Reviews & Analysis

Whole-genome sequencing data of individuals from the UK Biobank and Iceland and a somatic mutation barcoding strategy enabled detection of clonal hematopoiesis at scale. This comprehensive study provides insights into the epidemiology, somatic and germline genetics, and disease associations of clonal hematopoiesis.

Previous studies reported an effect of N⁶-methyladenosine (m⁶A) of super-enhancer RNAs (seRNAs) on chromatin accessibility and gene transcription. We investigated seRNA m⁶A levels in pancreatic ductal adenocarcinoma (PDAC) and found that aberrantly increased m⁶A methylation promoted local chromatin accessibility, resulting in increased transcription of oncogenes acting in PDAC progression.

We present an analysis that shows that although nearly half of the human genome comprises repetitive sequences, recombination between homologous repeats has a minor role in cancer chromosomal evolution.

The pancreas is an essential organ present in all vertebrates, and human pancreatic agenesis is an extremely rare disorder of largely unknown genetic determinants. A study now demonstrates that a primate-specific regulatory network controlled by the KRAB zinc-finger protein ZNF808 is essential for pancreas development.

Whole-exome and genome sequencing in consanguineous families with unsolved lipodystrophy identified biallelic pathogenic loss-of-function variants in the phospholipase gene PLAAT3. Multi-omics and functional analyses in human and mouse PLAAT3-deficient adipose tissue and adipose stem cells revealed an adipocyte differentiation defect that is mediated by an altered gene network downstream of the adipogenesis master regulator PPARγ.

This Review discusses how embryonic transcriptional programs, such as epithelial–mesenchymal plasticity and stemness, may be harnessed in adult tissues to drive processes and diseases such as regeneration and cancer.

Brain somatic mosaicism is linked to several neurological disorders and is thought to arise post-zygotically. A study suggests that pre-zygotic aneuploidy followed by post-zygotic partial reversion leads to a recurrent form of brain mosaicism-related epilepsy.

The mechanisms of many disease-associated variants are uncertain because of limited power to detect their modest effects on gene expression. This study finds that natural selection leads to preferential detection of disease-associated versus expression-associated variants.

We developed a computational, age-dependent topic model to identify longitudinal comorbidity patterns from hospital diagnosis data. The inferred comorbidity patterns are robust across UK and US populations and identify disease subtypes with distinct genetic profiles.

Genome-wide association analyses of placental weight identify 40 association signals, partially overlapping with birth weight genetics. We find parent-of-origin effects and connections to placental development and morphology, and transport of amino acids and antibodies. Mendelian randomization reveals a fetal contribution to preeclampsia and implicates fetal insulin in the regulation of placental growth.

DNA mismatch repair deficiency (MMRd) is associated with elevated tumor mutational burden (TMB) and exceptional immunotherapy responses, yet some patients experience no clinical benefit. Recent work proposes that high intra-tumoral heterogeneity can offset immunogenicity in sporadic MMRd, suggesting a potential mechanism of immunotherapy failure.

Polygenic risk scores (PRSs) are increasingly able to predict complex traits; however, they perform suboptimally in populations not of European ancestry. We present CT-SLEB, a powerful method that enables the calculation of PRSs from multi-ancestry samples and provides insights into the opportunities and challenges of enhancing polygenic risk prediction across populations of diverse ancestry.

Many precision cancer therapies function by inhibiting oncogenic signaling pathways. A new study describes the counterintuitive finding that forced hyperactivation of the same pathways can also enable selective tumor targeting.

Genetic studies have associated thousands of non-coding variants with Alzheimer’s disease (AD), yet the functions of these variants remain elusive. We conducted cell-type-specific genetic fine mapping of AD variants and performed extensive functional characterization to unravel the causal variants that contribute to transcriptional regulation and AD­related phenotypes in microglia.

We re-sequenced and phenotyped 2,839 rice hybrid cultivars and 9,839 F₂ individuals from elite hybrids. Based on the dataset, the genetic improvement during rice hybrid breeding was investigated, and the genetic basis underlying strong heterosis was quantitatively evaluated. Furthermore, a genomic selection model was constructed to optimize heterotic combinations.

Using data from the UK Biobank, we reveal the roles of selection and mutation in shaping the genetic diversity of mosaic chromosomal alterations in healthy blood.

Transformation of a myeloproliferative neoplasm to a secondary acute myeloid leukemia is rare but devastating. Single-cell, multi-omic characterization of hematopoietic stem and progenitor cells now shows the role of inflammation in transformation driven by mutations in TP53, with effects on the mutant clone but also non-mutant counterparts.

The symmetric inheritance of histone modifications by the nascent chromatin fibers during DNA replication is essential for proper developmental progression. Two new studies using mouse embryonic stem cells further illuminate the role of histone inheritance in early cell fate decisions.

In this issue of Nature Genetics, Lara-Astiaso et al. systematically characterized the functional roles of several chromatin factors in hematopoiesis by combining functional CRISPR screens with single-cell transcriptomics and chromatin accessibility profiling, revealing lineage biases and relationships with important transcription factors.

A novel pipeline that expands the utility of the protein language model ESM1b has provided variant effect predictions for more than 40,000 protein isoforms. This strategy outperformed several state-of-the-art methods over multiple benchmarks.