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Selenium is a fascinating element that has a long history, most of which documents it as a deleterious element to health. In more recent years, selenium has been found to be an essential element in the diet of humans, all other mammals, and many other life forms. It has many health benefits that include, for example, roles in preventing heart disease and certain forms of cancer, slowing AIDS progression in HIV patients, supporting male reproduction, inhibiting viral expression, and boosting the immune system, and it also plays essential roles in mammalian development. Elucidating the molecular biology of selenium over the past 40 years generated an entirely new field of science which encompassed the many novel features of selenium. These features were (1) how this element makes its way into protein as the 21st amino acid in the genetic code, selenocysteine (Sec); (2) the vast amount of machinery dedicated to synthesizing Sec uniquely on its tRNA; (3) the incorporation of Sec into protein; and (4) the roles of the resulting Sec-containing proteins (selenoproteins) in health and development. One of the research areas receiving the most attention regarding selenium in health has been its role in cancer prevention, but further research has also exposed the role of this element as a facilitator of various maladies, including cancer.

Children are known to be better protected from COVID-19 than adults, but their susceptibility patterns and the risk relative to other diseases are insufficiently defined. Here, we found that the COVID-19 mortality rate is U-shaped in childhood: it initially decreases, reaching the minimum at the ages 3-10 years, and then increases throughout life. All-cause mortality and mortality from other diseases, such as pneumonia and influenza, show a similar pattern; however, childhood mortality rates from COVID-19 are considerably lower than from other diseases, with the best relative protection achieved at the youngest ages. Consistent with this, the fraction of COVID-19 deaths among all deaths increases as a function of age throughout childhood and the entire life. We discuss implications of the elevated postnatal COVID-19 risk and lower childhood COVID-19 mortality compared to other diseases.

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.

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 known to preferentially target older subjects and those 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 all countries tested, 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 antiviral approaches, by approaches that target the aging process., This study establishes COVID‐19 as an emergent disease of aging, based on (a) an exponential growth of the COVID‐19 mortality rate with age, (b) the COVID‐19 mortality rate doubling time approaching that of all‐cause human mortality, (c) higher mortality in men than in women, (d) strong association with pre‐existing age‐related diseases, and (e) COVID‐19 being a subset of all‐cause pneumonia, which we find itself is a disease of aging.

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.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.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.

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., This work has been funded by INRAE (France) and by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 764840 for the ITN IGNITE project. Rosa Fernandez was funded by a Juan de la Cierva-Incorporación Fellowship (Government of Spain, IJCI-2015-26627) and a Marie Skłodowska-Curie Fellowship (747607). Angela Douglas was supported by the US National Institute of Food and Agriculture Grant 12216941. Honglin Feng was supported by a University of Miami Maytag Fellowship, William H. Evoy Graduate Research Support Fund, and a Molecular Biosciences Graduate Research Award from the Department of Biology.

Ngatiwai Trust Board. et al., The tuatara (Sphenodon punctatus)—the only living member of the reptilian order Rhynchocephalia (Sphenodontia), once widespread across Gondwana1,2—is an iconic species that is endemic to New Zealand2,3. A key link to the now-extinct stem reptiles (from which dinosaurs, modern reptiles, birds and mammals evolved), the tuatara provides key insights into the ancestral amniotes2,4. Here we analyse the genome of the tuatara, which—at approximately 5 Gb—is among the largest of the vertebrate genomes yet assembled. Our analyses of this genome, along with comparisons with other vertebrate genomes, reinforce the uniqueness of the tuatara. Phylogenetic analyses indicate that the tuatara lineage diverged from that of snakes and lizards around 250 million years ago. This lineage also shows moderate rates of molecular evolution, with instances of punctuated evolution. Our genome sequence analysis identifies expansions of proteins, non-protein-coding RNA families and repeat elements, the latter of which show an amalgam of reptilian and mammalian features. The sequencing of the tuatara genome provides a valuable resource for deep comparative analyses of tetrapods, as well as for tuatara biology and conservation. Our study also provides important insights into both the technical challenges and the cultural obligations that are associated with genome sequencing., N.J.G. acknowledges the support of Ngatiwai iwi, Allan Wilson Centre, University of Otago, New Zealand Department of Conservation, New Zealand Genomics and Illumina. J.I.A. was supported by CONICYT National Doctoral Scholarship No. 21130515. M.W. was supported by NIH grant R35 GM124827. Ensembl annotation was supported by the Wellcome Trust (WT108749/Z/15/Z) and the European Molecular Biology Laboratory.

