ABSTRACT
Infectious disease is widely considered to be a major driver of evolution. A preponderance of signatures of balancing selection at blood group-related genes is thought to be driven by inherent trade-offs in susceptibility to disease. B4galnt2 is subject to long-term balancing selection in house mice, where two divergent allele classes direct alternative tissue-specific expression of a glycosyltransferase in the intestine versus blood vessels. The blood vessel allele class leads to prolonged bleeding times similar to von Willebrand disease in humans, yet has been maintained for millions of years. Based on in vivo functional studies in inbred lab strains, it is hypothesized that the cost of prolonged bleeding times may be offset by an evolutionary trade-off involving susceptibility to a yet unknown pathogen(s). To identify candidate pathogens for which resistance could be mediated by B4galnt2 genotype, we here employed a novel “pathometagenomic” approach in a wild mouse population, which combines bacterial 16S rRNA gene-based community profiling with histopathology of gut tissue. Through subsequent isolation, genome sequencing and controlled experiments in lab mice, we show that the presence of the blood vessel allele is associated with resistance to a newly identified subspecies of Morganella morganii, a clinically important opportunistic pathogen. Given the increasing importance of zoonotic events, the approach outlined here may find useful application in the detection of emerging diseases in wild animal populations.
Acknowledgments
We thank Jan Schubert, Janin Braun, Theresa Wolff, Janice Seidel, and Jana Neckelmann for field assistance, Jan Schubert, Silke Carstensen, and Katja Cloppenborg-Schmidt for excellent technical assistance.
Author contributions:
JFB, GAG, MV, and JMJ conceived and designed the experiments. MV and MB performed the field work. MV performed molecular biology methods and analyses, with support from AC. GAG, AS, KE, and AG performed histological analysis, microbiology methods, and laboratory mice experiments. DB designed FISH probes. MV designed and performed statistics and bioinformatics analyses. MV and JFB wrote the first draft of manuscript with significant input from GAG. All authors contributed to the final manuscript.
Disclosure statement
No potential conflict of interest was reported by the authors.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2022.2164448