Genomic survey uncovers evolutionary origins of secretoglobins

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At a conference in Washington, D.C., in 2000, the secretoglobin super family of proteins was named to classify proteins with structural similarities to its founding member uteroglobin. Now, 25 years later, there is still little known about the basic functions of these proteins, prompting researchers at the Carl R. Woese Institute for Genomic Biology to dive into their evolutionary origins.

This bioinformatic survey reported that secretoglobins, or SCGBs—originally thought to be exclusive to mammals—are also found in turtles, crocodilians, lizards, and birds. These new findings, published in Genome Biology and Evolution, suggest that these proteins evolved earlier than dinosaurs and share a basic function that is not yet discovered.

"We have a series of Scgb genes within the human genome, but no one knows what their function is," said Christina Laukaitis (EIRH/RBTE), a clinical associate professor at the Carle Illinois College of Medicine.

"If we want to understand ourselves, we have to understand what we share and don't share with other organisms. We hope that by identifying what other organisms have these genes, we can determine a shared protein function."

"A first principle of biology is the question of structure versus function," said Bob Karn (GNDP), a professor in the department of biomedical and translational sciences at the Carle Illinois College of Medicine. "This is a classic case where we know the SCGBs' structures, but in most cases, not their functions."

While their main biological functions are still unknown, researchers have shown that Scgb genes which encode SCGB proteins are expressed in secretory epithelial tissues. Further, dysregulation of these genes may have implications in lung and respiratory tract diseases, kidney disease, inflammation, and cancer.

"However, none of these are basic functions, but rather what they do in the right circumstances," Laukaitis said.

The challenge is that SCGBs are mainly studied in the context of human health and disease and in common model organisms like mice, rats, and rabbits. From this limited vantage point, much of the story is incomplete, making it difficult to pinpoint the basic functions of these proteins.

"No one has looked beyond mammals, so the basic question we're asking is whether we can find SCGBs in non-mammals. This was a bioinformatics survey of all the available genomes of different groups of organisms to figure out who has the different members of this secretoglobin family, essentially a comparative genomics project," Laukaitis said.

Karn and Laukaitis performed a deep dive into animal genomes, using bioinformatic methods to search for Scgb genes. Some of the genes identified in the study were previously predicted using the NIH's National Center for Biotechnology Information algorithms. However, they were never curated for their structural characteristics or officially published in the scientific literature.

Using comparative genomics, Karn also discovered new gene sequences by manually employing the BLAT tool on the University of California, Santa Cruz's genome browser for gene sequence alignments and then building SCGB phylogenies.

The overall results of their study were surprising. Not only are SCGBs found beyond mammals, but they have a widespread presence across different species of turtles, crocodilians, lizards, and birds. Furthermore, the data suggest that SCGBs evolved in early aminotes 320 million years ago during the Carboniferous Period, before dinosaurs roamed Earth.

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"Secretoglobins seem to be an amniote invention," Karn said.

Amniota, reptiles that don't need to lay their eggs in water, is a major group of vertebrate terrestrial and semiaquatic tetrapods which consists of two main clades: synapsids and sauropsids. Humans and other mammals are part of the synapsid clade.

"When we went back to amphibians, fish, and invertebrates, there were no indications of any Scgb genes. So, it seems to be a very clear-cut line," Karn said.

Establishing the evolutionary origin of these proteins lays the groundwork for future studies to investigate the basic shared functions of the SCGB protein family. One hypothesis that the team has confirmed is that one group of SCGBs play a role in animal communication.

"That group of SCGBs is called Androgen Binding Proteins, or ABPs, and they are only found in mammals. In our work with mice, we found them only in the glands of the face and neck. Since the first thing that rodents do when they meet each other is sniff around each other's faces and necks, that suggests a kind of recognition function," Karn said.

"And our further work showed that they prefer to mate with mice that share their own type of ABP. In other words, they mediate sexual selection in the mouse population."

Moving forward, Karn and Laukaitis plan to explore this hypothesis more and hope that overall, their findings bring a renewed excitement for this field of research.

Karn said, "A lot of these SCGBs could be valuable for medical issues. Since nobody knows what these small cytokine-like proteins do, they might very well be involved in something we need to know about. The group of evolutionary biologists and geneticists that ran the meeting 25 years ago essentially have all retired, so we're hoping that more people will get interested in this area."

More information: Robert C Karn et al, A Broad Genome Survey Reveals Widespread Presence of Secretoglobin Genes in Squamate and Archosaur Reptiles that Flowered into Diversity in Mammals, Genome Biology and Evolution (2025). DOI: 10.1093/gbe/evaf024

Journal information: Genome Biology and Evolution

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