The largest reservoir of mitochondrial introns is a relic of an ancestral split gene

In eukaryotes, introns are located in nuclear and organelle genes from several kingdoms (ref. 1-4). Large introns (0.1 to 5 kbp) are frequent in mitochondrial genomes of plant and fungi (ref. 1,5) but scarce in Metazoa, despite these organisms are grouped with fungi among Opisthokonts. Introns are classified in two main groups (I and II) according to their RNA secondary structure involved in the intron self-splicing mechanism (ref. 5,6). Most of the group I introns carry a "Homing Endonuclease Gene" (ref. 7-9) encoding a DNA endonuclease acting in the transfer and site specific integration "homing") and allowing the intron spreading and gain after lateral transfer even between species from different kingdoms (ref. 10,11). Opposite to this "late intron" paradigm, the "early intron" theory indicates that introns, which would have been abundant in the ancestral genes, would mainly evolve by loss (ref. 12,13).

Here we report the sequence of the cox1 gene of the button mushroom _Agaricus bisporus_, the most worldwide cultivated mushroom. This gene is both the longest mitochondrial gene (29,902 nt) and the largest Group I intron reservoir reported to date. An analysis of the group I introns available in _cox1_ genes shows that they are ancestral mobile genetic elements, whose frequent events of loss (according to the "late theory") and gain by lateral transfer ("early theory") must be combined to explain their wide and patchy distribution extending on several kingdoms. This allows the conciliation of the "early" and "late intron" paradigms, which are still matters of much debate (ref. 14,15). The overview of the intron distribution indicates that they evolve towards elimination. In such a landscape of eroded and lost intron sequences, the _A. bisporus_ largest intron reservoir, by its singular dynamics of intron keeping and catching, constitutes the most fitted relic of an early split gene

A new type of CP symmetry, family replication and fermion mass hierarchies

We study a two-Higgs-doublet model with four generalised CP symmetries in the scalar sector. Electroweak symmetry breaking leads automatically to spontaneous breaking of two of them. We require that these four CP symmetries can be extended from the scalar sector to the full Lagrangian and call this requirement the principle of maximal CP invariance. The Yukawa interactions of the fermions are severely restricted by this requirement. In particular, a single fermion family cannot be coupled to the Higgs fields. For two fermion families, however, this is possible. Enforcing the absence of flavour-changing neutral currents, we find degenerate masses in both families or one family massless and one massive. In the latter case the Lagrangian is highly symmetric, with the mass hierarchy being generated by electroweak symmetry breaking. Adding a third family uncoupled to the Higgs fields and thus keeping it massless we get a model which gives a rough approximation of some features of the fermions observed in Nature. We discuss a number of predictions of the model which may be checked in future experiments at the LHC.Comment: 24 pages. Version published in EPJC. Minor changes as suggested by the refere

Probing the charged Higgs boson at the LHC in the CP-violating type-II 2HDM

We present a phenomenological study of a CP-violating two-Higgs-doublet Model with type-II Yukawa couplings at the Large Hadron Collider (LHC). In the light of recent LHC data, we focus on the parameter space that survives the current and past experimental constraints as well as theoretical bounds on the model. Once the phenomenological scenario is set, we analyse the scope of the LHC in exploring this model through the discovery of a charged Higgs boson produced in association with a W boson, with the former decaying into the lightest neutral Higgs and a second W state, altogether yielding a b\bar b W^+W^- signature, of which we exploit the W^+W^- semileptonic decays.Comment: 37 pages, 16 figures; v2 updated treatment of LHC constraint

A Prospective Cohort of SARS-CoV-2-Infected Health Care Workers: Clinical Characteristics, Outcomes, and Follow-up Strategy

Background. During the coronavirus disease 2019 (COVID-19) outbreaks, health care workers (HCWs) are at a high risk of infection. Strategies to reduce in-hospital transmission between HCWs and to safely manage infected HCWs are lacking. Our aim was to describe an active strategy for the management of COVID-19 in severe acute respiratory syndrome coronavirus 2 (SARSCoV-2)-infected HCWs and investigate its outcomes. Methods. A prospective cohort study of SARS-CoV-2-infected health care workers in a tertiary teaching hospital in Barcelona, Spain, was performed. An active strategy of weekly polymerase chain reaction screening of HCWs for SARS-CoV-2 was established by the Occupational Health department. Every positive HCW was admitted to the Hospital at Home Unit with daily assessment online and in-person discretionary visits. Clinical and epidemiological data were recorded. Results. Of the 590 HCWs included in the cohort, 134 (22%) were asymptomatic at diagnosis, and 15% (89 patients) remained asymptomatic during follow-up. A third of positive cases were detected during routine screening. The most frequent symptoms were cough (68%), hyposmia/anosmia (49%), and fever (41%). Ten percent of the patients required specific treatment at home, while only 4% of the patients developed pneumonia. Seventeen patients required a visit to the outpatient clinic for further evaluation, and 6 of these (1%) required hospital admission. None of the HCWs included in this cohort required intensive care unit admission or died. Conclusions. Active screening for SARS-CoV-2 among HCWs for early diagnosis and stopping in-hospital transmission chains proved efficacious in our institution, particularly due to the high percentage of asymptomatic HCWs. Follow-up of HCWs in Hospital at Home units is safe and effective, with low rates of severe infection and readmission. Keywords. coronavirus; COVID-19; health care workers; Hospital at Home; SARS-CoV-2

Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high-B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Contains fulltext : 158967.pdf (publisher's version ) (Open Access)Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine

Genome-wide meta-analysis of common variant differences between men and women

The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10−8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased trait

Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population