The tuatara (Sphenodon punctatus), the only living member of the archaic reptilian order Rhynchocephalia (Sphenodontia) once widespread across Gondwana, is an iconic and enigmatic terrestrial vertebrate endemic to New Zealand. A key link to the now extinct stem reptiles from which dinosaurs, modern reptiles, birds and mammals evolved, the tuatara provides exclusive insights into the ancestral amniotes. The tuatara genome, at ∼5 Gbp, is among the largest vertebrate genomes assembled. Analysis of this genome and comparisons to other vertebrates reinforces the uniqueness of the tuatara. Phylogenetic analyses indicate tuatara diverged from the snakes and lizards ∼250 MYA. This lineage also shows moderate rates of molecular evolution, with instances of punctuated evolution. Genome sequence analysis identifies expansions of protein, non-protein-coding RNA families, and repeat elements, the latter of which show an extraordinary amalgam of reptilian and mammalian features. Sequencing of this genome provides a valuable resource for deep comparative analyses of tetrapods, as well as for tuatara biology and conservation. It also provides important insights into both the technical challenges and the cultural obligations associated with genome sequencing.

Heritability of human lifespan is 23-33% as evident from twin studies. Genome-wide association studies explored this question by linking particular alleles to lifespan traits. However, genetic variants identified so far can explain only a small fraction of lifespan heritability in humans. Here, we report that the burden of rarest protein-truncating variants (PTVs) in two large cohorts is negatively associated with human healthspan and lifespan, accounting for 0.4 and 1.3 years of their variability, respectively. In addition, longer-living individuals possess both fewer rarest PTVs and less damaging PTVs. We further estimated that somatic accumulation of PTVs accounts for only a small fraction of mortality and morbidity acceleration and hence is unlikely to be causal in aging. We conclude that rare damaging mutations, both inherited and accumulated throughout life, contribute to the aging process, and that burden of ultra-rare variants in combination with common alleles better explain apparent heritability of human lifespan.Most living things undergo biological changes as they get older, a process that we generally refer to as aging. Despite being a widespread phenomenon, scientists do not fully understand why we age, though it appears that a combination of genetics and lifestyle factors, such as diet, play a role in influencing lifespan. Aging increases the risk of developing a wide range of diseases, including cancer, Alzheimer’s disease and diabetes. As such, finding ways to slow the aging process would help to postpone the onset of illness and potentially improve health in old age. Genes are thought to be responsible for between one quarter and one third of the variation in human lifespans. The relationship between genes, aging and lifespan is complex and not well understood. One set of rare genetic changes that have been shown to have significant effects on diseases are called protein truncation variants (PTVs). PTVs cause damage by altering the production of certain proteins. There are many possible PTVs and people can be born with them or they can develop them in some cells later in life. The full influence of PTVs on aging is not known. Shindyapina, Zenin et al. have now studied observational data collected from two groups of over 40,000 people in the UK. Both groups recorded over 1,000 deaths, and the study examined the influence of PTVs on natural lifespan. The results show that each person is born with an average of six PTVs, which can vary in the impact that they have on aging. Having more, or more severe, PTVs could reduce life expectancy on average by 1.3 years. PTVs affect both total lifespan and healthy lifespan, the period of time lived prior to developing the first age-related disease. While PTVs that people are born with have a significant effect on aging, this study also showed that PTVs that are acquired due to spontaneous mutations through a person’s life have much less of an impact. This is a key insight into the relationship between genes and aging. These discoveries could help in using genetics to anticipate future health, it also helps to identify some of the biological systems that have a role in aging. This could lead to new ways to delay the aging process and its effects on health.

Mouse has emerged as the most common model organism in biomedicine. Here, we analyzed the tolerance to the loss-of-function (LoF) of selenoprotein genes, estimated from mouse knockouts and the frequency of LoF variants in humans. We found not only a general correspondence in tolerance (e.g., GPX1, GPX2) and intolerance (TXNRD1, SELENOT) to gene LoF between humans and mice but also important differences. Notably, humans are intolerant to the loss of iodothyronine deiodinases, whereas their deletion in mice leads to mild phenotypes, and this is consistent with phenotype differences in selenocysteine machinery loss between these species. In contrast, loss of TXNRD2 and GPX4 is lethal in mice but may be tolerated in humans. We further identified the first human SELENOP variants coding for proteins varying in selenocysteine content. Finally, our analyses suggested that premature termination codons in selenoprotein genes trigger nonsense-mediated decay, but do this inefficiently when UGA codon is gained. Overall, our study highlights differences in the physiological importance of selenoproteins between human and mouse.

