Ecological and demographic factors can significantly shape the evolution of microbial populations both directly and indirectly, as when changes in the effective population size affect the efficiency of natural selection on the mutation rate. However, it remains unclear how rapidly the mutation-rate responds evolutionarily to the entanglement of ecological and population-genetic factors over time. Here, we directly assess the mutation rate and spectrum of Escherichia coli clones isolated from populations evolving in response to 1000 days of different transfer volumes and resource-replenishment intervals. The evolution of mutation rates proceeded rapidly in response to demographic and/or environmental changes, with substantial bidirectional shifts observed as early as 59 generations. These results highlight the remarkable rapidity by which mutation rates are shaped in asexual lineages in response to environmental and population-genetic forces, and are broadly consistent with the drift-barrier hypothesis for the evolution of mutation rates, while also highlighting situations in which mutator genotypes may be promoted by positive selection.

BACKGROUND: CNP (C-type natriuretic peptide), an endogenous short peptide in the natriuretic peptide family, has emerged as an important regulator to govern vascular homeostasis. However, its role in the development of atherosclerosis remains unclear. This study aimed to investigate the impact of CNP on the progression of atherosclerotic plaques and elucidate its underlying mechanisms. METHODS: Plasma CNP levels were measured in patients with acute coronary syndrome. The potential atheroprotective role of CNP was evaluated in apolipoprotein E-deficient (ApoE ^−/− ) mice through CNP supplementation via osmotic pumps, genetic overexpression, or LCZ696 administration. Various functional experiments involving CNP treatment were performed on primary macrophages derived from wild-type and CD36 (cluster of differentiation 36) knockout mice. Proteomics and multiple biochemical analyses were conducted to unravel the underlying mechanism. RESULTS: We observed a negative correlation between plasma CNP concentration and the burden of coronary atherosclerosis in patients. In early atherosclerotic plaques, CNP predominantly accumulated in macrophages but significantly decreased in advanced plaques. Supplementing CNP via osmotic pumps or genetic overexpression ameliorated atherosclerotic plaque formation and enhanced plaque stability in ApoE ^−/− mice. CNP promoted an anti-inflammatory macrophage phenotype and efferocytosis and reduced foam cell formation and necroptosis. Mechanistically, we found that CNP could accelerate HIF-1α (hypoxia-inducible factor 1-alpha) degradation in macrophages by enhancing the interaction between PHD (prolyl hydroxylase domain–containing protein) 2 and HIF-1α. Furthermore, we observed that CD36 bound to CNP and mediated its endocytosis in macrophages. Moreover, we demonstrated that the administration of LCZ696, an orally bioavailable drug recently approved for treating chronic heart failure with reduced ejection fraction, could amplify the bioactivity of CNP and ameliorate atherosclerotic plaque formation. CONCLUSIONS: Our study reveals that CNP enhanced plaque stability and alleviated macrophage inflammatory responses by promoting HIF-1α degradation, suggesting a novel atheroprotective role of CNP. Enhancing CNP bioactivity may offer a novel pharmacological strategy for treating related diseases.

Dysregulation of SUMOylation is implicated in cancer progression. While the role of SUMO-activating enzyme (SAE) and its mechanisms in cancer remain unclear. We investigated the role of SAE subunit 1 (SAE1) in hepatocellular carcinoma (HCC) metastasis. We analyzed SAE1 expression across 28 pan-cancer subtypes. SAE1 complexes were identified and characterized using interactome analysis, Co-IP, immunofluorescence, and AlphaFold3 predictions. These findings were validated using in situ and vein tail injection xenograft mouse models, HCC organoids, and IHC using HCC tissue samples. Increased SAE1 expression was correlated with poorer prognosis and higher driver gene mutation frequencies in six pan-cancers, particularly HCC. We identified a novel interaction between SAE1 and yin-yang 1 (YY1), where SAE1 enhances YY1 stability and activity, leading to Wnt3a transcription and subsequent activation of the Wnt pathway, eventually promoting cell migration and invasion. Moreover, a positive correlation between SAE1 and Wnt3a expression was confirmed in HCC organoids and HCC tissue samples. This study established SAE1 as a novel independent prognostic biomarker in multiple cancers and identified its mechanistic role in HCC progression, suggesting its potential value for future translational research toward therapeutic development.

Spontaneous mutations are the primary source of genetic variation and play a central role in shaping evolutionary processes. To investigate mutational dynamics in Daphnia obtusa, we generated a chromosome-level genome assembly spanning 129.4 Mb across 12 chromosomes, encompassing 15,321 predicted protein-coding genes. Leveraging whole-genome sequencing of eight mutation-accumulation (MA) lines propagated for an average of 482 generations (spanning over 20 years), we estimated a spontaneous single-nucleotide mutation (SNM) rate of 2.45 × 10−9 and an indel mutation rate of 3.34 × 10−10 per site per generation. The SNM spectrum was strongly biased toward C:G > T:A transitions. Despite the design of MA experiments to minimize selection, nonsynonymous mutations were strongly underrepresented, providing rare evidence that purifying selection can act detectably even during mutation accumulation. Comparative analyses with natural population data revealed that exonic mutations observed in the MA lines were significantly less likely to be present in standing variation than intronic or intergenic mutations, suggesting that purifying selection in natural populations acts to remove deleterious alleles. We also identified 48 loss-of-heterozygosity (LOH) events, comprising 8 heterozygous deletions and 40 gene-conversion events, yet found no evidence of GC-biased gene conversion. Instead, while mutation predicts a substantially lower equilibrium GC content, the observed GC level is maintained at higher values, implicating natural selection as the primary force stabilizing base composition. Together, these results provide one of the most comprehensive assessments of the interplay among mutation, selection, and genome stability in an ecologically important species.

The evolution of genetic sex determination (GSD) from environmental sex determination (ESD) remains a fundamental issue in evolutionary biology. However, the mechanisms driving the transition, particularly in its earliest stages, are largely unknown. Here, we report a genetic variant in the ESD species, Daphnia pulex , in which structural variations on chromosome I have suppressed recombination. This suppression appears to have facilitated the accumulation of divergent features of two chromosome I haplotypes, resulting in differentiation of the linked sex-determining gene Dfh . This process has led to the emergence of a mixed-mating system, in which sex determination is jointly regulated by genetic and environmental factors, with ongoing divergence in chromosomal structure continuing to develop between the two haplotypes at the population level. These findings suggest that processes analogous to early sex-chromosome evolution are occurring in this ESD species, offering insights into the molecular mechanisms underlying the emergence of GSD.

A substantial fraction of human long noncoding RNAs (lncRNAs) are lineage specific and increasingly implicated in cancer, yet the evolutionary origins of their oncogenic relevance remain unclear. It is unknown whether such roles arise through adaptive refinement or as incidental by-products of transcriptomic complexity under weak selection. Here, we show that newly evolved cancer-associated lncRNAs, predominantly of primate origin, arise through a stepwise process initiated by increased transcriptional activity. Once expression surpasses a threshold, these lncRNAs undergo sequence expansion, with 73.3% incorporating external or local genomic fragments, facilitating integration into deeply conserved cancer-related pathways. We validate this model through MIR497HG , which originated near a microRNA in the human-macaque ancestor, and subsequently expanded and integrated into the ancient AMPK (adenosine monophosphate–activated protein kinase)/ferroptosis network in humans, influencing oncogenesis. Collectively, our findings support a model in which weak selection permits neutral transcriptional innovations to persist and gradually infiltrate ancient regulatory architectures, consistent with constructive neutral evolution.