Phenotypic effects of genetic variants associated with autism

While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants

Systematic detection of brain protein-coding genes under positive selection during primate evolution and their roles in cognition

International audienceThe human brain differs from that of other primates, but the genetic basis of these differences remains unclear. We investigated the evolutionary pressures acting on almost all human protein-coding genes (N = 11,667; 1:1 orthologs in primates) based on their divergence from those of early hominins, such as Neanderthals, and non-human primates. We confirm that genes encoding brain-related proteins are among the most strongly conserved protein-coding genes in the human genome. Combining our evolutionary pressure metrics for the protein-coding genome with recent data sets, we found that this conservation applied to genes functionally associated with the synapse and expressed in brain structures such as the prefrontal cortex and the cerebellum. Conversely, several genes presenting signatures commonly associated with positive selection appear as causing brain diseases or conditions, such as micro/macrocephaly, Joubert syndrome, dyslexia, and autism. Among those, a number of DNA damage response genes associated with microcephaly in humans such as BRCA1, NHEJ1, TOP3A, and RNF168 show strong signs of positive selection and might have played a role in human brain size expansion during primate evolution. We also showed that cerebellum granule neurons express a set of genes also presenting signatures of positive selection and that may have contributed to the emergence of fine motor skills and social cognition in humans. This resource is available online and can be used to estimate evolutionary constraints acting on a set of genes and to explore their relative contributions to human traits

Web development, expertise of the Web INTEgRation group in the Bioinformatic and Biostatistics Hub

International audienceThe expertise group named WINTER, for Web INTEgRation, is a software development team whose aim is to build websites and apps using Web technologies. Like all members of Bioinformatics and Biostatistics Hub, the team provides support to Institut Pasteur’s research units and platforms for publishing and sharing analysis, data, scientific tools, and workflows. Several competences and informatic languages are necessary to create a complete user-friendly web tool. The web development process follows some essential steps: - Design and create the interface model considering user experience (UX) and user interface (UI) aspects, according to user needs. - Develop the front-end, which is the visible part of the website, involving the implementation of the interface code from the previously designed model, - Develop the back-end, the hidden part of website, to carry out actions enabled by the interface, and to store and manage the data in database. - Maintain and deploy the website through continuous integration and continuous delivery/deployment as well as versioning. The Winter Team consists of several members who are experts in web development. We provide our expertise to the scientists on campus, covering a broad range of services to design, develop, deploy, maintain web interface and databases creating fully functional dedicated tools for scientific topics. Depending on the project’s needs and size, Winter team members can work alone as full-stack DevOps members or contribute specifically to a stage as domain experts (such as UX/UI Designer, Front-end Developer or Back-end Developer), in close collaboration with the other team members. Thanks to projects covering a wide variety of scientific topics such as Structural Bioinformatics, Transcriptomics, Statistical Genetics, Antibiotic Resistance, Phylogeny, and Oncology, we collaborate with several research units and teams on campus, as well as other groups within the Hub, with the support of the IT department. Over the past years, the team has created more than 15 web applications and databases and has participated in various projects, including: - ABSD - AMR Spread - Bioflow-Insight - DefenseFinder - InDeep-net - JASS Additionally, our group is involved in external collaborations with national bioinformatic partners such as the “French Institute of Bioinformatics” (e.g. participation and leadership in WP6 of ABRomics project) and European partners (e.g development of oncodash software in DECIDER project) We oversee the Galaxy server of the Institut Pasteur, an integration platform to publish and use bioinformatics tools and workflows in a web interface

Operative list of genes associated with autism and neurodevelopmental disorders based on database review

International audienceThe genetics of neurodevelopmental disorders (NDD) has made tremendous progress during the last few decades with the identification of more than 1,500 genes associated with conditions such as intellectual disability and autism. The functional roles of these genes are currently studied to uncover the biological mechanisms influencing the clinical outcome of the mutation carriers. To integrate the data, several databases and curated gene lists have been generated. Here, we provide an overview of the main databases focusing on the genetics of NDD, that are widely used by the medical and scientific communities, and extract a list of high confidence NDD genes (HC-NDD). This gene set can be used as a first filter for interpreting large scale omics dataset or for diagnostic purposes. Overall HC-NDD genes (N = 1,586) are expressed at very early stages of fetal brain development and enriched in several biological pathways such as chromosome organization, cell cycle, metabolism and synaptic function. Among those HC-NDD genes, 204 (12,9%) are listed in the synaptic gene ontology SynGO and are enriched in genes expressed after birth in the cerebellum and the cortex of the human brain. Finally, we point at several limitations regarding the relatively poor standardized information available, especially on the carriers of the mutations. Progress on the phenotypic characterization and genetic profiling of the carriers will be crucial to improve our knowledge on the biological mechanisms and on risk and protective factors for NDD

Web development, expertise of the Web INTEgRation group in the Bioinformatic and Biostatistics Hub

