Evolution of selenophosphate synthetases: emergence and relocation of function through independent duplications and recurrent subfunctionalization

Selenoproteins are proteins that incorporate selenocysteine (Sec), a nonstandard amino acid encoded by UGA, normally a stop codon. Sec synthesis requires the enzyme Selenophosphate synthetase (SPS or SelD), conserved in all prokaryotic and eukaryotic genomes encoding selenoproteins. Here, we study the evolutionary history of SPS genes, providing a map of selenoprotein function spanning the whole tree of life. SPS is itself a selenoprotein in many species, although functionally equivalent homologs that replace the Sec site with cysteine (Cys) are common. Many metazoans, however, possess SPS genes with substitutions other than Sec or Cys (collectively referred to as SPS1). Using complementation assays in fly mutants, we show that these genes share a common function, which appears to be distinct from the synthesis of selenophosphate carried out by the Sec- and Cys- SPS genes (termed SPS2), and unrelated to Sec synthesis. We show here that SPS1 genes originated through a number of independent gene duplications from an ancestral metazoan selenoprotein SPS2 gene that most likely already carried the SPS1 function. Thus, in SPS genes, parallel duplications and subsequent convergent subfunctionalization have resulted in the segregation to different loci of functions initially carried by a single gene. This evolutionary history constitutes a remarkable example of emergence and evolution of gene function, which we have been able to trace thanks to the singular features of SPS genes, wherein the amino acid at a single site determines unequivocally protein function and is intertwined to the evolutionary fate of the entire selenoproteome

SelenoDB 2.0: annotation of selenoprotein genes in animals and their genetic diversity in humans

SelenoDB (http://www.selenodb.org) aims to provide high-quality annotations of selenoprotein genes, proteins and SECIS elements. Selenoproteins are proteins that contain the amino acid selenocysteine (Sec) and the first release of the database included annotations for eight species. Since the release of SelenoDB 1.0 many new animal genomes have been sequenced. The annotations of selenoproteins in new genomes usually contain many errors in major databases. For this reason, we have now fully annotated selenoprotein genes in 58 animal genomes. We provide manually curated annotations for human selenoproteins, whereas we use an automatic annotation pipeline to annotate selenoprotein genes in other animal genomes. In addition, we annotate the homologous genes containing cysteine (Cys) instead of Sec. Finally, we have surveyed genetic variation in the annotated genes in humans. We use exon capture and resequencing approaches to identify single nucleotide polymorphisms in more than 50 human populations around the world. We thus present a detailed view of the genetic divergence of Sec- and Cys-containing genes in animals and their diversity in humans. The addition of these data sets into the second release of the database provides a valuable resource for addressing medical and evolutionary questions in selenium biology

Human selenoprotein P and S variant mRNAs with different numbers of SECIS elements and inferences from mutant mice of the roles of multiple SECIS elements

Dynamic redefinition of the 10 UGAs in human and mouse selenoprotein P (Sepp1) mRNAs to specify selenocysteine instead of termination involves two 3′ UTR structural elements (SECIS) and is regulated by selenium availability. In addition to the previously known human Sepp1 mRNA poly(A) addition site just 3′ of SECIS 2, two further sites were identified with one resulting in 10–25% of the mRNA lacking SECIS 2. To address function, mutant mice were generated with either SECIS 1 or SECIS 2 deleted or with the first UGA substituted with a serine codon. They were fed on either high or selenium-deficient diets. The mutants had very different effects on the proportions of shorter and longer product Sepp1 protein isoforms isolated from plasma, and on viability. Spatially and functionally distinctive effects of the two SECIS elements on UGA decoding were inferred. We also bioinformatically identify two selenoprotein S mRNAs with different 5′ sequences predicted to yield products with different N-termini. These results provide insights into SECIS function and mRNA processing in selenoprotein isoform diversity

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

The Genome Sequence of the Grape Phylloxera Provides Insights into the Evolution, Adaptation, and Invasion Routes of an Iconic Pest

