The effects of pathogenic and likely pathogenic variants for inherited hemostasis disorders in 140 214 UK Biobank participants.

Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it is imperative to estimate the effect of each independent variant and improve their pathogenicity classification. Our study of 140 214 unrelated UK Biobank (UKB) participants found that each of them carries a median of 7 variants previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade gene (DGG) variants for rare bleeding, thrombotic, and platelet disorders (BTPDs) observed in 12 367 UKB participants. By association analysis, for a subset of these variants, we estimated effect sizes for platelet count and volume, and odds ratios for bleeding and thrombosis. Variants causal of some autosomal recessive platelet disorders revealed phenotypic consequences in carriers. Loss-of-function variants in MPL, which cause chronic amegakaryocytic thrombocytopenia if biallelic, were unexpectedly associated with increased platelet counts in carriers. We also demonstrated that common variants identified by genome-wide association studies (GWAS) for platelet count or thrombosis risk may influence the penetrance of rare variants in BTPD DGGs on their associated hemostasis disorders. Network-propagation analysis applied to an interactome of 18 410 nodes and 571 917 edges showed that GWAS variants with large effect sizes are enriched in DGGs and their first-order interactors. Finally, we illustrate the modifying effect of polygenic scores for platelet count and thrombosis risk on disease severity in participants carrying rare variants in TUBB1 or PROC and PROS1, respectively. Our findings demonstrate the power of association analyses using large population datasets in improving pathogenicity classifications of rare variants.

The VGNC: expanding standardized vertebrate gene nomenclature.

The Vertebrate Gene Nomenclature Committee (VGNC) was established in 2016 as a sister project to the HUGO Gene Nomenclature Committee, to approve gene nomenclature in vertebrate species without an existing dedicated nomenclature committee. The VGNC aims to harmonize gene nomenclature across selected vertebrate species in line with human gene nomenclature, with orthologs assigned the same nomenclature where possible. This article presents an overview of the VGNC project and discussion of key findings resulting from this work to date. VGNC-approved nomenclature is accessible at https://vertebrate.genenames.org and is additionally displayed by the NCBI, Ensembl, and UniProt databases.

Genenames.org: the HGNC resources in 2023.

The HUGO Gene Nomenclature Committee (HGNC) assigns unique symbols and names to human genes. The HGNC database (www.genenames.org) currently contains over 43 000 approved gene symbols, over 19 200 of which are assigned to protein-coding genes, 14 000 to pseudogenes and nearly 9000 to non-coding RNA genes. The public website, www.genenames.org, displays all approved nomenclature within Symbol Reports that contain data curated by HGNC nomenclature advisors and links to related genomic, clinical, and proteomic information. Here, we describe updates to our resource, including improvements to our search facility and new download features.

A standardised nomenclature for long non-coding RNAs.

The HUGO Gene Nomenclature Committee (HGNC) is the sole group with the authority to approve symbols for human genes, including long non-coding RNA (lncRNA) genes. Use of approved symbols ensures that publications and biomedical databases are easily searchable and reduces the risks of confusion that can be caused by using the same symbol to refer to different genes or using many different symbols for the same gene. Here, we describe how the HGNC names lncRNA genes and review the nomenclature of the seven lncRNA genes most mentioned in the scientific literature.

The bridge-like lipid transfer protein (BLTP) gene group: introducing new nomenclature based on structural homology indicating shared function.

The HUGO Gene Nomenclature Committee assigns unique symbols and names to human genes. The use of approved nomenclature enables effective communication between researchers, and there are multiple examples of how the usage of unapproved alias symbols can lead to confusion. We discuss here a recent nomenclature update (May 2022) for a set of genes that encode proteins with a shared repeating ß-groove domain. Some of the proteins encoded by genes in this group have already been shown to function as lipid transporters. By working with researchers in the field, we have been able to introduce a new root symbol (BLTP, which stands for "bridge-like lipid transfer protein") for this domain-based gene group. This new nomenclature not only reflects the shared domain in these proteins, but also takes into consideration the mounting evidence of a shared lipid transport function.

The importance of being the HGNC.

The HUGO Gene Nomenclature Committee (HGNC) has been providing standardized symbols and names for human genes since the late 1970s. As funding agencies change their priorities, finding financial support for critical biomedical resources such as the HGNC becomes ever more challenging. In this article, we outline the key roles the HGNC currently plays in aiding communication and the need for these activities to be maintained.

Placing human gene families into their evolutionary context.

