Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Dynamic NMDAR-mediated properties of place cells during the object place memory task

N-methyl-D-aspartate receptors (NMDAR) in the hippocampus participate in encoding and recalling the location of objects in the environment, but the ensemble mechanisms by which NMDARs mediate these processes have not been completely elucidated. To address this issue, we examined the firing patterns of place cells in the dorsal CA1 area of the hippocampus of mice (n = 7) that performed an object place memory (OPM) task, consisting of familiarization (T1), sample (T2) and choice (T3) trials, after systemic injection of 3-((±)2-carboxypiperazin-4yl)propyl-1-phosphate (CPP), a specific NMDAR antagonist. Place cell properties under CPP (CPP–PCs) were compared to those after control saline injection (SAL–PCs) in the same mice. We analyzed place cells across the OPM task to determine whether they signaled the introduction or movement of objects by NMDAR-mediated changes of their spatial coding. On T2, when two objects were first introduced to a familiar chamber, CPP–PCs and SAL–PCs showed stable, vanishing or moving place fields in addition to changes in spatial information (SI). These metrics were comparable between groups. Remarkably, previously inactive CPP–PCs (with place fields emerging de novo on T2) had significantly weaker SI increases than SAL–PCs. On T3, when one object was moved, CPP–PCs showed reduced center-of-mass (COM) shift of their place fields. Indeed, a subset of SAL–PCs with large COM shifts (>7 cm) was largely absent in the CPP condition. Notably, for SAL–PCs that exhibited COM shifts, those initially close to the moving object followed the trajectory of the object, whereas those far from the object did the opposite. Our results strongly suggest that the SI changes and COM shifts of place fields that occur during the OPM task reflect key dynamic properties that are mediated by NMDARs and might be responsible for binding object identity with location

Gearing up to handle the mosaic nature of life in the quest for orthologs

The Quest for Orthologs (QfO) is an open collaboration framework for experts in comparative phylogenomics and related research areas who have an interest in highly accurate orthology predictions and their applications. We here report highlights and discussion points from the QfO meeting 2015 held in Barcelona. Achievements in recent years have established a basis to support developments for improved orthology prediction and to explore new approaches. Central to the QfO effort is proper benchmarking of methods and services, as well as design of standardized datasets and standardized formats to allow sharing and comparison of results. Simultaneously, analysis pipelines have been improved, evaluated, and adapted to handle large datasets. All this would not have occurred without the long-term collaboration of Consortium members. Meeting regularly to review and coordinate complementary activities from a broad spectrum of innovative researchers clearly benefits the community. Highlights of the meeting include addressing sources of and legitimacy of disagreements between orthology calls, the context dependency of orthology definitions, special challenges encountered when analyzing very anciently rooted orthologies, orthology in the light of whole-genome duplications, and the concept of orthologous versus paralogous relationships at different levels, including domain-level orthology. Furthermore, particular needs for different applications (e.g. plant genomics, ancient gene families, and others) and the infrastructure for making orthology inferences available (e.g. interfaces with model organism databases) were discussed, with several ongoing efforts that are expected to be reported on during the upcoming 2017 QfO meeting.This work was supported by Spanish Ministry of Economy and Competitiveness grant BIO2012-37161 (to T.G.), Qatar National Research Fund NPRP 5-298-3-086 (to T.G.), European Research Council grant ERC-2012-StG-310325 (to T.G.), National Institutes of Health (NIH) grant R24 OD011883 (to S.E.L.), U41 HG002273 (to S.E.L. and P.D.T.), Swiss National Science Foundation grant PP00P3_150654 (to C.D.), UK Biotechnology and Biological Sciences Research Council grant BB/M015009/1 (to C.D.), Swiss State Secretariat for Education, Research and Innovation (SERI) funding (to B.B. and C.D.). M.M. and M.P. acknowledge support from the Wellcome Trust (grant number WT108749/Z/15/Z) and the European Molecular Biology Laboratory. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 222664 (Quantomics)

Gearing up to handle the mosaic nature of life in the quest for orthologs

Abstract Summary: The Quest for Orthologs (QfO) is an open collaboration framework for experts in comparative phylogenomics and related research areas who have an interest in highly accurate orthology predictions and their applications. We here report highlights and discussion points from the QfO meeting 2015 held in Barcelona. Achievements in recent years have established a basis to support developments for improved orthology prediction and to explore new approaches. Central to the QfO effort is proper benchmarking of methods and services, as well as design of standardized datasets and standardized formats to allow sharing and comparison of results. Simultaneously, analysis pipelines have been improved, evaluated and adapted to handle large datasets. All this would not have occurred without the long-term collaboration of Consortium members. Meeting regularly to review and coordinate complementary activities from a broad spectrum of innovative researchers clearly benefits the community. Highlights of the meeting include addressing sources of and legitimacy of disagreements between orthology calls, the context dependency of orthology definitions, special challenges encountered when analyzing very anciently rooted orthologies, orthology in the light of whole-genome duplications, and the concept of orthologous versus paralogous relationships at different levels, including domain-level orthology. Furthermore, particular needs for different applications (e.g. plant genomics, ancient gene families and others) and the infrastructure for making orthology inferences available (e.g. interfaces with model organism databases) were discussed, with several ongoing efforts that are expected to be reported on during the upcoming 2017 QfO meeting