Volume 55 Issue 3, March 2023

Current risk assessment and treatment strategies for venous thromboembolism (VTE) consider genetic factors only in a limited way. New work shows a more pervasive role of common variants in VTE risk, inspiring genetic predictors that surpass and complement individual clinical risk factors and monogenic thrombophilia testing.

Multi-omic profiling of lesions at autopsy reveals a plethora of resistance mechanisms present within individual patients with ovarian cancer. This highlights the extreme challenge faced in treating end-stage disease and underscores the need for new methods of early detection and intervention.

A meta-analysis of harmonized human brain RNA-seq datasets creates expression quantitative trait locus (eQTL) maps for multiple ancestries and brain regions, predicts cell-type-dependent eQTLs and produces gene networks. This prioritizes genes for multiple brain-related diseases, serving as a promising step toward the identification of central nervous system (CNS) drug targets.

Interacting proteins commonly perform similar functions. A protein interaction network analysis of genes linked to 1,002 human traits identifies molecular mechanisms that are shared across traits and so-called pleiotropic biological processes, whose disruption might affect many aspects of human biology.

The expression of murine endogenous retrovirus-L (MERVL) is transiently upregulated at the two-cell stage in mouse embryos, coinciding with zygotic genome activation and the acquisition of totipotency; however, its role in embryogenesis remains elusive. We show that nuclear expression of MERVL is required for accurate regulation of the host transcriptome and chromatin state during preimplantation development.

Targeted sequencing finds a higher burden of rare protein-truncating variants in constrained genes among schizophrenia cases of diverse ancestries. Meta-analyses with existing datasets show that this excess burden is consistent across five ancestral populations.

Brain expression quantitative trait locus (eQTL) and network analyses encompassing 8,613 RNA-sequencing samples from 14 eQTL datasets reveal downstream effects and putative drivers for brain-related diseases.

Network expansion of trait-associated genes for 1,002 human phenotypes identifies pleiotropic gene modules and biological processes associated with multiple traits, and potential opportunities for drug repurposing and development.

Genome-wide association analyses identify 93 risk loci for venous thromboembolism (VTE). A polygenic score derived from these results identifies individuals at increased VTE risk equivalent to monogenic forms of the disease.

Multi-ancestry genome-wide association analyses and systematic variant-to-gene mapping strategies implicate new genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Meta-analyses of genome-wide association studies for endometriosis identify 49 distinct association signals. Fine-mapping of causal variants explores functional effects across various tissues. Genetic correlations between endometriosis and other pain conditions are also highlighted.

Multiple samples collected at autopsy from women with homologous recombination-deficient high-grade serous ovarian cancer highlight substantial inter- and intratumoral heterogeneity. A plethora of resistance mechanisms were identified within and between patients.

Immune dN/dS is the ratio of nonsynonymous to synonymous mutations in the MHC-bound immunopeptidome. Application of immune dN/dS to cancer datasets shows that it distinguishes immune evasion and escape and predicts response to immunotherapies.

The identification of genes and enhancers associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) in women highlights variants within Alu retrotransposons. The WHRadjBMI-linked gene SNX10 plays a role in human adipocyte differentiation and diet-induced adipose expansion in female mice.

The canonical BRG1/BRM-associated factor (cBAF) complex is recruited by HNF1A/B to angiotensin-converting enzyme 2 (ACE2) enhancers, promoting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inhibition of the catalytic activity of SMARCA4 precludes ACE2 expression and reduces susceptibility to SARS-CoV-1 and major SARS-CoV-2 variants.

MERVL transcripts, but not MERVL-encoded proteins, are essential for mouse preimplantation development. Depletion of MERVL RNA perturbs early lineage specification and leads to increased chromatin accessibility at, and transcription of, two-cell-specific genes.

High-quality genome assembly of a prominent drought-resistant maize germplasm CIMBL55 and genetic variation analyses provide a resource for genetic dissection and result in the improvement of maize drought resistance.

A graph-based pan-genome constructed using de novo genome assemblies of ten pearl millet accessions adapted to different climates worldwide identifies structural variations and their contribution to heat tolerance in pearl millet.