Background: Although native to North America, the invasion of the aphid-like grape phylloxera Daktulosphaira vitifoliae across the globe altered the course of grape cultivation. For the past 150 years, viticulture relied on grafting-resistant North American Vitis species as rootstocks, thereby limiting genetic stocks tolerant to other stressors such as pathogens and climate change. Limited understanding of the insect genetics resulted in successive outbreaks across the globe when rootstocks failed. Here we report the 294-Mb genome of D. vitifoliae as a basic tool to understand host plant manipulation, nutritional endosymbiosis, and enhance global viticulture. Results: Using a combination of genome, RNA, and population resequencing, we found grape phylloxera showed high duplication rates since its common ancestor with aphids, but similarity in most metabolic genes, despite lacking obligate nutritional symbioses and feeding from parenchyma. Similarly, no enrichment occurred in development genes in relation to viviparity. However, phylloxera evolved > 2700 unique genes that resemble putative effectors and are active during feeding. Population sequencing revealed the global invasion began from the upper Mississippi River in North America, spread to Europe and from there to the rest of the world. Conclusions: The grape phylloxera genome reveals genetic architecture relative to the evolution of nutritional endosymbiosis, viviparity, and herbivory. The extraordinary expansion in effector genes also suggests novel adaptations to plant feeding and how insects induce complex plant phenotypes, for instance galls. Finally, our understanding of the origin of this invasive species and its genome provide genetics resources to alleviate rootstock bottlenecks restricting the advancement of viticulture

Selenoproteins across the tree of life: Methods and applications

La selenocïsteina és coneguda com a l'aminoàcid 21. Les selenoproteïnes incorporen selenocïsteina en resposta a codons UGA específics mitjançant un mecanisme de recodificació, el qual és present en els tres dominis de la vida, però no en tots els organismes. Els programes estàndard per a la predicció de gens consideren UGA només com a codó stop, per aquesta raó l'anotació de selenoproteínes és, generalment, incorrecte. Hem desenvolupat mètodes computacionals per a la predicció de selenoproteïnes. Mitjançant l'aplicació d'aquestes i altres eines, hem caracteritzat selenoproteïnes a través de l'Arbre de la Vida, on hem observat una evolució dinàmica en la utilització de selenocïsteina en els diferents llinatges. Hem caracteritzat l'abundància i distribució de selenoproteïnes en el microbioma humà. Hem caracteritzat les selenoproteïnes presents a Lokiarchaeota, les quals presenten trets eucariòtics. Finalment hem dedicat especial atenció als insectes, en els quals una progressiva reducció en el nombre de selenoproteïnes culminà en múltiples extincions de selenoproteïnes en esdeveniments evolutius independents.Selenocysteine is known as the 21st amino acid. Selenoproteins incorporate selenocysteine in response to specific UGA codons through a recoding mechanism, which present in the three domains of life, but not in all organisms. Standard gene prediction programs consider UGA only as stop, and selenoproteins are normally misannotated. We have developed computational methods for prediction of selenoproteins. By applying these and other tools, we have characterized selenoproteins across the Tree of Life, showing a diverse evolution of the utilization of selenocysteine in different lineages. We have characterized the abundance and distribution of selenoproteins in the human microbiota. We characterized the selenoproteins in Lokiarchaeota, which have some eukaryotic-like features. Finally we gave special attention to insects, in which a progressive reduction in the number of selenoproteins culminated in multiple independent selenoprotein extinctions

COVID-19 is an emergent disease of aging

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greatest challenges to public health in recent years. SARS-CoV-2 is highly contagious and often leads to severe viral pneumonia with respiratory failure and death in the elderly and subjects with pre-existing conditions, but the reason for this age dependence is unclear. Here, we found that the case fatality rate for COVID-19 grows exponentially with age in Italy, Spain, South Korea, and China, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its major risk factors. In turn, this suggests that COVID-19, and deadly respiratory diseases in general, may be targeted, in addition to therapeutic approaches that affect specific pathways, by approaches that target the aging process