International audienceThe expertise group named WINTER, for Web INTEgRation, is a software development team whose aim is to build websites and apps using Web technologies. Like all members of Bioinformatics and Biostatistics Hub, the team provides support to Institut Pasteur’s research units and platforms for publishing and sharing analysis, data, scientific tools, and workflows. Several competences and informatic languages are necessary to create a complete user-friendly web tool. The web development process follows some essential steps: - Design and create the interface model considering user experience (UX) and user interface (UI) aspects, according to user needs. - Develop the front-end, which is the visible part of the website, involving the implementation of the interface code from the previously designed model, - Develop the back-end, the hidden part of website, to carry out actions enabled by the interface, and to store and manage the data in database. - Maintain and deploy the website through continuous integration and continuous delivery/deployment as well as versioning. The Winter Team consists of several members who are experts in web development. We provide our expertise to the scientists on campus, covering a broad range of services to design, develop, deploy, maintain web interface and databases creating fully functional dedicated tools for scientific topics. Depending on the project’s needs and size, Winter team members can work alone as full-stack DevOps members or contribute specifically to a stage as domain experts (such as UX/UI Designer, Front-end Developer or Back-end Developer), in close collaboration with the other team members. Thanks to projects covering a wide variety of scientific topics such as Structural Bioinformatics, Transcriptomics, Statistical Genetics, Antibiotic Resistance, Phylogeny, and Oncology, we collaborate with several research units and teams on campus, as well as other groups within the Hub, with the support of the IT department. Over the past years, the team has created more than 15 web applications and databases and has participated in various projects, including: - ABSD - AMR Spread - Bioflow-Insight - DefenseFinder - InDeep-net - JASS Additionally, our group is involved in external collaborations with national bioinformatic partners such as the “French Institute of Bioinformatics” (e.g. participation and leadership in WP6 of ABRomics project) and European partners (e.g development of oncodash software in DECIDER project) We oversee the Galaxy server of the Institut Pasteur, an integration platform to publish and use bioinformatics tools and workflows in a web interface

Web development, expertise of the Web INTEgRation group in the Bioinformatic and Biostatistics Hub

International audienceThe expertise group named WINTER, for Web INTEgRation, is a software development team whose aim is to build websites and apps using Web technologies. Like all members of Bioinformatics and Biostatistics Hub, the team provides support to Institut Pasteur’s research units and platforms for publishing and sharing analysis, data, scientific tools, and workflows. Several competences and informatic languages are necessary to create a complete user-friendly web tool. The web development process follows some essential steps: - Design and create the interface model considering user experience (UX) and user interface (UI) aspects, according to user needs. - Develop the front-end, which is the visible part of the website, involving the implementation of the interface code from the previously designed model, - Develop the back-end, the hidden part of website, to carry out actions enabled by the interface, and to store and manage the data in database. - Maintain and deploy the website through continuous integration and continuous delivery/deployment as well as versioning. The Winter Team consists of several members who are experts in web development. We provide our expertise to the scientists on campus, covering a broad range of services to design, develop, deploy, maintain web interface and databases creating fully functional dedicated tools for scientific topics. Depending on the project’s needs and size, Winter team members can work alone as full-stack DevOps members or contribute specifically to a stage as domain experts (such as UX/UI Designer, Front-end Developer or Back-end Developer), in close collaboration with the other team members. Thanks to projects covering a wide variety of scientific topics such as Structural Bioinformatics, Transcriptomics, Statistical Genetics, Antibiotic Resistance, Phylogeny, and Oncology, we collaborate with several research units and teams on campus, as well as other groups within the Hub, with the support of the IT department. Over the past years, the team has created more than 15 web applications and databases and has participated in various projects, including: - ABSD - AMR Spread - Bioflow-Insight - DefenseFinder - InDeep-net - JASS Additionally, our group is involved in external collaborations with national bioinformatic partners such as the “French Institute of Bioinformatics” (e.g. participation and leadership in WP6 of ABRomics project) and European partners (e.g development of oncodash software in DECIDER project) We oversee the Galaxy server of the Institut Pasteur, an integration platform to publish and use bioinformatics tools and workflows in a web interface

Flat band and Lifshitz transition in long-range-ordered supergraphene obtained by Erbium intercalation

International audienceWe report the observation of graphene doped up to the Lifshitz transition obtained solely by the intercalation of Erbium atoms. ARPES measurements show that a wide flat band is generated around the M point of the Brillouin zone. We propose that this is the effect of an induced spin-orbit coupling. Scanning Tunneling Microscopy (STM) experiments reveal a longrange ordered hexagonal superstructure: we argue that this reflects the ordering of the intercalated Er atoms acting as impurities. This system provides a playground to study the interaction between a magnetic order and a divergent density of states at the Fermi level

Phenotypic effects of genetic variants associated with autism.

Funder: Institut Pasteur; doi: https://doi.org/10.13039/501100003762Funder: Fondation Bettencourt Schueller (Bettencourt Schueller Foundation); doi: https://doi.org/10.13039/501100007492Funder: Aarhus Universitet (Aarhus University); doi: https://doi.org/10.13039/100007605Funder: Københavns Universitet (University of Copenhagen); doi: https://doi.org/10.13039/501100001734Funder: Autism Speaks (Autism Speaks Inc.); doi: https://doi.org/10.13039/100000073Funder: European Federation of Pharmaceutical Industries and Associations (EFPIA); doi: https://doi.org/10.13039/100013322Funder: Autistica; doi: https://doi.org/10.13039/100011706Funder: Templeton World Charity Foundation (Templeton World Charity Foundation, Inc.); doi: https://doi.org/10.13039/501100011730Funder: RCUK | MRC | Medical Research Foundation; doi: https://doi.org/10.13039/501100009187Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272Funder: Université Paris Diderot (Paris Diderot); doi: https://doi.org/10.13039/501100005736Funder: This work was funded by the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Eranet-Neuron (ALTRUISM), and the GenMed Labex.While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants