Multi-omics fine-mapping uncovers a pleiotropic intestinal enhancer variant linking PMAIP1 regulation to pig growth and fatness
- 1Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Laboratory of Swine Genetics and Breeding of Ministry o
Abstract
Genetic loci influencing multiple complex traits often remain difficult to interpret because the underlying functional variants, target genes and tissue contexts are unresolved. Here, we investigated the regulatory basis of a shared signal for average daily gain (ADG) and backfat thickness (BF) in Yorkshire pigs. By integrating GWAS in 7,972 pigs, targeted capture sequencing, LD-based fine-mapping, porcine epigenomic annotations, three-dimensional chromatin interaction maps and functional assays, we narrowed the shared SSC1 signal to a 1.59-Mb interval and functionally prioritized rs334769214 (T>G) as the leading candidate variant. The T>G substitution produced marked allele-specific differences in enhancer activity and nuclear-protein binding, while transcription-factor co-transfection assays identified FOXL1-responsive, allele-dependent regulatory activity. Chromatin interaction and CRISPRa analyses supported a regulatory connection between the rs334769214-containing enhancer and PMAIP1, and PMAIP1 overexpression promoted apoptosis in porcine intestinal epithelial cells. In the capture-sequenced subset, the G allele was associated with higher ADG and BF, consistent with a relative loss-of-activation model. Together, these findings delineate a candidate FOXL1-enhancer-PMAIP1 regulatory pathway and demonstrate how multi-omics fine-mapping can advance a shared quantitative-trait locus toward a testable molecular mechanism underlying variation in growth and fatness.
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BibTeX
@misc{yang2026multiomics,
title = {{Multi-omics fine-mapping uncovers a pleiotropic intestinal enhancer variant linking PMAIP1 regulation to pig growth and fatness}},
author = {H. Yang and M. Hu and Y. Xu and J. Zhang and Y. Zhang and Y. Gou and X. Du and H. Wang and X. Li and Y. Zhao and T. Xiang},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.754598},
url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754598v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Multi-omics fine-mapping uncovers a pleiotropic intestinal enhancer variant linking PMAIP1 regulation to pig growth and fatness
AU - H. Yang
AU - M. Hu
AU - Y. Xu
AU - J. Zhang
AU - Y. Zhang
AU - Y. Gou
AU - X. Du
AU - H. Wang
AU - X. Li
AU - Y. Zhao
AU - T. Xiang
PY - 2026
DA - 2026/09/26
PB - bioRxiv
DO - 10.64898/2026.09.26.754598
UR - https://www.biorxiv.org/content/10.64898/2026.09.26.754598v1
AB - Genetic loci influencing multiple complex traits often remain difficult to interpret because the underlying functional variants, target genes and tissue contexts are unresolved. Here, we investigated the regulatory basis of a shared signal for average daily gain (ADG) and backfat thickness (BF) in Yorkshire pigs. By integrating GWAS in 7,972 pigs, targeted capture sequencing, LD-based fine-mapping, porcine epigenomic annotations, three-dimensional chromatin interaction maps and functional assays, we narrowed the shared SSC1 signal to a 1.59-Mb interval and functionally prioritized rs334769214 (T>G) as the leading candidate variant. The T>G substitution produced marked allele-specific differences in enhancer activity and nuclear-protein binding, while transcription-factor co-transfection assays identified FOXL1-responsive, allele-dependent regulatory activity. Chromatin interaction and CRISPRa analyses supported a regulatory connection between the rs334769214-containing enhancer and PMAIP1, and PMAIP1 overexpression promoted apoptosis in porcine intestinal epithelial cells. In the capture-sequenced subset, the G allele was associated with higher ADG and BF, consistent with a relative loss-of-activation model. Together, these findings delineate a candidate FOXL1-enhancer-PMAIP1 regulatory pathway and demonstrate how multi-omics fine-mapping can advance a shared quantitative-trait locus toward a testable molecular mechanism underlying variation in growth and fatness.
ER -