In a groundbreaking exploration into the evolutionary origins of a little-understood protein family, researchers at the Carl R. Woese Institute for Genomic Biology have uncovered evidence that secretoglobins—previously thought to be unique to mammals—actually have a far broader biological presence. This discovery not only challenges long-standing assumptions but also opens new avenues for understanding the fundamental roles these proteins play across a diverse range of terrestrial vertebrates. Utilizing advanced bioinformatics and comparative genomics, the team revealed that secretoglobin genes (SCGBs) are found widespread among turtles, crocodilians, lizards, and birds, indicating that these proteins emerged in early amniotes some 320 million years ago during the Carboniferous Period, well before the age of dinosaurs.
Secretoglobins, a superfamily initially named at a 2000 conference in Washington D.C., have fascinated researchers for decades due to their structural conservation combined with enigmatic biological functions. Despite near-ubiquity in mammalian genomes and known expression in secretory epithelial tissues, the exact physiological roles of these small, cytokine-like proteins remain largely elusive. The research led by Christina Laukaitis and Bob Karn employs a comparative genomics framework to trace the lineage and distribution of SCGB genes beyond mammals, revealing a remarkable evolutionary continuity that had gone undetected due to the field’s historical focus on mammalian health and disease models.
The study’s methodology combined automated gene predictions with manual curation to precisely identify secretoglobin sequences across multiple species. By applying the BLAT alignment tool on the University of California, Santa Cruz (UCSC) genome browser and constructing detailed phylogenetic trees, the researchers confirmed not only previously predicted but also novel SCGB sequences in non-mammalian reptiles and avian species. This comprehensive genomic survey contradicts the earlier narrow view that confined SCGBs solely to mammals, demonstrating that these proteins originated with early amniotes, vertebrates characterized by their ability to lay eggs on land rather than in water.
Amniotes comprise two major evolutionary clades: synapsids, which include mammals, and sauropsids, encompassing reptiles and birds. Karn and Laukaitis’ results point to an intriguing demarcation; while SCGB genes are extensively present across sauropsid species such as lizards, crocodilians, and birds, they are absent in more basal vertebrates such as amphibians, fishes, and invertebrates. This stark phylogenetic boundary suggests a definitive evolutionary innovation coincident with the emergence of terrestrial egg-laying vertebrates, presenting SCGBs as a key molecular invention in the adaptation to a terrestrial lifestyle.
Functionally, secretoglobins are known to be expressed in various secretory epithelial cells, with prior research implicating their involvement in lung and respiratory tract physiology, renal function, immune modulation, and cancer biology. However, these roles represent context-dependent outcomes rather than core biological functionalities. The widespread occurrence of SCGBs across evolutionary distant species highlights the existence of yet unidentified, conserved roles integral to amniote biology. Laukaitis emphasizes the importance of comparative genomics in deciphering these fundamental functions by bridging the functional knowledge gap across species.
One particularly compelling hypothesis emerging from the study relates to the subfamily of SCGBs known as Androgen Binding Proteins (ABPs), which appears to be restricted to mammals. These proteins have been implicated in facilitating animal communication, particularly in sexual selection. Karn’s prior work with murine models demonstrated that ABPs localized to facial and neck glands serve as chemical recognition signals essential for mate choice, revealing a critical behavioral function of secretoglobins in reproductive biology. This functional subset provides a window into how diversification within the SCGB family may have contributed to species-specific adaptations.
The revelations from this genomic survey underscore the vast potential for future research to elucidate SCGB functions at molecular, physiological, and ecological levels. Given that the foundational cohort of evolutionary biologists who coined the secretoglobin family term are largely retired, Karn and Laukaitis hope their findings will catalyze renewed scientific interest. The small cytokine-like properties of SCGBs hint at possible undiscovered involvements in immune regulation and other critical biological processes that could have significant biomedical implications.
Expanding the scope of research beyond traditional mammalian models to include reptiles and birds equipped with SCGB genes enables a more holistic understanding of protein function evolution. This evolutionary perspective could reveal conserved mechanisms and new regulatory pathways. Secretoglobins’ potential role in structural biology, signaling, and environmental adaptation remains an open field, with the evolutionary timeline stretching back to early terrestrial vertebrates further emphasizing their significance.
The study’s bioinformatic approach exemplifies the power of integrative genomics techniques, combining computational prediction with manual validation to overcome previous annotation gaps. By assembling SCGB sequences from public genome databases and verifying their structural congruence, the research team has set a new standard for protein family phylogenetics. This integrative strategy not only identifies gene presence but also reconstructs evolutionary trajectories and functional diversification.
In conclusion, the expansive distribution of secretoglobin genes across synapsid and sauropsid lineages fundamentally alters how biologists conceptualize this protein family’s origin and significance. Far from a mammalian idiosyncrasy, secretoglobins represent an ancient molecular toolkit that has been conserved and potentially adapted for species-specific roles over hundreds of millions of years. The ongoing deciphering of their functions promises to illuminate new facets of vertebrate biology, ranging from molecular evolution and developmental biology to medical science.
As the research community embraces these findings, the next steps will involve experimental validation of the putative functions, characterization of protein interactions, and functional assays beyond the mammalian system. This renewed attention holds promise for unlocking the biomedical potential of secretoglobins, which have remained enigmatic despite their ubiquitous presence. Through multidisciplinary investigations, secretoglobin biology may soon transition from cryptic to central in understanding terrestrial vertebrate physiology and evolution.
Subject of Research: Evolutionary genomics and functional analysis of secretoglobin (SCGB) protein family across amniote vertebrates
Article Title: A Broad Genome Survey Reveals Widespread Presence of Secretoglobin Genes in Squamate and Archosaur Reptiles that Flowered into Diversity in Mammals
News Publication Date: 14-Feb-2025
Web References:
https://doi.org/10.1093/gbe/evaf024
Image Credits: Bob Karn
Keywords: Comparative genomics, phylogenetic analysis, evolutionary genetics, protein families, secretoglobins, amniote evolution
Tags: bioinformatics in protein researchcomparative genomics of secretoglobinsevolutionary history of amniotesevolutionary origins of secretoglobinsgenomic survey of protein familieshistorical significance of secretoglobinsphysiological roles of secretoglobinsprotein family evolution in vertebratesresearch on cytokine-like proteinssecretoglobins beyond mammalssecretoglobins in terrestrial vertebratesstructural conservation of secretoglobins
