Cellular mechanism of gain-of-function mutation I173M in sheep MC4R gene identified in year-round and seasonal estrus breeds through whole-genome resequencing
Abstract
BackgroundInvestigating key genes regulating year-round estrus can improve sheep reproductive performance and industry efficiency. Although several candidate genes have been proposed, the key regulators underlying estrus seasonality remain unclear. Therefore, this study aimed to identify critical genetic variants associated with year-round estrus using whole-genome resequencing data from multiple sheep breeds.ResultsIn this study, we analyzed whole-genome resequencing data from 392 sheep across six year-round and ten seasonal estrus breeds, and identified the Melanocortin 4 receptor (MC4R) gene as a key regulator of estrus seasonality. A missense mutation in the MC4R gene, I173M (g.59480440G > C; p.Ile173Met), was significantly enriched in year-round estrus breeds. Transcriptome analysis following MC4R I173M transfection revealed differential expression of genes enriched in reproductive pathways. Subsequent functional experiments demonstrated that the I173M mutation increased MC4R constitutive activity, activated cAMP and MAPK/ERK signaling, and promoted both granulosa cell proliferation and the expression of steroidogenic regulatory genes. Cells harboring the I173M mutation exhibited substantially amplified transcription levels of gonadotropin signaling components. Specifically, follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) were expressed at much higher levels relative to wild-type (WT) controls.ConclusionsOur study provides evidence that MC4R functions as a molecular modulator of estrous cyclicity, with the I173M missense mutation identified as a critical functional variant driving constitutive estrous activity in ovine species.
Related
- T1R2/T1R3 Identified as the Aβ Receptor: A New Mechanism Linking Aβ42/40 Ratio to Neuronal Hyperexcitability in Alzheimer's Disease
- Why are some neurons spared in neurodegeneration? Cellular subtype identity maintenance as a candidate threshold-setting mechanism
- A Zap70 gain-of-function mutation alters mouse thymic maturation
- Loss of function of LprG-Rv1410c and MmpL11 homologues in Mycobacterium smegmatis leads to altered glycopeptidolipid profile and decreased cellular c-di-GMP levels during biofilm formation
- Intravital single-cell behavior profiling reveals disrupted germinal center B cell motility and interactions by EZH2 gain-of-function mutation
BibTeX
@article{yang2026cellular,
title = {{Cellular mechanism of gain-of-function mutation I173M in sheep MC4R gene identified in year-round and seasonal estrus breeds through whole-genome resequencing}},
author = {Yuta Yang and Yuxin Kang and Peiyao Liu and Chunna Cao and Yang Li and Ran Li and Xianyong Lan and Chuanying Pan},
journal = {Genetics Selection Evolution},
year = {2026},
month = oct,
doi = {10.1186/s12711-026-01091-4},
url = {https://hal.science/hal-05804901v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cellular mechanism of gain-of-function mutation I173M in sheep MC4R gene identified in year-round and seasonal estrus breeds through whole-genome resequencing
AU - Yuta Yang
AU - Yuxin Kang
AU - Peiyao Liu
AU - Chunna Cao
AU - Yang Li
AU - Ran Li
AU - Xianyong Lan
AU - Chuanying Pan
PY - 2026
DA - 2026/10/12
JO - Genetics Selection Evolution
DO - 10.1186/s12711-026-01091-4
UR - https://hal.science/hal-05804901v1
AB - BackgroundInvestigating key genes regulating year-round estrus can improve sheep reproductive performance and industry efficiency. Although several candidate genes have been proposed, the key regulators underlying estrus seasonality remain unclear. Therefore, this study aimed to identify critical genetic variants associated with year-round estrus using whole-genome resequencing data from multiple sheep breeds.ResultsIn this study, we analyzed whole-genome resequencing data from 392 sheep across six year-round and ten seasonal estrus breeds, and identified the Melanocortin 4 receptor (MC4R) gene as a key regulator of estrus seasonality. A missense mutation in the MC4R gene, I173M (g.59480440G > C; p.Ile173Met), was significantly enriched in year-round estrus breeds. Transcriptome analysis following MC4R I173M transfection revealed differential expression of genes enriched in reproductive pathways. Subsequent functional experiments demonstrated that the I173M mutation increased MC4R constitutive activity, activated cAMP and MAPK/ERK signaling, and promoted both granulosa cell proliferation and the expression of steroidogenic regulatory genes. Cells harboring the I173M mutation exhibited substantially amplified transcription levels of gonadotropin signaling components. Specifically, follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) were expressed at much higher levels relative to wild-type (WT) controls.ConclusionsOur study provides evidence that MC4R functions as a molecular modulator of estrous cyclicity, with the I173M missense mutation identified as a critical functional variant driving constitutive estrous activity in ovine species.
SN - 0999-193X
SN - 1297-9686
ER -