Selenoproteins typically contain a single selenocysteine, the 21st amino acid, encoded by a context-redefined UGA. However, human selenoprotein P (SelenoP) has a redox-functioning selenocysteine in its N-terminal domain and nine selenium transporter-functioning selenocysteines in its C-terminal domain. Here we show that diverse SelenoP genes are present across metazoa with highly variable numbers of Sec-UGAs, ranging from a single UGA in certain insects, to 9 in common spider, and up to 132 in bivalve molluscs. SelenoP genes were shaped by a dynamic evolutionary process linked to selenium usage. Gene evolution featured modular expansions of an ancestral multi-Sec domain, which led to particularly Sec-rich SelenoP proteins in many aquatic organisms. We focused on molluscs, and chose Pacific oyster Magallana gigas as experimental model. We show that oyster SelenoP mRNA with 46 UGAs is translated full-length in vivo. Ribosome profiling indicates that selenocysteine specification occurs with ~5% efficiency at UGA1 and approaches 100% efficiency at distal 3' UGAs. We report genetic elements relevant to its expression, including a leader open reading frame and an RNA structure overlapping the initiation codon that modulates ribosome progression in a selenium-dependent manner. Unlike their mammalian counterparts, the two SECIS elements in oyster SelenoP (3'UTR recoding elements) do not show functional differentiation in vitro. Oysters can increase their tissue selenium level up to 50-fold upon supplementation, which also results in extensive changes in selenoprotein expression. The work was supported by the following grants: NIH DK117149, GM065204, and AG021518 (V.N.G.); BIO2014-57291-R from the Spanish Ministry of Economy and Competitiveness (R.G.), NIH GM077073 (P.R.C.), Science Foundation Ireland (13/IA/1853), and Irish Research Council (IRCLA/2019/74 n) (J.F.A).

Selenocysteine (Sec) is the 21st amino acid in the genetic code, inserted in response to UGA codons with the help of RNA structures, the SEC Insertion Sequence (SECIS) elements. The three domains of life feature distinct strategies for Sec insertion in proteins and its utilization. While bacteria and archaea possess similar sets of selenoproteins, Sec biosynthesis is more similar among archaea and eukaryotes. However, SECIS elements are completely different in the three domains of life. Here, we analyze the archaeon Lokiarchaeota that resolves the relationships among Sec insertion systems. This organism has selenoproteins representing five protein families, three of which have multiple Sec residues. Remarkably, these archaeal selenoprotein genes possess conserved RNA structures that strongly resemble the eukaryotic SECIS element, including key eukaryotic protein-binding sites. These structures also share similarity with the SECIS element in archaeal selenoprotein VhuD, suggesting a relation of direct descent. These results identify Lokiarchaeota as an intermediate form between the archaeal and eukaryotic Sec-encoding systems and clarify the evolution of the Sec insertion system. This study was supported by NIH GM061603, GM065205 and CA080946. B.M. is partly supported by The Pew Charitable Trust postdoctoral fellow program.

The tuatara (Sphenodon punctatus)-the only living member of the reptilian order Rhynchocephalia (Sphenodontia), once widespread across Gondwana

