Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.04.29.591686

An extended omnigenic model explains genome-phenome relationships for complex traits in global sorghum diversity

Hu, Z.·Wang, X.·Marla, S. R.·Poland, J.·Morris, G. P.
View original source ↗Export metadata ↓

Abstract

A central finding of complex trait genetics is the geometric distribution of effect sizes, but the biological basis of this phenomena is not understood. The omnigenic model (OM) could explain this architecture, with oligogenic variation arising from direct regulatory genes (core genes) and polygenic variation from indirect regulators (peripheral trans regulators). Plant yield is a canonical complex trait and here we tested the OM using genome-phenome analysis of biomass yield in global sorghum diversity. We used field-based phenomics to characterize dynamic growth and yield formation traits, then decomposed oligogenic and polygenic components of variation using genome-wide association studies (GWAS), genome-wide prediction (GWP), and tissue-specific transcriptome analyses. We identified major dynamic QTL, including several persistent (Dw1, Dw3) or transient (ELF3) QTL at known genes, consistent with the oligogenic-core of the OM. Next, we evaluated a key prediction on the peripheral-polygenic component - a positive correlation between GWP marker loadings and gene expression in relevant tissues. GWP loadings are indeed correlated with gene expression in relevant tissues. However, correlations are often higher with non-relevant tissues from earlier growth stages or tissues, which is not predicted by within-tissue trans regulation for the peripheral-polygenic component (the "omnigenic in space" model). Therefore, these findings suggest that genes expressed in early growth stages, with indirect effects on later traits, are contributing to polygenic variation ("omnigenic in time"). Together, our findings suggest that an extended OM, with regulatory effects both in space and in time, could explain the ubiquitous geometric genetic architecture of complex traits.

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Hu, Z., Wang, X., Marla, S. R., Poland, J., Morris, G. P.. 2024-04-29. An extended omnigenic model explains genome-phenome relationships for complex traits in global sorghum diversity. https://doi.org/10.1101/2024.04.29.591686

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.

genetics↗
bioRxiv2026

Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age

Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.

genetics↗
bioRxiv2026

Innate immune stress pathway activation underlies heterochromatin dysfunction pathology

Heterochromatin loss disrupts nuclear architecture, gene regulation and repetitive element silencing, and is associated with diverse human diseases. However, mechanisms linking heterochromatin dysfunction to pathological phenotypes remain unclear. Using genetic interaction screening and genomic analyses in C. elegans, we identify secondary activation of the Intracellular Pathogen Response (IPR), an innate immune stress pathway, as a major contributor to heterochromatin mutant phenotypes. Constitutive IPR activation phenocopies slow growth and indirect transcriptional changes observed in these mutants. Depletion of genetic enhancers further increased, whereas suppressor RNAi attenuated IPR activation, with direct heterochromatin targets remaining substantially deregulated. Notably, many suppressors encode active chromatin components, and mild reduction of RNA polymerase II activity ameliorates growth defects in C. elegans HP1 mutants and human HP1-deficient cells. Our findings reveal secondary stress response activation as an important mechanism linking heterochromatin dysfunction to pathology and identify transcriptional dampening as a potential therapeutic strategy for mitigating these effects.

genetics↗