Yu, C. T. | bioRxiv Science

bioRxiv2025

Human genetic variation shapes the response of neurons to interferons

Inflammation is increasingly recognized as important to neuropathology, including more classic neuroimmune disease as well as neurodegenerative and neuropsychiatric disorders. Interferons (IFN) are important mediators of central nervous system inflammation. Individuals appear to vary in susceptibility to neuroinflammatory pathology, suggesting that identifying human genetic modifiers of the neuronal IFN response might provide insight into disease pathophysiology. To identify potential modifiers, we stimulated neuronal "cellular villages" of iPSC-derived neurons from over one hundred donors with IFN-alpha (IFNa) or IFN-gamma (IFNg). We then correlated allele states of common variable SNPs to gene expression to identify hundreds of expression quantitative trait loci (eQTLs), many of which emerged specifically upon IFN treatment. We characterized the distinct but overlapping neuronal transcriptional responses to IFNa and IFNg, and identified specific response QTLs. Functional annotation of STAT1 binding to the genome in response to IFN stimulus identified STAT1 binding sites as enriched for response-regulating human genetic variation and also enabled identification of loci with IFN-dependent allele-specific binding of STAT1. These results demonstrate how human genetic variation can influence IFN-dependent mechanisms in neurons in disease-relevant ways.

molecular biology↗

bioRxiv2024

The metabolic costs of meiotic drive

Selfish genetic elements, such as meiotic drive genes, disrupt Mendels law of equal segregation by biasing their own transmission, often at a detriment to the rest of the genome. The Malaysian stalk-eyed fly (Teleopsis dalmanni) sex-ratio (SR) meiotic drive system is located within a series of large inversions on the X chromosome subject to low recombination and is associated with deleterious effects on fitness. Here we examine the metabolic effects of meiotic drive across male and female stalk-eyed flies. High-resolution O2k respirometry coupled with whole-organism respirometry were used to obtain mitochondrial function and metabolic rates. Complimentary assays on food consumption established downstream effects of metabolism on nutrient acquisition. The experiments demonstrate that individuals with SR meiotic drive elements have impaired mitochondrial function and reduced capacity for ATP synthesis, as shown by a lower respiratory control ratio and weaker contribution of Complex I to respiration. Drive individuals also exhibited an increased basal metabolic rate and consumed a greater amount of food than wild-type individuals. These findings show that the drive genotype imposes metabolic costs in both male and female hosts. The disruption in mitochondrial function likely leads to compensation via an increase in both basal metabolic rate and nutrient acquisition. A potential cause lies in the accumulation of deleterious mutations in the inversions on the X chromosome that house the meiotic drive, which are subject to weak natural selection. In females, the drive chromosome has a dominant effect, with a single copy causing substantial metabolic compromise. There was little evidence of male-specific metabolic costs, nor evidence of an accumulation of sexually antagonistic effects of drive chromosomes on female metabolism. These results suggest that direct metabolic costs from meiotic drive on spermatogenesis and from sexually antagonistic selection are relatively weak. This research provides new insight into the interplay between meiotic drive and metabolism, drawing attention to the broader physiological repercussions selfish genetic elements may have on their hosts.

evolutionary biology↗