Selenocysteine (Sec) is known as the 21st amino acid, a cysteine analogue with selenium replacing sulphur. Sec is inserted co-translationally in a small fraction of proteins called selenoproteins. In selenoprotein genes, the Sec specific tRNA (tRNASec) drives the recoding of highly specific UGA codons from stop signals to Sec. Although found in organisms from the three domains of life, Sec is not universal. Many species are completely devoid of selenoprotein genes and lack the ability to synthesize Sec. Since tRNASec is a key component in selenoprotein biosynthesis, its efficient identification in genomes is instrumental to characterize the utilization of Sec across lineages. Available tRNA prediction methods fail to accurately predict tRNASec, due to its unusual structural fold. Here, we present Secmarker, a method based on manually curated covariance models capturing the specific tRNASec structure in archaea, bacteria and eukaryotes. We exploited the non-universality of Sec to build a proper benchmark set for tRNASec predictions, which is not possible for the predictions of other tRNAs. We show that Secmarker greatly improves the accuracy of previously existing methods constituting a valuable tool to identify tRNASec genes, and to efficiently determine whether a genome contains selenoproteins. We used Secmarker to analyze a large set of fully sequenced genomes, and the results revealed new insights in the biology of tRNASec, led to the discovery of a novel bacterial selenoprotein family, and shed additional light on the phylogenetic distribution of selenoprotein containing genomes. Secmarker is freely accessible for download, or online analysis through a web server at http://secmarker.crg.cat., Author summary Most proteins are made of twenty amino acids. However, there is a small group of proteins that incorporate a 21st amino acid, Selenocysteine (Sec). These proteins are called selenoproteins and are present in some, but not all, species from the three domains of life. Sec is inserted in selenoproteins in response to the UGA codon, normally a stop codon. A Sec specific tRNA (tRNASec), which only exists in the organisms that synthesize selenoproteins recognizes the UGA codon. tRNASec is not only indispensable for Sec incorporation into selenoproteins, but also for Sec synthesis, since Sec is synthesized on its own tRNA. The structure of tRNASec differs from that of canonical tRNAs, and general tRNA detection methods fail to accurately predict it. We developed Secmarker, a tRNASec specific identification tool based on the characteristic structural features of the tRNASec. Our benchmark shows that Secmarker produces nearly flawless tRNASec predictions. We used Secmarker to scan all currently available genome sequences. The analysis of the highly accurate predictions obtained revealed new insights into the biology of tRNASec.

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.

(a) Alignment of SECIS elements in selenoprotein P genes of representative vertebrate species (b) Average distance tree computed by Jalview based on the alignment shown in panel (c) Structure of SECIS elements as predicted by SECISearch3 webserver

Sequences of primers used for human selenoprotein P alternative transcript quantification and sequences of primers used for the generation of mouse lines

