Adaptive evolution and loss of a putative magnetoreceptor in passerines.

Migratory birds possess remarkable accuracy in orientation and navigation, which involves various compass systems including the magnetic compass. Identifying the primary magnetosensor remains a fundamental open question. Cryptochromes (Cry) have been shown to be magnetically sensitive, and Cry4a from a migratory songbird seems to show enhanced magnetic sensitivity in vitro compared to Cry4a from resident species. We investigate Cry and their potential involvement in magnetoreception in a phylogenetic framework, integrating molecular evolutionary analyses with protein dynamics modelling. Our analysis is based on 363 bird genomes and identifies different selection regimes in passerines. We show that Cry4a is characterized by strong positive selection and high variability, typical characteristics of sensor proteins. We identify key sites that are likely to have facilitated the evolution of an optimized sensory protein for night-time orientation in songbirds. Additionally, we show that Cry4 was lost in hummingbirds, parrots and Tyranni (Suboscines), and thus identified a gene deletion, which might facilitate testing the function of Cry4a in birds. In contrast, the other avian Cry (Cry1 and Cry2) were highly conserved across all species, indicating basal, non-sensory functions. Our results support a specialization or functional differentiation of Cry4 in songbirds which could be magnetosensation.

Fine-Scale Map Reveals Highly Variable Recombination Rates Associated with Genomic Features in the Eurasian Blackcap.

Recombination is responsible for breaking up haplotypes, influencing genetic variability, and the efficacy of selection. Bird genomes lack the protein PR domain-containing protein 9, a key determinant of recombination dynamics in most metazoans. Historical recombination maps in birds show an apparent stasis in positioning recombination events. This highly conserved recombination pattern over long timescales may constrain the evolution of recombination in birds. At the same time, extensive variation in recombination rate is observed across the genome and between different species of birds. Here, we characterize the fine-scale historical recombination map of an iconic migratory songbird, the Eurasian blackcap (Sylvia atricapilla), using a linkage disequilibrium-based approach that accounts for population demography. Our results reveal variable recombination rates among and within chromosomes, which associate positively with nucleotide diversity and GC content and negatively with chromosome size. Recombination rates increased significantly at regulatory regions but not necessarily at gene bodies. CpG islands are associated strongly with recombination rates, though their specific position and local DNA methylation patterns likely influence this relationship. The association with retrotransposons varied according to specific family and location. Our results also provide evidence of heterogeneous intrachromosomal conservation of recombination maps between the blackcap and its closest sister taxon, the garden warbler. These findings highlight the considerable variability of recombination rates at different scales and the role of specific genomic features in shaping this variation. This study opens the possibility of further investigating the impact of recombination on specific population-genomic features.

Mutational Study of the Tryptophan Tetrad Important for Electron Transfer in European Robin Cryptochrome 4a.

The ability of migratory birds to sense magnetic fields has been known for decades, although the understanding of the underlying mechanism is still elusive. Currently, the strongest magnetoreceptor candidate in birds is a protein called cryptochrome 4a. The cryptochrome 4a protein has changed through evolution, apparently endowing some birds with a more pronounced magnetic sensitivity than others. Using phylogenetic tools, we show that a specific tryptophan tetrad and a tyrosine residue predicted to be essential for cryptochrome activation are highly conserved in the avian clade. Through state-of-the-art molecular dynamics simulations and associated analyses, we also studied the role of these specific residues and the associated mutants on the overall dynamics of the protein. The analyses of the single residue mutations were used to judge how far a local change in the protein structure can impact specific dynamics of European robin cryptochrome 4a. We conclude that the replacements of each of the tryptophans one by one with a phenylalanine do not compromise the overall stability of the protein.

Computational Reconstruction and Analysis of Structural Models of Avian Cryptochrome 4.

A recent study by Xu et al. (Nature, 2021, 594, 535-540) provided strong evidence that cryptochrome 4 (Cry4) is a key protein to endow migratory birds with the magnetic compass sense. The investigation compared the magnetic field response of Cry4 from migratory and nonmigratory bird species and suggested that a difference in magnetic sensitivity could exist. This finding prompted an in-depth investigation into Cry4 protein differences on the structural and dynamic levels. In the present study, the pigeon Cry4 (ClCry4) crystal structure was used to reconstruct the missing avian Cry4 protein structures via homology modeling for carefully selected bird species. The reconstructed Cry4 structure from European robin, Eurasian blackcap, zebra finch, chicken, and pigeon were subsequently simulated dynamically and analyzed. The studied avian Cry4 structures show flexibility in analogous regions pointing to similar activation mechanisms and/or signaling interaction partners. It can be concluded that the experimentally recorded difference in the magnetic field sensitivity of Cry4 from different birds is unlikely to be due to solely intrinsic dynamics of the proteins but requires additional factors that have not yet been identified.

The rise in expression and activity of 11ß-HSD1 in human mesenchymal progenitor cells induces adipogenesis through increased local cortisol synthesis.

11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1) plays an important role in pre-receptor glucocorticoid metabolism. This enzyme is expressed in bone, increases with age, and catalyzes the conversion of the inactive glucocorticoid cortisone into the active glucocorticoid cortisol and vice versa. Here we hypothesized that the physiological activity of 11ß-HSD1 to produce cortisol in human mesenchymal progenitor cells (hMSC) is principally sufficient to shift the differentiation potential in the direction of adipogenic. We thus investigated differentiating hMSCs and the mesenchymal stem cell line SCP-1 cultured under osteogenic conditions and stimulated with supra-physiological cortisone levels. The release of active cortisol into the medium was monitored and the influence on cell differentiation analyzed. We revealed an increase in 11ß-HSD1 expression followed by increased reductive activity of the enzyme, thereby inducing a more adipogenic phenotype of the cell models via cortisol with negative effects on osteogenesis. Through inhibition experiments with the specific inhibitor 10 j, we proved the enzyme specificity for cortisol synthesis and adipogenic differentiation. Increased expression of 11ß-HSD1 followed by higher cortisol levels might thus explain bone marrow adiposity followed by reduced bone quality and stability in old age or in situations of supra-physiological glucocorticoid exposure.