{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T03:54:31Z","timestamp":1784433271573,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tianyou Youth Talent Lift Program of Lanzhou Jiaotong University","award":["1520260502"],"award-info":[{"award-number":["1520260502"]}]},{"name":"Tianyou Youth Talent Lift Program of Lanzhou Jiaotong University","award":["1520260501"],"award-info":[{"award-number":["1520260501"]}]},{"name":"Tianyou Youth Talent Lift Program of Lanzhou Jiaotong University","award":["GSWSKY2024-13"],"award-info":[{"award-number":["GSWSKY2024-13"]}]},{"name":"Tianyou Youth Talent Lift Program of Lanzhou Jiaotong University","award":["2025QB-032"],"award-info":[{"award-number":["2025QB-032"]}]},{"name":"Tianyou Youth Talent Lift Program of Lanzhou Jiaotong University","award":["25JRRA958"],"award-info":[{"award-number":["25JRRA958"]}]},{"name":"Health and Wellness Industry Research Program of Gansu Province","award":["1520260502"],"award-info":[{"award-number":["1520260502"]}]},{"name":"Health and Wellness Industry Research Program of Gansu Province","award":["1520260501"],"award-info":[{"award-number":["1520260501"]}]},{"name":"Health and Wellness Industry Research Program of Gansu Province","award":["GSWSKY2024-13"],"award-info":[{"award-number":["GSWSKY2024-13"]}]},{"name":"Health and Wellness Industry Research Program of Gansu Province","award":["2025QB-032"],"award-info":[{"award-number":["2025QB-032"]}]},{"name":"Health and Wellness Industry Research Program of Gansu Province","award":["25JRRA958"],"award-info":[{"award-number":["25JRRA958"]}]},{"name":"Education Institutions of Gansu of Gansu Provincial Education Department","award":["1520260502"],"award-info":[{"award-number":["1520260502"]}]},{"name":"Education Institutions of Gansu of Gansu Provincial Education Department","award":["1520260501"],"award-info":[{"award-number":["1520260501"]}]},{"name":"Education Institutions of Gansu of Gansu Provincial Education Department","award":["GSWSKY2024-13"],"award-info":[{"award-number":["GSWSKY2024-13"]}]},{"name":"Education Institutions of Gansu of Gansu Provincial Education Department","award":["2025QB-032"],"award-info":[{"award-number":["2025QB-032"]}]},{"name":"Education Institutions of Gansu of Gansu Provincial Education Department","award":["25JRRA958"],"award-info":[{"award-number":["25JRRA958"]}]},{"name":"Natural Science Foundation for Young Scholars of Gansu Province","award":["1520260502"],"award-info":[{"award-number":["1520260502"]}]},{"name":"Natural Science Foundation for Young Scholars of Gansu Province","award":["1520260501"],"award-info":[{"award-number":["1520260501"]}]},{"name":"Natural Science Foundation for Young Scholars of Gansu Province","award":["GSWSKY2024-13"],"award-info":[{"award-number":["GSWSKY2024-13"]}]},{"name":"Natural Science Foundation for Young Scholars of Gansu Province","award":["2025QB-032"],"award-info":[{"award-number":["2025QB-032"]}]},{"name":"Natural Science Foundation for Young Scholars of Gansu Province","award":["25JRRA958"],"award-info":[{"award-number":["25JRRA958"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Complete environmental adaptation requires both survival and reproductive success. The hypoxic Qinghai-Tibet Plateau (&gt;3000 m) challenges reproduction in indigenous species. Tibetan sheep, a key plateau-adapted breed, possess remarkable hypoxic tolerance, yet the genetic basis of their reproductive success remains poorly understood. Methods: We integrated transcriptomic and genomic data from Tibetan sheep and two lowland breeds (Small-tailed Han sheep and Hu sheep) to identify Tibetan sheep reproduction-associated genes (TSRGs). Results: We identified 165 TSRGs: four genes were differentially expressed (DEGs) versus Small-tailed Han sheep, 77 DEGs versus Hu sheep were found, and 73 genes were annotated in reproductive pathways. Functional analyses revealed enrichment for spermatogenesis, embryonic development, and transcriptional regulation. Notably, three top-ranked selection signals (VEPH1, HBB, and MEIKIN) showed differential expression. Murine Gene Informatics (MGI) confirmed that knockout orthologs exhibit significant phenotypes including male infertility, abnormal meiosis (male\/female), oligozoospermia, and reduced neonatal weight. Conclusions: Tibetan sheep utilize an evolved suite of genes underpinning gametogenesis and embryogenesis under chronic hypoxia, ensuring high reproductive fitness\u2014a vital component of their adaptation to plateaus. These genes provide valuable genetic markers for the selection, breeding, and conservation of Tibetan sheep as a critical genetic resource.