Made available in DSpace on 2015-10-21T20:31:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-04-24. Added 1 bitstream(s) on 2015-10-22T09:48:01Z : No. of bitstreams: 1 WOS000353676700001.pdf: 2518339 bytes, checksum: d1f8d18bd059b76504f3fcd9aa639a74 (MD5) National Institutes of Health (NIH) Agriculture and Food Research Initiative Competitive grant from the USDA National Institute of Food and Agriculture Research Council of Norway (NFR) PEW Charitable Trust University of East Anglia, UK Israel Science Foundation (ISF) Biotechnology and Biological Sciences Research Council, UK University of East Anglia University of Alabama College of Arts and Sciences Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Marie Curie International Outgoing Fellowship Swiss National Science Foundation New Faculty Initiative Grant (NFIG) from Illinois State University College of Arts and Sciences DFG Instituto Nacional de Bioinformatica (INB) from ISCIII in Spain 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. Illinois State Univ, Sch Biol Sci, Normal, IL 61790 USA ETH, Inst Integrat Biol, Expt Ecol, CH-8092 Zurich, Switzerland E Carolina Univ, Dept Biol, Greenville, NC 27858 USA Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Ecol Evolut &Behav, Jerusalem, Israel Univ Ghent, Fac Sci, Lab Zoophysiol, B-9000 Ghent, Belgium Univ Otago, Dept Biochem, Labo Evolut &Dev Genet, Dunedin 9054, New Zealand Univ Otago, Dept Biochem, Natl Res Ctr Growth &Dev, Dunedin 9054, New Zealand Univ Missouri, Div Plant Sci, Div Anim Sci, Columbia, MO 65211 USA Univ Missouri, MU Informat Inst, Columbia, MO 65211 USA Georgetown Univ, Dept Biol, Washington, DC 20057 USA Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA Univ Copenhagen, Dept Biol, Ctr Funct &Comparat Insect Gen, Copenhagen, Denmark Univ Hohenheim, Inst Anim Sci, D-70599 Stuttgart, Germany Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA Univ Illinois, Dept Entomol, Urbana, IL 61801 USA Univ Ghent, Fac Biosci Engn, Dept Crop Protect, Lab Agrozool, B-9000 Ghent, Belgium Univ Halle Wittenberg, Inst Biol, Wittenberg, Germany Univ Geneva, Sch Med, Dept Genet Med &Dev, CH-1211 Geneva, Switzerland Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland MIT, Comp Sci &Artificial Intelligence Lab, Cambridge, MA 02139 USA MIT &Harvard, Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA Univ Munster, Inst Evolut &Biodivers, D-48149 Munster, Germany Ctr Genom Regulat CRG, Barcelona 08003, Spain UPF, Barcelona, Spain Ernst Moritz Arndt Univ Greifswald, Inst Math &Comp Sci, D-17487 Greifswald, Germany Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA 94720 USA Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA Norwegian Univ Food Sci, Dept Chem Biotechnol &Food Sci, N-1432 As, Norway Univ E Anglia, Sch Comp Sci, Norwich NR4 7TJ, Norfolk, England Univ Dusseldorf, Inst Evolut Genet, D-40225 Dusseldorf, Germany Univ Cologne, Inst Genet, Cologne, Germany Univ Sao Paulo, Dept Biol, Fac Filosofia Ciencias &Letras Ribeirao Preto, BR-14040901 Ribeirao Preto, Brazil Univ Edinburgh, Ashworth Labs, Inst Evolutionary Biol &Edinburgh Gen, Edinburgh EH9 3FL, Midlothian, Scotland Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England Royal Holloway Univ London, Sch Biol Sci, London, England Maynooth Univ, Dept Biol, Co, Kildare, Ireland Univ Bristol, Sch Biol Sci, Bristol BS8 1TQ, Avon, England CSIRO, Land &Water Flagship, Canberra, ACT, Australia Trin Coll Dublin, Sch Nat Sci, Dept Zool, Dublin, Ireland Zool Soc London, Inst Zool, London NW1 4RY, England ETH, Inst Integrat Biol, Theoret Biol, CH-8092 Zurich, Switzerland Swiss Inst Bioinformat, Lausanne, Switzerland Swiss Fed Inst Technol, Dept Biosyst Sci &Engn, Computat Evolut, Basel, Switzerland USDA ARS, Bee Res Lab, Washington, DC 20250 USA Univ Sao Paulo, Dept Genet, Fac Med Ribeirao Preto, BR-14040900 Ribeirao Preto, Brazil N Carolina State Univ, Ctr Res Sci Computat, Raleigh, NC 27695 USA Kyoto Univ, Grad Sch Agr, Lab Insect Ecol, Kyoto, Japan Univ Sao Paulo, Dept Biol Celular &Mol &Bioagentes Patogen, Fac Med Ribeirao Preto, BR-14040900 Ribeirao Preto, Brazil Inst Fed Educ Ciencia &Tecnol Sao Paulo, BR-15991502 Matao, Brazil Ohio State Univ, Dept Entomol, Wooster, OH 44791 USA Oxford Brookes Univ, Fac Hlth &Life Sci, Dept Biol &Med Sci, Oxford OX3 0BP, England Xian Jiaotong Liverpool Univ, Dept Biol Sci, Suzhou, Peoples R China Univ Hosp Halle Saale, Dept Lab Med, Halle, Germany German Ctr Integrat Biodivers Res iDiv, Leipzig, Germany Univ Southampton, Southampton, Hants, England Univ Leicester, Dept Biol, Leicester, Leics, England Univ Fed Sao Carlos, Ctr Ciencias Biol &Saude, Dept Genet &Evolucao, BR-13565905 Sao Carlos, SP, Brazil Univ Estadual Paulista, Fac Ciencias Agr &Vet, Dept Tecnol, BR-14884900 Jaboticabal, Brazil Univ N Carolina, Dept Biol, Greensboro, NC 27403 USA Natl Ctr Sci Res Demokritos, Inst Biosci &Applicat, Athens, Greece Univ Munich, Munich, Germany Baylor Coll Med, Dept Mol &Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA Univ Illinois, Roy J Carver Biotechnol, Urbana, IL 61801 USA Univ Illinois, Dept Crop Sci, Urbana, IL 61801 USA Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA MD Anderson Canc Ctr, Sch Hlth Profess, Mol Genet Technol Program, Unit 2, Houston, TX 77025 USA Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA Univ Ghent, Dept Biochem &Microbiol, Lab Prot Biochem &Biomol Engn, B-9000 Ghent, Belgium Queen Mary Univ London, Sch Biol &Chem Sci, Dept Biol &Expt Psychol, London E1 4NS, England Guangzhou Univ, Sch Life Sci, Guangzhou, Guangdong, Peoples R China Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Ctr Computat Biol, Baltimore, MD 21205 USA Univ Illinois, Neurosci Program, Dept Entomol, Carl R Woese Inst Genom Biol, Urbana, IL 61801 USA Departamento de Tecnologia, Faculdade de Ciências Agrárias e Veterinárias, Universidade Estadual Paulista, Jaboticabal, 14884-900, Brazi National Institutes of Health (NIH): DP1 OD006416 National Institutes of Health (NIH): U54 HG003273 Agriculture and Food Research Initiative Competitive grant from the USDA National Institute of Food and Agriculture: 2010-65106-21301 FAPESP: 11/03171-5 Marie Curie International Outgoing Fellowship: PIOF-GA-2011-303312 Swiss National Science Foundation: 31003A-125350 Swiss National Science Foundation: 31003A-143936

