Fauna Bio collaborates with the Zoonomia Consortium to glean insights into mechanisms of disease resistance and reversal honed over 100 million years of evolution

Fauna Bio’s collaboration with the Zoonomia Consortium recently produced a whole-genome alignment of 240 mammals, and protein-coding alignments for 428 mammals, which today is the subject of a special issue of Science. As part of this, Fauna Bio collaborated with over 150 researchers across 7 time zones in the Zoonomia Consortium to delve into the treasure trove of secrets of how various mammals adapted to their diverse niches revealed by the largest alignment of mammalian genomes to date. This work not only reveals novel insights into human health, but also highlights the importance of biodiversity - some of the key findings rely on endangered species. Multiple species in the alignment display adaptations that may be leveraged to develop human therapeutics, such as the Siberian musk deer, which displays resistance to inflammation (Almohaimeed et al. 2021), the Java mouse-deer, which may be resistant to anemia (Weathers and Snyder 1977), and the North American beaver, which displays longevity and anti-cancer traits (Zhang et al. 2020).Of course, Fauna’s favorite is the 13-lined ground squirrel, which is able to resist or reverse a host of pathologies at various stages of hibernation including fibrosis (Andres-Mateos et al. 2012) and retinopathies (Merriman et al. 2016). 

Phylogenetic tree describing relatedness of the species in the Zoonomia dataset in the context of the time periods defined above, courtesy of Nicole Foley (Christmas, Kaplow et al. 2023)

Fauna has already developed multiple preclinical therapeutic candidates based solely on hibernation adaptations observed in the 13-lined ground squirrel, and more are certain to be discovered based on the 21 additional deep hibernators included in the Zoonomia alignment, including species from every deep mammalian lineage (Christmas et al. 2023). Finding hibernators in multiple branches of the mammalian tree supports the hypothesis that hibernation is an ancestral trait - suggesting that under the right conditions, it can be reactivated in mammals that don’t normally hibernate. Researchers further identified a set of genes that are evolving slowly in hibernators compared with non-hibernators, and these genes are enriched for roles in DNA repair, a known contributor to longevity (Ma et al. 2016). These findings are in line with Fauna’s current pipeline of therapeutics that target genes that are differentially expressed at key points of 13-lined ground squirrel hibernation, where the animals resist or reverse disease pathology induced by the harsh conditions of hibernation. 

Beyond hibernators, researchers confirmed prior findings that the genes that are the most similar between different species are most likely to be disease-associated in humans (Sullivan et al. 2023). This makes intuitive sense -  genes are always mutating, but the absence of observable mutations in a gene suggests that the animals who had these mutations didn't survive. Thus, genes that haven’t accumulated many mutations over 100 million years of mammal evolution are extremely important to health. Intriguingly, 697 sites were identified in 330 genes where variation in the human genome causes disease, but in other species variation is tolerated with no apparent outcome. For example, variants in the gene SOD1, which is responsible for amyotrophic lateral sclerosis in humans, are naturally observed in animals including the Southern tamandua, Indian rhinoceros, and Seba's short-tailed bat. These genes represent potential therapeutic opportunities where other species have developed resistance or reversal strategies to pathology induced by the variant. Importantly, many of the species represented in Zoonomia are endangered, and thus the secrets of how they resist or reverse disease are at risk of being lost. Therefore this dataset highlights the importance of conservation efforts not just to biodiversity, but also to human health. 

Other Zoonomia papers published today revealed that mammals diversified before the mass dinosaur extinction; uncovered a genetic explanation for why a famous sled dog from the 1920s named Balto was able to survive the harsh landscape of Alaska; discovered human-specific changes to genome organization; used machine learning to identify regions of the genome associated with brain size; described the evolution of regulatory sequences in the human genome; focused on sequences of DNA that move around the genome; discovered that species with smaller populations historically are at higher risk of extinction today; and compared genes between nearly 500 species of mammals. Additional preprints utilizing the data have already been posted, including a study of dental gene loss that corresponds to dietary shifts in species (Emerling et al. 2022), and a study of the genomic underpinnings of skin-derived scales in pangolins (Pinto et al. 2022), amongst others. Traditionally one of the biggest roadblocks in therapeutic development was lack of understanding of the disease or therapeutic mechanism, or both. As Albert Einstein said, “Look deep into nature, and then you will understand everything better” - the Zoonomia dataset enables us to do just that.