Volume 56 Issue 7, July 2024

Efforts to integrate computational tools for variant effect prediction into the process of clinical decision-making are in progress. However, for such efforts to succeed and help to provide more informed clinical decisions, it is necessary to enhance transparency and address the current limitations of computational predictors.

The impact of transposable elements (TEs) on gene regulatory networks and how they are governed remain poorly understood. A new study identifies a role for LINE1, a specific subset of TEs, in the long-range regulation of gene expression, particularly during embryonic development.

Comprehensive dissection of the transcriptional basis of basal-like differentiation of pancreatic ductal adenocarcinoma (PDAC) revealed MED12 as a core regulator of this abnormal identity. Mechanistic studies demonstrate that MED12 cooperates with the basal-like master regulator transcription factor ΔNp63 by bridging it with the critical Mediator co-activator complex.

Relentless accumulation of somatic mutations renders mismatch repair (MMR)-deficient cancers immunogenic. The evolutionary strategies that these hypermutator tumors use to drive immune evasion remain unknown. We identify repetitive homopolymer sequences in MMR genes as genetic ON/OFF switches, which vary mutation rate and bias during tumor evolution to fuel intratumor heterogeneity.

Microbats utilize ultrasonic echolocation to navigate and locate prey, whereas megabats primarily perceive human-audible sound in daily life. High-quality genomes and single-cell atlases of auditory cortices from microbat and megabat species identify parvalbumin-positive inhibitory neurons and the complexin-1 gene to be crucial in mammalian ultrasound perception.

We identify an elite haplotype of the transcription factor gene OsGATA8 in rice that is associated with enhanced nitrogen uptake and a higher proportion of productive tillers. Revealing how OsGATA8 regulates nitrogen use efficiency (NUE) enables insights into coordination of nitrogen uptake and productive tiller formation to achieve high NUE in rice.

Kaiser et al. propose a nuanced and inclusive definition of genetic discrimination that reflects its multifaceted impact. This adaptive definition is intended to remain relevant in the face of an evolving social context and advancing genomic science.

Infant genetic research is currently underexplored but, as highlighted in this Perspective, has the potential to impact basic science and affect educational policy, public health and clinical practice.

This Review discusses emerging technologies and insights from mitochondrial DNA variant profiling obtained by single-cell multi-omics, demonstrating how the powerhouse of the cell may record clonal lineages and contribute to disease heterogeneity.

Analysis of the FGF14-SCA27B repeat locus identifies a common 5′-flanking insertion that represents the major allele, is present exclusively on nonpathogenic alleles, enhances repeat stability and increases chromatin accessibility.

Analysis of exome sequencing data identifies a missense variant in RAB32 associated with high risk of familial Parkinson’s disease. Functional studies show that this risk variant increases LRRK2 kinase activity.

Marker-based CRISPR screens in pancreatic cancer cells followed by functional validation highlight a role for MED12 in bridging ΔNp63 and components of the Mediator family. This interaction helps drive basal cell identity in pancreatic ductal adenocarcinoma.

CalPred is a framework that adjusts polygenic score (PGS) prediction intervals based on joint modeling of multiple contexts, such as age, sex and genetic ancestry. PGS show pervasive context-specific accuracy, suggesting that accounting for this will improve portability across contexts.

A multi-ancestry genome-wide association study for age at menarche followed by fine mapping and downstream analysis implicates 665 pubertal timing genes, such as the G-protein-coupled receptor 83 (GPR83) and other genes expressed in the ovaries involved in the DNA damage response.

A machine learning-based, continuous in silico coronary artery disease (CAD) score built using electronic health record data is applied to rare variant association analysis of CAD, implicating novel candidate genes and biological mechanisms.

Mismatch repair-deficient colorectal cancer clones adapt their mutation landscape by toggling homopolymer sequences in MutS homolog 3 (MSH3) and MutS homolog 6 (MSH6). This increases the subclonal mutation rate and clonal diversity, favoring immune escape and tumor growth.

Saturation genome editing characterizes BAP1 variants and their association with disease presentation. A phenome-wide association analysis in the UK finds that BAP1 variants identified as deleterious in the study are associated with higher serum IGF-1 levels.

Saturation genome editing characterizes von Hippel–Lindau (VHL) coding variants and their associations with diseases. Function scores for 2,268 VHL single-nucleotide variants (SNVs) classify pathogenic alleles driving renal cell carcinoma and suggest new mechanisms by which variants impact function.

Upon inflammation and targeted gene mutation, some fully differentiated secretory and postmitotic intestinal epithelial lineages dedifferentiate to acquire stem-like features and promote tumor formation.

Single-cell transcriptome profiling of human aneuploid blastocysts highlights global transcriptomic alteration and identifies novel dosage-sensitive genes in aneuploidy. Aneuploid embryos undergo unstable epiblast maturation caused by defects in the TGF-β and FGF pathways that impact trophectoderm progression.

This study finds that CRISPR-knockout phenotypes from genome-wide screens systematically show increased similarity to knockouts of unrelated genomically proximal genes located on the same chromosome arm. Multiple lines of evidence suggest that this proximity bias is caused by telomeric truncations of chromosome arms and is consistent across cell types, labs and Cas9 delivery methods.

A CRISPR–Cas9 screen identifies genes that modulate long interspersed nuclear element-1 (LINE-1) expression in human cells. LINE-1 5′ UTRs have enhancer features and can activate long-range gene expression, including during zygotic genome activation.

High-quality genomes and single-cell atlases of auditory cortices from microbat and megabat species identify neuronal populations related to ultrasound perception and implicate complexin-1 as a key component of ultrasound transmission in mammals.

The study identifies transcription factor OsGATA8 as a negative regulator of nitrogen uptake and tiller formation in rice and OsGATA8-H as an elite haplotype with reduced expression and enhanced nitrogen use efficiency.

This study presents a synthetic surrogate (SynSurr) method for imputing missing phenotypes in biobank datasets. Joint analysis of the partially observed and imputed surrogate phenotype improves power in genome-wide association studies while being robust to imputation errors.