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. . R.G. group research was funded by grants BIO2011-26205 from the Spanish Ministry of Science and grant SGR-1430 from the Catalan Government. M.M. received a FPU doctoral fellowship AP2008-04334 from the Spanish Ministry of Education. T.G. group research was funded in part by a grant from the Spanish Ministry of Economy and Competitiveness (BIO2012-37161), a grant from the Qatar National Research Fund (Grant No. NPRP 5-298-3-086), and a grant from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC (Grant Agreement n. ERC-2012-StG-310325). R.G. and T.G. acknowledge support of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017,” SEV-2012-0208. V.N.G. group research was supported by the National Institutes of Health (NIH) GM061603.

Rhodnius prolixus not only has served as a model organism for the study of insect physiology, but also is a major vector of Chagas disease, an illness that affects approximately seven million people worldwide. We sequenced the genome of R. prolixus, generated assembled sequences covering 95% of the genome (∼702 Mb), including 15,456 putative protein-coding genes, and completed comprehensive genomic analyses of this obligate blood-feeding insect. Although immunedeficiency (IMD)-mediated immune responses were observed, R. prolixus putatively lacks key components of the IMD pathway, suggesting a reorganization of the canonical immune signaling network. Although both Toll and IMD effectors controlled intestinal microbiota, neither affected Trypanosoma cruzi, the causal agent of Chagas disease, implying the existence of evasion or tolerance mechanisms. R. prolixus has experienced an extensive loss of selenoprotein genes, with its repertoire reduced to only two proteins, one of which is a selenocysteine-based glutathione peroxidase, the first found in insects. The genome contained actively transcribed, horizontally transferred genes from Wolbachia sp., which showed evidence of codon use evolution toward the insect use pattern. Comparative protein analyses revealed many lineage-specific expansions and putative gene absences in R. prolixus, including tandem expansions of genes related to chemoreception, feeding, and digestion that possibly contributed to the evolution of a blood-feeding lifestyle. The genome assembly and these associated analyses provide critical information on the physiology and evolution of this important vector species and should be instrumental for the development of innovative disease control methods., La lista completa de autores que integran el documento puede consultarse en el archivo, Este documento tiene una corrección (ver documento relacionado)., Centro Regional de Estudios Genómicos, Instituto de Investigaciones Bioquímicas de La Plata

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 datasets into the second release of the database provides a valuable resource for addressing medical and evolutionary questions in selenium biology. This work was supported by the Plan Nacional and the Instituto Nacional de BIoinformatica (Spain)