<\/jats:p>","DOI":"10.3390\/genes16080909","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T07:37:23Z","timestamp":1753861043000},"page":"909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular Genetic Basis of Reproductive Fitness in Tibetan Sheep on the Qinghai-Tibet Plateau"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6174-4746","authenticated-orcid":false,"given":"Wangshan","family":"Zheng","sequence":"first","affiliation":[{"name":"School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China"},{"name":"Provincial R&D Institute of Ruminants in Gansu, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Ge","sequence":"additional","affiliation":[{"name":"School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehui","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Primate Biomedical Research, Kunming University of Science and Technology, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Li","sequence":"additional","affiliation":[{"name":"School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Leng","sequence":"additional","affiliation":[{"name":"School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohu","family":"Kang","sequence":"additional","affiliation":[{"name":"School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrong","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1126\/science.aaf5098","article-title":"Going global by adapting local: A review of recent human adaptation","volume":"354","author":"Fan","year":"2016","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.quaint.2016.09.045","article-title":"Human Genetic Adaptation to High Altitudes: Current Status and Future Prospects","volume":"461","author":"Moore","year":"2017","journal-title":"Quat. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4037","DOI":"10.1016\/j.cub.2023.08.021","article-title":"Polygenic adaptation leads to a higher reproductive fitness of native Tibetans at high altitude","volume":"33","author":"He","year":"2023","journal-title":"Curr. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"R1064","DOI":"10.1016\/j.cub.2023.09.023","article-title":"Human genetics: An extreme fitness landscape","volume":"33","author":"Mathieson","year":"2023","journal-title":"Curr. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s10739-018-9509-z","article-title":"Darwin\u2019s two theories, 1844 and 1859","volume":"51","author":"Partridge","year":"2018","journal-title":"J. Hist Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1002\/ajhb.1102","article-title":"Tibetan protection from intrauterine growth restriction (IUGR) and reproductive loss at high altitude","volume":"13","author":"Moore","year":"2001","journal-title":"Am. J. Hum Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"RP89004","DOI":"10.7554\/eLife.89004","article-title":"Sex-biased regulatory changes in the placenta of native highlanders contribute to adaptive fetal development","volume":"12","author":"Yue","year":"2024","journal-title":"eLife"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zheng, W., He, Y., Guo, Y., Yue, T., Zhang, H., Li, J., Zhou, B., Zeng, X., Li, L., and Wang, B. (2023). Large-scale genome sequencing redefines the genetic footprints of high-altitude adaptation in Tibetans. Genome Biol., 24.","DOI":"10.1186\/s13059-023-02912-1"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Li, X., Han, B., Liu, D., Wang, S., Wang, L., Pei, Q., Zhang, Z., Zhao, J., Huang, B., and Zhang, F. (2024). Whole-genome resequencing to investigate the genetic diversity and mechanisms of plateau adaptation in Tibetan sheep. J. Anim Sci. Biotechnol., 15.","DOI":"10.1186\/s40104-024-01125-1"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1093\/nsr\/nwz213","article-title":"Convergent genomic signatures of high-altitude adaptation among domestic mammals","volume":"7","author":"Wu","year":"2020","journal-title":"Natl. Sci. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yang, Y., Yuan, H., Yao, B., Zhao, S., Wang, X., Xu, L., and Zhang, L. (2024). Genetic Adaptations of the Tibetan Pig to High-Altitude Hypoxia on the Qinghai-Tibet Plateau. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252011303"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.resp.2011.04.017","article-title":"Humans at high altitude: Hypoxia and fetal growth","volume":"178","author":"Moore","year":"2011","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2322291121","DOI":"10.1073\/pnas.2322291121","article-title":"Genomic structural variation contributes to evolved changes in gene expression in high-altitude Tibetan sheep","volume":"121","author":"Liang","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Shi, H., Li, T., Su, M., Wang, H., Li, Q., Lang, X., and Ma, Y. (2023). Whole genome sequencing revealed genetic diversity, population structure, and selective signature of Panou Tibetan sheep. BMC Genom., 24.","DOI":"10.1186\/s12864-023-09146-2"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Liu, H., Hu, L., Han, X., Zhao, N., Xu, T., Ma, L., Wang, X., Zhang, X., Kang, S., and Zhao, X. (2020). Tibetan Sheep Adapt to Plant Phenology in Alpine Meadows by Changing Rumen Microbial Community Structure and Function. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.587558"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1111\/rda.14432","article-title":"The role of GnRH in Tibetan male sheep and goat reproduction","volume":"58","author":"Zhao","year":"2023","journal-title":"Reprod. Domest. Anim."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"110973","DOI":"10.1016\/j.ygeno.2024.110973","article-title":"Transcriptome and metabolome revealed the effects of hypoxic environment on ovarian development of Tibetan sheep","volume":"117","author":"Zhang","year":"2025","journal-title":"Genomics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"991","DOI":"10.5713\/ab.22.0432","article-title":"Genetic diversity and selection of Tibetan sheep breeds revealed by whole-genome resequencing","volume":"36","author":"Tian","year":"2023","journal-title":"Anim. Biosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"dvac029","DOI":"10.1093\/eep\/dvac029","article-title":"Effects of paternal methionine supplementation on sperm DNA methylation and embryo transcriptome in sheep","volume":"9","author":"Townsend","year":"2023","journal-title":"Environ. Epigenet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Li, C., Wu, Y., Chen, B., Cai, Y., Guo, J., Leonard, A.S., Kalds, P., Zhou, S., Zhang, J., and Zhou, P. (2022). Markhor-derived Introgression of a Genomic Region Encompassing PAPSS2 Confers High-altitude Adaptability in Tibetan Goats. Mol. Biol. Evol., 39.","DOI":"10.1093\/molbev\/msac253"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e70037","DOI":"10.1111\/rda.70037","article-title":"Transcriptomic Study of Testicular Hypoxia Adaptation in Tibetan Sheep","volume":"60","author":"Yu","year":"2025","journal-title":"Reprod. Domest. Anim."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1126\/science.1183863","article-title":"A composite of multiple signals distinguishes causal variants in regions of positive selection","volume":"327","author":"Grossman","year":"2010","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/s41586-022-05275-y","article-title":"A saturated map of common genetic variants associated with human height","volume":"610","author":"Yengo","year":"2022","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"bbaa227","DOI":"10.1093\/bib\/bbaa227","article-title":"LDBlockShow: A fast and convenient tool for visualizing linkage disequilibrium and haplotype blocks based on variant call format files","volume":"22","author":"Dong","year":"2021","journal-title":"Brief. Bioinform."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/ijlh.12828","article-title":"Genetic basis of congenital erythrocytosis","volume":"40","author":"Bento","year":"2018","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, C., Chen, B., Langda, S., Pu, P., Zhu, X., Zhou, S., Kalds, P., