In the case of SARS-CoV-2, a progenitor virus has been identified in wild bats which signifies that there might be a chance that bats may be the primary host for SARS-CoV-2. Even though they are hosts of many viruses, they are tolerant to viral infection which fascinates and raises answers that they may have unusual features in their innate immune response. So all these adaptations and features make the bat a powerful system to investigate a wide variety of genotype-to-phenotype relationships, including several with implications for human health. 

So through the decade, many sequences have been released from 44 bat species. This extensive effort has been accelerated by collaborative projects like the Bat1K global genome consortium, DNA Zoo, and Vertebrate Genome Project. These genome sequences have revealed intriguing features of bats' immune systems. Bats appear to have adaptively evolved their innate immune system including genes responsible for pathogen sensing, type I interferons (IFNs), and antiviral defences. Particularly, they have lost the mammalian PYHIN DNA-sensing gene family (a group of genes in mammals that are involved in detecting and responding to DNA molecules in the cell) which is commonly found in mammals. They also show positive selection in pathogen sensing Toll-like receptors (TLRs) and have copy number variation (CNV) which are induced by TLRs. It is believed that the bat's specific modification in immune response, tumour suppressors, DNA damage checkpoint-DNA repair pathway genes, and growth hormone which results in adaptation in innate immunity and cancer resistance are due to their coevolution with viruses. Additionally, their need for enhanced DNA repair may be linked to the high levels of reactive oxygen species (ROS) generated during powered flight. 

To add to the existing studies, a paper "Long-Read Sequencing Reveals Rapid Evolution of Immunity- and Cancer-Related Genes in Bats" has been released in Genome Biology and Evolution, in which they have added to the existing knowledge by sequencing Jamaican fruit bats (Artibeus jamaicensis) and the Mesoamerican moustached bat (Pteronotus mesoamericanus) which comprises approximately 16% of bats diversity through Oxford Nanopore Technologies long-read platform. 

In the study, they have presented a comprehensive analysis of these two species with 13 previously assembled bats and other mammalian genomes. High-quality, long-read genome assemblies have unveiled intriguing insights into the immune system of bats. These findings challenge previous assumptions regarding the constitutive expression of interferon (IFN)-α, a key component of the immune response. The genomes revealed that in certain bat species, there was a significant reduction in IFN-α genes, leading to a shift in the relative copy numbers of IFN-ω and IFN-α. This shift is significant because it might contribute to bats' remarkable ability to tolerate viral infections, ultimately making them common reservoirs for viruses that can potentially jump to humans.

Notably, not only did IFN genes exhibit this fascinating evolutionary change, but other antiviral genes stimulated by type I IFNs also displayed rapid evolution. This included lineage-specific duplications of IFN-induced transmembrane genes and positive selection in IFIT2, indicating a complex and dynamic arms race between bats and the viruses they host.

Moreover, the genomic analysis identified 33 tumour suppressor genes and 6 DNA-repair genes that showed signs of positive selection. This suggests that bats have evolved mechanisms that contribute to their increased longevity and reduced cancer rates, making them exceptional in the mammalian world.

In summary, the genomic data highlights the remarkable adaptability and complexity of bat immune systems. It underscores the coexistence of both widely shared and species-specific evolutionary strategies within their immune gene repertoire. These insights not only provide invaluable genomic resources for the study of bats but also shed new light on the extraordinary molecular evolution that underpins the crucial role of bats as reservoirs for various viruses and their potential implications for human health.

Enhancing the understanding of the bat immune system's mechanisms for tolerating viral infections, could potentially empower researchers to mitigate zoonotic outbreaks. Furthermore, conducting comparative genomic analyses between bats and mammals prone to cancer susceptibility might provide new insights into the origins of cancer and the intricate connections between cancer and immune responses. It is worth noting that these studies on bats and other non-model organisms complement research based on mouse models, which, while more amenable to experimental manipulation, lack certain naturally occurring adaptations that are relevant to human disease.

REFERENCE

Scheben A, Mendivil Ramos O, Kramer M, Goodwin S, Oppenheim S, Becker DJ, et al. Long-read sequencing reveals rapid evolution of immunity- and cancer-related genes in bats. Genome Biology and Evolution. 2023;15(9). doi:10.1093/gbe/evad148