Genetics

Sequencing of individual human lymphocyte clones shows that they are highly prone to mutations, with higher burdens in memory cells than in naive cells arising from mutational processes associated with differentiation and tissue residency.

Experiments in mice show that a LINE-1 transposable element, Lx9c11, has a functional role in immunity by negatively regulating the response to viral infection to protect the host from an over-reactive immune response.

To understand the contribution of variants to transcript expression regulation, long-read transcriptome data are generated from the GTEx resource, and a new software package to perform allele-specific analysis is developed.

cis-RNA editing quantitative trait loci, which are associated with immunogenic double-stranded RNAs, underlie genome-wide association study variants in common autoimmune and inflammatory diseases.

Examination of archaeological pottery residues and modern genes suggest that environmental conditions, subsistence economics and pathogen exposure may explain selection for lactase persistence better than prehistoric consumption of milk.

To measure selection on variants, whole-genome sequencing of approximately 150,000 individuals from the UK Biobank is used to rank sequence variants by their level of depletion.

Endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells, and APOBEC3A is the main driver of these mutations.

Deep whole-genome sequencing of serial blood samples and matched metastatic tissue reveals that circulating tumour DNA profiling enables detailed study of treatment-driven subclone dynamics, epigenomics and genome-wide somatic evolution in metastatic human cancers.

Active super-enhancers are highly and specifically hypermutated in 92% of diffuse large B cell lymphoma samples and display signatures of activation-induced cytidine deaminase activity, leading to the dysregulation of genes encoding B cell developmental regulators and oncogenes.

Using differences among strains as a model for inter-individual variation, this paper identifies a conserved metabolicadaptation in C. elegans that compensates for genetic variation.

Structures of the Dcr-2–Loqs-PD complex while it is processing a double-stranded RNA (dsRNA) substrate elucidate the interactions between Dcr-2 and Loqs-PD, and show that Dcr-2 undergoes substantial conformational changes during a dsRNA-processing cycle.

An immune signature characterized by activated antigen-specific CD8 T cells is identified in the brain and blood of mice with amyotrophic lateral sclerosis-4 (ALS4), suggesting that the immune system is involved in ALS4 neurodegeneration.

A precise catalogue of more than 19 million variants from 838 tomato genomes, including 32 new reference-level genome assemblies, advances the understanding of the heritability of complex traits and demonstrates the power of the graph pangenome in crop breeding.

A study shows that the three-dimensional conformation of the human genome influences the positioning of DNA replication initiation zones, highlighting cohesin-mediated loop anchors as essential determinants of their precise location.

High-quality diploid assemblies of potato genomes from 24 wild and 20 cultivated potatoes provide insights into the complex evolution and diversity of potatoes, and could have applications in the breeding of hybrid potatoes.

A survey of 8,341 mutations in 21 yeast genes shows that synonymous mutations are nearly as harmful as nonsynonymous mutations, in part because they both affect the mRNA level of the gene mutated.

The lineage transcription factor PAX8 is shown to play a pivotal part in determining cancer risk in clear cell renal cell carcinoma, providing insights into how genetic mutations lead to specific types of cancer.

The systematic categorization of human enhancers by their cofactor dependencies provides a conceptual framework to understand the sequence and chromatin diversity of enhancers and their roles in different gene-regulatory programmes.

Assembly and analysis of the Schmidtea mediterranea genome indicate that this planarian’s chromosome 1 may be evolving into a sex chromosome.

Haematopoiesis has high clonal diversity up to about 65 years of age, after which diversity drops precipitously owing to positive selection acting on a handful of clones that expand exponentially throughout adulthood.

A long-term study of 385 human donors reports that driver gene mutations and age determine the lifelong dynamics of clonal haematopoiesis

A new high-throughput assay applied to 1,000 enhancers and 1,000 promoters in human cells reveals how different classes of enhancers and promoters control RNA expression.

Assembly of the hexaploid oat genome and its diploid and tetraploid relatives clarifies the evolutionary history of oat and allows mapping of genes for agronomic traits.

Pregestational hyperglycaemia in mothers increases the probability of glucose intolerance in the offspring, an effect controlled by TET3-dependent DNA demethylation of genes involved in insulin secretion.

The POU2F3–OCA-T complex is the master regulator of tuft cell identity and a prominent molecular vulnerability of tuft-cell-like small-cell lung cancer.

A study of 21,879 families with rare genetic diseases identifies 12 with 2- to 7-fold excess of germline mutations, most of which are due to DNA repair defects or exposure to mutagenic chemotherapy, although most individuals with a hypermutated genome will not have a genetic disease.

A single-cell Poisson model is used to analyse eQTLs in memory T cells across continuous, dynamic cell states, revealing that the cell context is critical to understanding variation in eQTLs and their association with disease.

Natural variation in the mouse gene Mutyh influences the rate of C>A germline mutations.

In Drosophila, there are extensive physical and functional associations of distant paralogous genes, including co-regulation by shared enhancers and co-transcriptional initiation over distances of nearly 250 kilobases.

The host blood-type-associated ABO genotype affects the abundance of specific bacteria in the pig intestine.

DNA damage during chromothripsis is caused by deoxyinosine formation on accumulated RNA–DNA hybrids in micronuclei that are then recognized by N-methyl-purine DNA glycosylase and cleaved by apurinic/apyrimidinic endonuclease.

A comprehensive analysis of brain somatic mosaicism across the neocortex demonstrates the origins and distribution patterns of cells within the human brain.

Analyses of single-cell whole-genome sequencing data show that somatic mutations are increased in the brain of individuals with Alzheimer’s disease compared to neurotypical individuals, with a pattern of genomic damage distinct from that of normal ageing.

Genome-scale CRISPR–Cas9-based synthetic lethality screens identify PKMYT1 as a potential therapeutic target in tumours with CCNE1 amplification.

The Human Pangenome Reference Consortium aims to offer the highest quality and most complete human pangenome reference that provides diverse genomic representation across human populations.

Whole-genome sequencing is used to analyse the landscape of somatic mutation in intestinal crypts from 16 mammalian species, revealing that rates of somatic mutation inversely scale with the lifespan of the animal across species.

Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.

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.

An approach that combines deep mutational scanning with neural network-based thermodynamic modelling is used to provide comprehensive maps of the energetic and allosteric effects of mutations in two common protein domains.

Matched Annotation from NCBI and EMBL-EBI (MANE) delivers joint transcript sets from Ensembl/GENCODE and RefSeq for standardizing variant reporting in clinical genomics and research.

Extensive DNA damage occurs during the first interphase following induction of tetraploidy in human cells, largely as a result of the lower amount of protein relative to DNA.

The rixosome associates with Polycomb repressive complexes and chromatin and has a role in silencing of Polycomb target gene expression in human cells via degradation of nascent RNA transcripts.

Human genetic variants that impair genes that are intolerant of damaging genetic variation are associated with lower reproductive success that is probably mediated by genetically associated cognitive and behavioural traits, particularly in males.

A framework for studying and engineering gene regulatory DNA sequences, based on deep neural sequence-to-expression models trained on large-scale libraries of random DNA, provides insight into the evolution, evolvability and fitness landscapes of regulatory DNA.

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.

A translationally silent KRAS^G60G mutation, preventing the formation of a cryptic splice donor site and  enabling expression of KRAS(Q61K), reveals a vulnerability in RAS^Q61 cancers that are therapeutically exploitable in a mutant-selective manner.