Following the draft sequence of the first human genome over 20 years ago, we have achieved unprecedented insights into the rules governing its evolution, often with direct translational relevance to specific diseases. However, staggering sequence complexity has also challenged the development of a more comprehensive understanding of human genome biology. In this context, interspecific genomic studies between humans and other animals have played a critical role in our efforts to decode human gene families. In this review, we focus on how the rapid surge of genome sequencing of both model and non-model organisms now provides a broader comparative framework poised to empower novel discoveries. We begin with a general overview of how comparative approaches are essential for understanding gene family evolution in the human genome, followed by a discussion of analyses of gene expression. We show how homology can provide insights into the genes and gene families associated with immune response, cancer biology, vision, chemosensation, and metabolism, by revealing similarity in processes among distant species. We then explain methodological tools that provide critical advances and show the limitations of common approaches. We conclude with a discussion of how these investigations position us to gain fundamental insights into the evolution of gene families among living organisms in general. We hope that our review catalyzes additional excitement and research on the emerging field of comparative genomics, while aiding the placement of the human genome into its existentially evolutionary context.

A standardized nomenclature for mammalian histone genes.

Histones have a long history of research in a wide range of species, leaving a legacy of complex nomenclature in the literature. Community-led discussions at the EMBO Workshop on Histone Variants in 2011 resulted in agreement amongst experts on a revised systematic protein nomenclature for histones, which is based on a combination of phylogenetic classification and historical symbol usage. Human and mouse histone gene symbols previously followed a genome-centric system that was not applicable across all vertebrate species and did not reflect the systematic histone protein nomenclature. This prompted a collaboration between histone experts, the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC) and Mouse Genomic Nomenclature Committee (MGNC) to revise human and mouse histone gene nomenclature aiming, where possible, to follow the new protein nomenclature whilst conforming to the guidelines for vertebrate gene naming. The updated nomenclature has also been applied to orthologous histone genes in chimpanzee, rhesus macaque, dog, cat, pig, horse and cattle, and can serve as a framework for naming other vertebrate histone genes in the future.

Comment on Herring et al. The Use of "Retardation" in FRAXA, FMRP, FMR1 and Other Designations. Cells 2022, 11, 1044.

This commentary is written in response to the recent article from Herring et al., discussing the eradication of the offensive term "retardation" from gene nomenclature. We discuss the work of the HUGO (Human Genome Organisation) Gene Nomenclature Committee (HGNC) and outline the steps already taken to remove this term from our gene names. We also highlight the latest nomenclature changes made as a result of discussions with the authors and agreement with the European Fragile X Network.

The Quest for Orthologs orthology benchmark service in 2022.

The Orthology Benchmark Service (https://orthology.benchmarkservice.org) is the gold standard for orthology inference evaluation, supported and maintained by the Quest for Orthologs consortium. It is an essential resource to compare existing and new methods of orthology inference (the bedrock for many comparative genomics and phylogenetic analysis) over a standard dataset and through common procedures. The Quest for Orthologs Consortium is dedicated to maintaining the resource up to date, through regular updates of the Reference Proteomes and increasingly accessible data through the OpenEBench platform. For this update, we have added a new benchmark based on curated orthology assertion from the Vertebrate Gene Nomenclature Committee, and provided an example meta-analysis of the public predictions present on the platform.

The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources.

PURPOSE: Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed. METHODS: The GenCC drafted harmonized definitions for differing levels of gene-disease validity on the basis of existing resources, and performed a modified Delphi survey with 3 rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members. RESULTS: On the basis of 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contained 15,241 gene-disease assertions on 4569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%. CONCLUSION: Terminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.

LY6S, a New IFN-Inducible Human Member of the Ly6a Subfamily Expressed by Spleen Cells and Associated with Inflammation and Viral Resistance.

Syntenic genomic loci on human chromosome 8 and mouse chromosome 15 (mChr15) code for LY6/Ly6 (lymphocyte Ag 6) family proteins. The 23 murine Ly6 family genes include eight genes that are flanked by the murine Ly6e and Ly6l genes and form an Ly6 subgroup referred to in this article as the Ly6a subfamily gene cluster. Ly6a, also known as Stem Cell Ag-1 and T cell-activating protein, is a member of the Ly6a subfamily gene cluster. No LY6 genes have been annotated within the syntenic LY6E to LY6L human locus. We report in this article on LY6S, a solitary human LY6 gene that is syntenic with the murine Ly6a subfamily gene cluster, and with which it shares a common ancestry. LY6S codes for the IFN-inducible GPI-linked LY6S-iso1 protein that contains only 9 of the 10 consensus LY6 cysteine residues and is most highly expressed in a nonclassical spleen cell population. Its expression leads to distinct shifts in patterns of gene expression, particularly of genes coding for inflammatory and immune response proteins, and LY6S-iso1-expressing cells show increased resistance to viral infection. Our findings reveal the presence of a previously unannotated human IFN-stimulated gene, LY6S, which has a 1:8 ortholog relationship with the genes of the Ly6a subfamily gene cluster, is most highly expressed in spleen cells of a nonclassical cell lineage, and whose expression induces viral resistance and is associated with an inflammatory phenotype and with the activation of genes that regulate immune responses.

