Search

Using a global molecular phylogenetic dataset of birds on islands, the sensitivity of island-specific rates of colonization, speciation and extinction to island features (area and isolation) is estimated.

Islands generally have fewer species than continental areas and are not thought to contribute significantly to continental diversity. Here, the authors show islands can be more dynamic and export many more evolutionary lineages than expected based on contemporary diversity patterns.

Species’ traits and environmental conditions determine the abundance of tree species across the globe. Here, the authors find that dominant tree species are taller and have softer wood compared to rare species and that these trait differences are more strongly associated with temperature than water availability.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

Geographic location can be a key determinant of human health outcomes. Here, the authors show that in large-scale trials, randomization that is pair matched by geography can lead to substantial improvements in statistical efficiency and enable insights into spatially varying intervention effects.

A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.

Triadic interactions, where one node regulates the interaction between two others, are a ubiquitous form of higher-order interaction. Here, the authors show that triadic interactions modulate mutual information between linked nodes and propose an algorithm to mine them in real biological data.

Samples of different body regions from hundreds of human donors are used to study how genetic variation influences gene expression levels in 44 disease-relevant tissues.

This megastudy testing different interventions finds that honesty oaths are effective and can mitigate tax evasion in an incentivized game.

A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

Exome sequencing data from 60,706 people of diverse geographic ancestry is presented, providing insight into genetic variation across populations, and illuminating the relationship between DNA variants and human disease.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

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.

Paul de Bakker, Cisca Wijmenga and colleagues report on The Genome of the Netherlands Project, including whole-genome sequencing of 769 individuals of Dutch ancestry from 250 parent-offspring families and construction of a phased haplotype map. Their intermediate-coverage population sequencing data set provides a complementary resource to other publicly available data sets, including the 1000 Genomes Project.

A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.

Lemischka and colleagues examine the effects of transient Nanog downregulation on the components of the pluripotent transcriptional regulatory network using single-cell gene expression analysis and modelling approaches. They observe that the initial changes induced by loss of Nanog are stochastic and reversible upon Nanog restoration, owing to the presence of feedback loops in the pluripotency network. Prolonged loss of Nanog compromises these feedback loops and reversion to pluripotency cannot be achieved upon Nanog restoration.

When stem cells develop into tissues intracellular signalling is rewired, errors in this process lead to cancer. Here, authors applied tools from differential geometry made by Albert Einstein’s General Relativity to understand and predict biological network rewiring in health and disease.

Multiple transcriptome approaches, including single-cell sequencing, demonstrate that escape from X chromosome inactivation is widespread and occasionally variable between cells, chromosomes, and tissues, resulting in sex-biased expression of at least 60 genes and potentially contributing to sex-specific differences in health and disease.

A survey across 90 societies reveals that variation and change in everyday norms are explained by a single value dimension: the priority societies place on individualizing versus binding moral concerns.

Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery.

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

The GREGoR consortium provides foundational resources and substrates for the future of rare disease genomics.

This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual.

Using the GTEx data and others, a comprehensive analysis of adenosine-to-inosine RNA editing in mammals is presented; targets of the various ADAR enzymes are identified, as are several potential regulators of editing, such as AIMP2.

Analysis of predicted loss-of-function variants from 125,748 human exomes and 15,708 whole genomes in the Genome Aggregation Database (gnomAD) provides a roadmap for human ‘knockout’ studies and a guide for future research into disease biology and drug-target selection.

Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in the skin. Here the authors show, by transcriptomic, epigenetic and CRISPR editing analyses, that during LC migration and maturation the transcription factor IRF4 regulates expression of antigen presentation and co-stimulatory gene modules while attenuating inflammatory response genes.

The authors show that rare genetic variants contribute to large gene expression changes across diverse human tissues and provide an integrative method for interpretation of rare variants in individual genomes.

As the European Union’s Artificial Intelligence Act takes effect, AI systems that mimic how human teams collaborate can improve trust in high-risk situations, such as clinical medicine.

A set of three papers in Nature reports a new proteomics resource from the UK Biobank and initial analysis of common and rare genetic variant associations with plasma protein levels.

Here, the authors used electronic healthcare records to analyse the genetic basis of variation in 42 routinely-acquired quantitative blood tests among up to 40,000 British South Asian volunteers from the Genes and Health study. By combining their results with genetic findings from UK Biobank, they explore similarities and differences between ancestries in the genetic basis of these traits.

Genome-wide association analysis of an improved telomere length score, calculated from quantitative PCR and whole-genome sequencing measurements in 462,666 individuals in the UK Biobank, identifies novel genes and variants underlying this trait.

Repeated cell divisions induce DNA damage in haematopoietic stem cells (HSC) and telomeres are sensitive to this damage. Here, the authors show in murine HSCs that the telomere binding protein POT1a inhibited the production of reactive oxygen species, and rejuvenated aged HSCs.

The identity of the cells that form the haematopoietic stem cell (HSC) niche in bone marrow has been unclear. These authors identify nestin-expressing mesenchymal stem cells as niche-forming cells. These nestin-expressing cells show a close physical association with HSCs and express high levels of genes involved in HSC maintenance, and their depletion reduces bone marrow homing of haematopoietic progenitors.

Stem cell differentiation and the maintenance of self-renewal are intrinsically complex processes. They require the coordinated and dynamic expression of hundreds of genes and proteins, in precise response to external signalling cues. Systems biology approaches are helping to dissect this complexity.

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics.

Jose Florez, Claudia Langenberg, Erik Ingelsson, Inga Prokopenko, Inês Barroso and colleagues perform large-scale association analyses using the Metabochip to gain further insights into the genetic architecture of glucose regulation. They identify 38 new loci influencing 1 or more glycemic traits and show that many of these loci also modify risk of type 2 diabetes.

Population-scale whole-genome sequencing across four remote Indigenous Australian communities reveals a large fraction of structural variants that are unique to these populations, emphasizing the genetic distinctiveness of and diversity among Indigenous Australians.

Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.