Host–parasite coevolution is expected to generate strong selection for resistance and infectivity that has the potential to erode genetic variation. Despite this, natural populations often retain extensive genetic variation in these traits. Genotype-by-genotype interactions on fitness can generate negative frequency-dependent selection, which helps maintain this variation by preventing any host or pathogen genotype from retaining a permanent advantage. Because these interactions place genetic variance in the interaction term rather than in additive differences among hosts or pathogens, that variance is masked from directional selection and can remain ‘cryptic’. Here we combine coevolutionary modelling with large‑scale experimental infection assays to quantify how host-pathogen interactions structure fitness variance in a vertically transmitted virus system, Drosophila melanogaster and sigma virus. Simulations show that coevolution typically erodes additive genetic variance in host and pathogen fitness, concentrating variance in host-virus interaction terms. Consistent with these predictions, experiments spanning 90 host-virus genotype combinations reveal that transmission, viral load, and virulence are overwhelmingly governed by host-virus genetic interactions rather than host or virus main effects. As a result, neither host resistance alleles nor viral genotypes confer consistently higher fitness across genetic backgrounds. Interactions tend to be sex‑specific, further limiting heritable fitness variation. Our results demonstrate that coevolution can substantially mask heritable genetic variation from directional selection by rendering fitness context-dependent. This extensive cryptic genetic variation may be revealed either when ecological or evolutionary conditions shift, or when the process of coevolution itself alters the direction of selection. This demonstrates the need to account for genotype-specific interactions when forecasting evolutionary responses.
How does the human brain represent the meaning of abstract symbols? Some theories postulate the existence of semantic spaces where concepts occupy positions that reflect their conceptual relationships. In the number domain, psychological evidence suggests that integers are represented along a mental number line which, with education, integrates higher-level number concepts such as fractions. To test this hypothesis, we recorded whole-brain 7T fMRI responses to integer and fraction symbols during an active magnitude comparison task designed to engage magnitude processing. Consistent with predictions, we found both behavioral and neural numerical distance effects. Activation vectors in intraparietal, inferior temporal, prefrontal, hippocampal, and parahippocampal cortices formed a two-dimensional semantic space organized by numerical magnitude and domain (fractions versus integers). Gaussian fits revealed a topographic map of numerical preferences in the anterior inferior parietal cortex, common to both domains. Our results suggest that, when educated adults engage in an explicit magnitude comparison task, their brain can construct an ordered representation that integrates fractions and integers, with a topographic organization in the anterior IPS/IPL.
In the human genome, mutation rates vary along genes, yet how their fine-scale structure contributes to gene evolution has remained largely unexplored. Here, we map inherited mutations at single-nucleotide resolution and uncover a striking hypermutation peak at transcription start sites (TSSs) of human protein-coding genes. This pattern is observed both in population polymorphisms and in de novo mutations from parent-offspring trios, and is dependent on transcriptional activity in testes. We also find similar hypermutation peaks at TSSs used to produce long noncoding RNAs and at intergenic RNA Polymerase II pause sites. In addition, we identify distinct mutational signatures at exon-intron boundaries and in introns. By comparing the current nucleotide content to predicted equilibrium levels, inferred from mutation and fixation rates, and by analyzing derived ancestral frequency spectrums, we detect signals that are compatible with a low level of ongoing background GC-biased gene conversion (gBGC) throughout the region and ancestral elevated gBGC activity that is centered right downstream from the TSS. Using a forward-in-time simulation algorithm, we show that the current nucleotide composition surrounding the TSS of protein-coding genes is best explained by local mutation biases coupled to ongoing and ancestral patterns of gene conversions. Our simulations allow us to infer several features of these gBGC events. Overall, these findings indicate that the nucleotide composition around TSSs is largely shaped by non-adaptive forces, particularly mutation bias and gBGC.
Macrophages play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). T-cell immunoglobulin and mucin domain-containing molecule 4 (TIMD4) is involved in the regulation of tissue-resident macrophages. TIMD4 expression is elevated in colonic tissues from patients with ulcerative colitis (UC) and mice with dextran sulfate sodium (DSS)-induced colitis, but its role in IBD pathogenesis remains unclear. In this study, we found that Timd4 deficiency aggravated DSS-induced colitis, accompanied by increased infiltration of monocytes into the colonic tissues. Treatment with a CCR2 antagonist attenuated colonic inflammation and reduced monocyte infiltration into colonic tissues in Timd4 KO mice. Mechanistically, in vitro studies revealed that TIMD4 stabilized the LKB1-STRAD-MO25 complex via its intracellular domain, thereby activating the AMPK pathway and suppressing NF-κB-dependent chemokine production in macrophages. Based on these findings, we designed a TIMD4-derived peptide and developed a macrophage-targeted nanoparticle system (T4 (365–378) ‑NPs). Treatment with T4 (365–378) -NPs reduced P65 phosphorylation and attenuated DSS-induced colitis in mice. Treatment with either T4 (365–378) -NPs or the CCR2 antagonist attenuated DSS-induced colitis, and no statistically significant differences in the assessed outcomes were detected between the two groups. Administration of T4 (365–378) -NPs before DSS exposure also attenuated subsequent colitis. Furthermore, combining the T4 (365–378) ‑NPs with anti-α4β7 or anti-TNF-α antibodies produced greater improvements than either monotherapy in the DSS-induced colitis model. These findings support further preclinical evaluation of TIMD4-derived peptide delivery as a potential therapeutic approach for intestinal inflammation.
Neurodegeneration is frequently associated with oxidative stress, yet the mechanisms that convert reactive oxygen species (ROS) into irreversible degenerative signals remain incompletely understood. Neurons in the central and peripheral nervous systems often differ in their responses to injury, but these differences cannot be reduced to a simple contrast between weak and strong antioxidant capacity. This Essay proposes that neuronal vulnerability is shaped by multilayered signaling thresholds comprising ROS production, antioxidant and thiol buffering, redox-sensitive signal detection, molecular gating, and commitment to degeneration, survival, or repair. This framework may help explain selective neuronal vulnerability in neurodegenerative diseases and identify intervention points downstream of global ROS suppression.