Selenocysteine Machinery Primarily Supports TXNRD1 and GPX4 Functions and Together They Are Functionally Linked with SCD and PRDX6

The human genome has 25 genes coding for selenocysteine (Sec)-containing proteins, whose synthesis is supported by specialized Sec machinery proteins. Here, we carried out an analysis of the co-essentiality network to identify functional partners of selenoproteins and Sec machinery. One outstanding cluster included all seven known Sec machinery proteins and two critical selenoproteins, GPX4 and TXNRD1. Additionally, these nine genes were further positively associated with PRDX6 and negatively with SCD, linking the latter two genes to the essential role of selenium. We analyzed the essentiality scores of gene knockouts in this cluster across one thousand cancer cell lines and found that Sec metabolism genes are strongly selective for a subset of primary tissues, suggesting that certain cancer cell lineages are particularly dependent on selenium. A separate outstanding cluster included selenophosphate synthetase SEPHS1, which was linked to a group of transcription factors, whereas the remaining selenoproteins were linked neither to these clusters nor among themselves. The data suggest that key components of Sec machinery have already been identified and that their primary role is to support the functions of GPX4 and TXNRD1, with further functional links to PRDX6 and SCD

Selenoproteins across the tree of life: Methods and applications

La selenocïsteina és coneguda com a l'aminoàcid 21. Les selenoproteïnes incorporen selenocïsteina en resposta a codons UGA específics mitjançant un mecanisme de recodificació, el qual és present en els tres dominis de la vida, però no en tots els organismes. Els programes estàndard per a la predicció de gens consideren UGA només com a codó stop, per aquesta raó l'anotació de selenoproteínes és, generalment, incorrecte. Hem desenvolupat mètodes computacionals per a la predicció de selenoproteïnes. Mitjançant l'aplicació d'aquestes i altres eines, hem caracteritzat selenoproteïnes a través de l'Arbre de la Vida, on hem observat una evolució dinàmica en la utilització de selenocïsteina en els diferents llinatges. Hem caracteritzat l'abundància i distribució de selenoproteïnes en el microbioma humà. Hem caracteritzat les selenoproteïnes presents a Lokiarchaeota, les quals presenten trets eucariòtics. Finalment hem dedicat especial atenció als insectes, en els quals una progressiva reducció en el nombre de selenoproteïnes culminà en múltiples extincions de selenoproteïnes en esdeveniments evolutius independents.Selenocysteine is known as the 21st amino acid. Selenoproteins incorporate selenocysteine in response to specific UGA codons through a recoding mechanism, which present in the three domains of life, but not in all organisms. Standard gene prediction programs consider UGA only as stop, and selenoproteins are normally misannotated. We have developed computational methods for prediction of selenoproteins. By applying these and other tools, we have characterized selenoproteins across the Tree of Life, showing a diverse evolution of the utilization of selenocysteine in different lineages. We have characterized the abundance and distribution of selenoproteins in the human microbiota. We characterized the selenoproteins in Lokiarchaeota, which have some eukaryotic-like features. Finally we gave special attention to insects, in which a progressive reduction in the number of selenoproteins culminated in multiple independent selenoprotein extinctions

Pathogenic Variants in Selenoproteins and Selenocysteine Biosynthesis Machinery

Selenium is incorporated into selenoproteins as the 21st amino acid selenocysteine (Sec). There are 25 selenoproteins encoded in the human genome, and their synthesis requires a dedicated machinery. Most selenoproteins are oxidoreductases with important functions in human health. A number of disorders have been associated with deficiency of selenoproteins, caused by mutations in selenoprotein genes or Sec machinery genes. We discuss mutations that are known to cause disease in humans and report their allele frequencies in the general population. The occurrence of protein-truncating variants in the same genes is also presented. We provide an overview of pathogenic variants in selenoproteins genes from a population genomics perspective