Recurrent Evolutionary Innovations in Mammalian Schlafen Genes Driven by Genetic Conflicts

Core Concepts

Mammalian Schlafen genes have undergone recurrent evolutionary innovations driven by genetic conflicts, including host-pathogen interactions and potential reproductive incompatibilities.

Abstract

The study provides a comprehensive phylogenomic analysis of the evolutionary trajectories and selective forces shaping mammalian Schlafen genes. Key findings include: Identification of a novel Schlafen-related orphan gene (SLFNL1) that likely arose in the last common ancestor of jawed vertebrates. Tracing lineage-specific amplifications and contractions of the clustered Schlafen genes in mammals, with distinct evolutionary patterns in primates and rodents. Detection of recurrent positive selection over Schlafen genes involved in viral interactions, such as SLFN11 and SLFN5, in both primates and rodents. Discovery of a novel class of rapidly evolving residues enriched at the contact interface between SCHLAFEN protein dimers, suggesting that inter-SCHLAFEN compatibilities are under strong selective pressures. Hypothesis that cycles of genetic conflicts with pathogens and between Schlafen paralogs drove their recurrent evolutionary innovations in mammals, shaping both antiviral and developmental functions.

Stats

"Schlafens rapid evolution might also relate to functions beyond antiviral antagonisms. This might be the case in mice where genetic mapping of a strain incompatibility locus was directly linked to the Schlafen gene cluster (Cohen-Tannoudji et al. 2000; Bell et al. 2006)." "Considering that many primates SLFN proteins have well described antiviral functions, their rapid diversification could result from an arms race with viral proteins (Kim and Weitzman 2022)." "Supporting this hypothesis, human SLFN5 and SLFN11 are the targets of viral antagonisms in the context of HSV-1 and HCMV restriction respectively (Kim et al. 2021; Nightingale et al. 2022)."

Quotes

"Genetic conflicts arise when co-evolving genetic entities engage in antagonistic interactions (Gardner and Ubeda 2017; McLaughlin and Malik 2017). This promotes rapid adaptation/counter-adaptation cycles, or evolutionary arms races, driving the expansion and positive selection of protein domains engaged in antagonism (Hurst and Werren 2001; McLaughlin and Malik 2017; Daugherty and Zanders 2019; Kuzmin et al. 2022)." "Considering the large time span of our analysis – ∼500My (Million years) – we used predicted SLFN proteins to run maximum likelihood (ML) phylogenetic analyses (see Methods). This identified five distinct Schlafen monophyletic clades: the four previously reported Schlafen gene clades with the addition of one novel clade related to SLFNL1 (Figure 1B, Supplemental Fig. S2 & Supplemental Table S1)."

Key Insights Distilled From

Recurrent Evolutionary Innovations in Rodent and Primate Schlafen Genes

by Mordier,J., ... at www.biorxiv.org 01-13-2024

https://www.biorxiv.org/content/10.1101/2024.01.12.575368v1

Deeper Inquiries

What are the potential developmental functions of Schlafen genes beyond their antiviral roles, and how might these contribute to reproductive isolation and speciation in mammals?

Schlafen genes, in addition to their well-known antiviral functions, have been implicated in various developmental processes and cellular functions. For example, they play a crucial role in regulating cellular rRNAs and tRNAs metabolism, which are essential for protein synthesis and cell growth. Schlafen proteins are structurally related to eukaryotic and viral RNase E and NTPase/Helicase enzymes, indicating their involvement in RNA processing and metabolism. These core cellular functions are vital for normal development and growth in mammals. The rapid evolution and diversification of Schlafen genes, driven by genetic conflicts with pathogens, can also lead to functional innovations that impact developmental processes. For instance, in mice, Schlafen genes have been linked to strain incompatibility loci, suggesting a role in reproductive isolation and potentially contributing to speciation. The genetic conflicts and arms races between Schlafen genes and pathogens may drive the evolution of novel functions that influence reproductive compatibility and ultimately lead to speciation events in mammals.

How do the rapidly evolving residues at the SCHLAFEN dimer interface impact the molecular functions and interactions of these proteins, and what are the evolutionary consequences of these changes?

The rapidly evolving residues at the SCHLAFEN dimer interface play a crucial role in shaping the molecular functions and interactions of these proteins. These residues are enriched at the contact interface between SCHLAFEN protein dimers, indicating that they are under strong selective pressures. The diversification of these residues likely affects the compatibility of interactions between SCHLAFEN proteins, both within the same ortholog and between paralogs. The changes at the dimer interface can influence the stability, specificity, and efficiency of protein-protein interactions, which are essential for the proper functioning of SCHLAFEN proteins. Alterations in these residues can impact the binding affinity, conformational changes, and overall activity of the proteins. This can lead to functional diversification, allowing SCHLAFEN proteins to adapt to new environmental challenges, such as evolving pathogens. From an evolutionary perspective, the rapid evolution of residues at the dimer interface reflects the ongoing genetic conflicts and arms races between SCHLAFEN proteins and pathogens. These changes contribute to the molecular diversity and functional innovations within the SCHLAFEN gene family, driving the adaptation and survival of mammals in response to changing environmental pressures.

Could the orphan SLFNL1 gene play a role in regulating RNA biology and retrotransposon activity, and how does its evolutionary history compare to the clustered Schlafen genes?

The orphan SLFNL1 gene, despite its distinct sequence and low identity with other SLFNs, contains a SCHLAFEN AlbA domain with conserved catalytic residues indicative of potential RNAse E functionality. This suggests that SLFNL1 may play a role in regulating RNA biology, potentially in RNA processing and metabolism similar to other Schlafen genes. Given its structural similarity to known RNA-related enzymes, SLFNL1 could be involved in RNA cleavage and processing, contributing to cellular functions such as protein synthesis and gene expression regulation. Furthermore, SLFNL1's potential involvement in RNA biology suggests that it may also have a role in retrotransposon activity. Retrotransposons are mobile genetic elements that can impact genome stability and gene expression. Schlafen genes, with their RNA-related functions, are known to be involved in retrotransposon restriction and regulation. Therefore, SLFNL1 could potentially contribute to retrotransposon control and genome stability in mammals. In terms of evolutionary history, SLFNL1 appears to be an ancestral gene in vertebrates, likely originating from the last common ancestor to all jawed vertebrates. Its presence in most vertebrate genomes suggests that SLFNL1 has been conserved throughout evolution, indicating its functional importance. Compared to the clustered Schlafen genes, SLFNL1's evolutionary trajectory is distinct, as it is not part of the Schlafen gene cluster and has a unique genomic location. This suggests that SLFNL1 may have specialized functions separate from the clustered Schlafen genes, highlighting its evolutionary significance in RNA biology and potential retrotransposon regulation.