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A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

A database of microbial signatures is used for systematic comparison of differential abundance patterns.

STAAR is a powerful rare variant association test that incorporates variant functional categories and complementary functional annotations using a dynamic weighting scheme based on annotation principal components. STAAR accounts for population structure and relatedness and is scalable for analyzing large whole-genome sequencing studies.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

Extracellular matrices are viscoelastic, yet how matrix viscoelasticity regulates the epigenome remains unclear. Here, the authors show that cells cultured on viscoelastic matrices exhibit changes in the nucleoskeleton and in chromatin that enhance cell reprogramming.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

Neural networks fundamentally dictate function. Here, the authors show thirteen uniquely connected neuron populations within the anterior thalamic nuclei, suggesting multiple parallel subnetworks support its emotional and cognitive functions.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1Rsignificantly associated with these traits.

Complete sequences of chromosomes telomere-to-telomere from chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang provide a comprehensive and valuable resource for future evolutionary comparisons.

Eye2Gene’s next-generation phenotyping of multimodal images increases diagnostic yield for inherited retinal diseases by improving screening, phenotype-driven variant prioritization and automatic similarity matching in phenotypic space to drive gene discovery.

The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.

Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes. Fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.

In CHIP, somatic mutations in a hematopoietic stem cell lead to a clonal subpopulation of blood cells. Here, the authors perform a CHIP meta-EWAS to establish its epigenetic features and age-related outcomes.

A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk.

As immune checkpoint therapy is more frequently used for cancer, side effects such as Stevens-Johson syndrome / toxic epidermal necrolysis (SJS/TEN) are becoming more common. Here the authors use single cell transcriptomics to implicate TNF and CXCL10 in recruitment of CXCR3⁺ cytotoxic T cell in SJS/TEN skin lesions.

A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.

Responses to immune checkpoint inhibitors in patients with pancreatic ductal adenocarcinoma (PDA) remain low and alternative combinatorial approaches are warranted. Here the authors report the results of a phase 2 clinical trial of entinostat (histone deacetylases inhibitor) and nivolumab (anti-PD-1 inhibitor) in patients with metastatic PDA.

It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk

Using a mutant version of E. coli alkaline phosphatase, we succeeded in trapping and determining the structure of the phospho-enzyme intermediate. The X-ray structure also revealed the catalytic water molecule, bound to one of the active site zinc ions, positioned ideally for the apical attack necessary for the hydrolysis of the intermediate.

Targeting resistant stem cells in leukaemia, Perry et al. show that doxorubicin at low doses decreases Akt-mediated β-catenin activity, downregulates expression of multiple immune-checkpoint genes and dampens tumorigenesis of leukaemia stem cells.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

MetaSTAAR enables functionally informed rare variant association analysis in biobank-scale cohorts using an efficient, sparse matrix approach for summary statistic storage.

Molecular ferroelectrics contain stimuli-responsive structure and ionic building blocks, promising for ionically tailored multifunctionality. Here, the authors report molecular ionic ferroelectrics exhibiting the coexistence of room-temperature ionic conductivity and ferroelectricity.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Systematic analysis from the Global Burden of Disease study reported that, despite global improvements from 1990 to 2021, dietary iron deficiency-associated disease burden remains high in women, children and residents in low socio-demographic index countries.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Trees come in all shapes and size, but what drives this incredible variation in tree form remains poorly understood. Using a global dataset, the authors show that a combination of climate, competition, disturbance and evolutionary history shape the crown architecture of the world’s trees and thereby constrain the 3D structure of woody ecosystems.

Cancer metabolism adapts the metabolic network of its cell of origin. Mahendralingam et al. find that lineage-rooted metabolic identities of normal mammary cells reflect breast cancer subtype metabolism.

The extracellular matrix (ECM) is critical for animal development and intricately patterned at multiple scales. Here Adams and Pooranachithra et al. show how specific collagens are precisely localized to struts, highly patterned sub-micron structures in the nematode cuticle ECM.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

A transancestral exome-wide association study for body-fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.

Omicron BA.1 is attenuated in infection models though the precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging. Here the authors present pGLUE, a plasmid-based viral genome assembly and rescue strategy, to systematically characterize Omicron mutations and show that Omicron NSP6 has weakened lipid flow to replication organelles and reduced viral RNA replication.

Mouse models of severe congenital neutropenia using patient-derived mutations in the GFI1 locus are used to determine the mechanisms by which the disease progresses.

Type-2 innate lymphoid cells (ILC2) affect adipose tissue metabolism and function. Here the authors show that the ILC2 are present in para-aortic adipose tissue and represent a major source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

The catalytic subunit of DNA-PK autophosphorylates and contributes to ribosome biogenesis and haematopoiesis by binding to the U3 small nucleolar RNA.

Boyd et al. monitored the effects of patient-derived acute myeloid leukaemia (AML) cells on human HSPCs in vivo and found that AML impairs bone marrow adipocyte differentiation, and this in turn impedes healthy endogenous haematopoiesis.

Group 1 and 3 innate lymphoid cells can be functionally plastic. Humbles and colleagues find that group 2 innate lymphoid cells in the lungs also exhibit phenotypic plasticity after exposure to infectious or noxious agents.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.