Additional file 1: Figures. S1-S22, Table S1-S20, Methods and Results. Figure S1. Mitochondrial genome view of grape phylloxera. Figure S2. Proportion of transposable elements (TE) in the genome. Figure S3. GO terms of phylloxera-specific genes. Figure S4. Enriched GO terms in the phylloxera genome with and without TEs. Figure S5. Gene gain/loss at different nodes or branches. Figure S6. Species phylogenetic tree based on insect genomes and the transcriptomes of Planoccoccus citri and Adelges tsugae. Figure S7. Diagram of the gap-filling and annotation process. Figure S8. Urea cycle in D. vitifoliae and A. pisum. Figure S9. IMD immune pathway in D. vitifoliae.Figure S10. Phylogenetic tree of RR-1 cuticular proteins.Figure S11. Phylogenetic tree of RR-2 cuticular proteins.Figure S12. Comparison of miRNAs in D. vitifoliae and other insect genomes. Figure S13. Phylogenetic tree of aquaporin protein sequences. Figure S14. Comparison of the phylloxera PER protein with other insects. Figure S15. Amino acid alignment of PTTH amino acid sequences. Figure S16. Phylogeny of hemipteran ORs. Figure S17. Phylogeny of hemipteran GRs. Figure S18. Phylogenetic analysis of OBPs. Figure S19. Phylogenetic analysis of CSPs. Figure S20. Phylogenetic analysis of NPC2s. Figure S21. Distribution of cluster sizes of putative effectors. Figure S22. Physical distribution of the three largest clusters of effectors. Table S1. Genes of bacterial and fungal origin. Table S2. Statistics on TEs. Table S3. GO enrichment of genes duplicated at different ancestral nodes. Table S4. Metabolic gaps in the D. vitifoliae reaction network. Table S5. Functional annotation of metabolic genes. Table S6. Genes of the TOLL pathway. Table S7. Genes of the IMD pathway. Table S8. Statistics on cuticular proteins. Table S9. Developmental genes in D. vitifoliae and A. pisum. Table S10. miRNAs. Table S11. Clock-related genes. Table S12. List of ORs and GRs. Table S13. Number of OBPs, CSPs and NPC2s. Table S14. List of Cytochromes P450. Table S15. List of genes involved in detoxification. Table S16. Effector genes with predicted domains and their corresponding functions. Table S17. Statistics on sequence reads and SRA accessions used for the reference genome. Table S18. List of species used to study gene expansions. Table S19. Sampling sites and SRA used for population genomics analyses. Table S20. Prior distribution of parameters used for ABC modeling of invasion routes.

Additional file 1: Figures. S1-S22, Table S1-S20, Methods and Results. Figure S1. Mitochondrial genome view of grape phylloxera. Figure S2. Proportion of transposable elements (TE) in the genome. Figure S3. GO terms of phylloxera-specific genes. Figure S4. Enriched GO terms in the phylloxera genome with and without TEs. Figure S5. Gene gain/loss at different nodes or branches. Figure S6. Species phylogenetic tree based on insect genomes and the transcriptomes of Planoccoccus citri and Adelges tsugae. Figure S7. Diagram of the gap-filling and annotation process. Figure S8. Urea cycle in D. vitifoliae and A. pisum. Figure S9. IMD immune pathway in D. vitifoliae.Figure S10. Phylogenetic tree of RR-1 cuticular proteins.Figure S11. Phylogenetic tree of RR-2 cuticular proteins.Figure S12. Comparison of miRNAs in D. vitifoliae and other insect genomes. Figure S13. Phylogenetic tree of aquaporin protein sequences. Figure S14. Comparison of the phylloxera PER protein with other insects. Figure S15. Amino acid alignment of PTTH amino acid sequences. Figure S16. Phylogeny of hemipteran ORs. Figure S17. Phylogeny of hemipteran GRs. Figure S18. Phylogenetic analysis of OBPs. Figure S19. Phylogenetic analysis of CSPs. Figure S20. Phylogenetic analysis of NPC2s. Figure S21. Distribution of cluster sizes of putative effectors. Figure S22. Physical distribution of the three largest clusters of effectors. Table S1. Genes of bacterial and fungal origin. Table S2. Statistics on TEs. Table S3. GO enrichment of genes duplicated at different ancestral nodes. Table S4. Metabolic gaps in the D. vitifoliae reaction network. Table S5. Functional annotation of metabolic genes. Table S6. Genes of the TOLL pathway. Table S7. Genes of the IMD pathway. Table S8. Statistics on cuticular proteins. Table S9. Developmental genes in D. vitifoliae and A. pisum. Table S10. miRNAs. Table S11. Clock-related genes. Table S12. List of ORs and GRs. Table S13. Number of OBPs, CSPs and NPC2s. Table S14. List of Cytochromes P450. Table S15. List of genes involved in detoxification. Table S16. Effector genes with predicted domains and their corresponding functions. Table S17. Statistics on sequence reads and SRA accessions used for the reference genome. Table S18. List of species used to study gene expansions. Table S19. Sampling sites and SRA used for population genomics analyses. Table S20. Prior distribution of parameters used for ABC modeling of invasion routes.