Consensus nomenclature for dyneins and associated assembly factors.

Dyneins are highly complex, multicomponent, microtubule-based molecular motors. These enzymes are responsible for numerous motile behaviors in cytoplasm, mediate retrograde intraflagellar transport (IFT), and power ciliary and flagellar motility. Variants in multiple genes encoding dyneins, outer dynein arm (ODA) docking complex subunits, and cytoplasmic factors involved in axonemal dynein preassembly (DNAAFs) are associated with human ciliopathies and are of clinical interest. Therefore, clear communication within this field is particularly important. Standardizing gene nomenclature, and basing it on orthology where possible, facilitates discussion and genetic comparison across species. Here, we discuss how the human gene nomenclature for dyneins, ODA docking complex subunits, and DNAAFs has been updated to be more functionally informative and consistent with that of the unicellular green alga Chlamydomonas reinhardtii, a key model organism for studying dyneins and ciliary function. We also detail additional nomenclature updates for vertebrate-specific genes that encode dynein chains and other proteins involved in dynein complex assembly.

Update of the keratin gene family: evolution, tissue-specific expression patterns, and relevance to clinical disorders.

Intermediate filament (IntFil) genes arose during early metazoan evolution, to provide mechanical support for plasma membranes contacting/interacting with other cells and the extracellular matrix. Keratin genes comprise the largest subset of IntFil genes. Whereas the first keratin gene appeared in sponge, and three genes in arthropods, more rapid increases in keratin genes occurred in lungfish and amphibian genomes, concomitant with land animal-sea animal divergence (~ 440 to 410 million years ago). Human, mouse and zebrafish genomes contain 18, 17 and 24 non-keratin IntFil genes, respectively. Human has 27 of 28 type I "acidic" keratin genes clustered at chromosome (Chr) 17q21.2, and all 26 type II "basic" keratin genes clustered at Chr 12q13.13. Mouse has 27 of 28 type I keratin genes clustered on Chr 11, and all 26 type II clustered on Chr 15. Zebrafish has 18 type I keratin genes scattered on five chromosomes, and 3 type II keratin genes on two chromosomes. Types I and II keratin clusters-reflecting evolutionary blooms of keratin genes along one chromosomal segment-are found in all land animal genomes examined, but not fishes; such rapid gene expansions likely reflect sudden requirements for many novel paralogous proteins having divergent functions to enhance species survival following sea-to-land transition. Using data from the Genotype-Tissue Expression (GTEx) project, tissue-specific keratin expression throughout the human body was reconstructed. Clustering of gene expression patterns revealed similarities in tissue-specific expression patterns for previously described "keratin pairs" (i.e., KRT1/KRT10, KRT8/KRT18, KRT5/KRT14, KRT6/KRT16 and KRT6/KRT17 proteins). The ClinVar database currently lists 26 human disease-causing variants within the various domains of keratin proteins.

HUGO Gene Nomenclature Committee (HGNC) recommendations for the designation of gene fusions.

Gene fusions have been discussed in the scientific literature since they were first detected in cancer cells in the early 1980s. There is currently no standardized way to denote the genes involved in fusions, but in the majority of publications the gene symbols in question are listed either separated by a hyphen (-) or by a forward slash (/). Both types of designation suffer from important shortcomings. HGNC has worked with the scientific community to determine a new, instantly recognizable and unique separator-a double colon (::)-to be used in the description of fusion genes, and advocates its usage in all databases and articles describing gene fusions.

The risks of using unapproved gene symbols.

The use of approved nomenclature in publications is vital to enable effective scientific communication and is particularly crucial when discussing genes of clinical relevance. Here, we discuss several examples of cases where the failure of researchers to use a HUGO Gene Nomenclature Committee (HGNC)-approved symbol in publications has led to confusion between unrelated human genes in the literature. We also inform authors of the steps they can take to ensure that they use approved nomenclature in their manuscripts and discuss how referencing HGNC IDs can remove ambiguity when referring to genes that have previously been published with confusing alias symbols.

Updates to HCOP: the HGNC comparison of orthology predictions tool.

Multiple resources currently exist that predict orthologous relationships between genes. These resources differ both in the methodologies used and in the species they make predictions for. The HGNC Comparison of Orthology Predictions (HCOP) search tool integrates and displays data from multiple ortholog prediction resources for a specified human gene or set of genes. An indication of the reliability of a prediction is provided by the number of resources that support it. HCOP was originally designed to show orthology predictions between human and mouse but has been expanded to include data from a current total of 20 selected vertebrate and model organism species. The HCOP pipeline used to fetch and integrate the information from the disparate ortholog and nomenclature data resources has recently been rewritten, both to enable the inclusion of new data and to take advantage of modern web technologies. Data from HCOP are used extensively in our work naming genes as the Vertebrate Gene Nomenclature Committee (https://vertebrate.genenames.org).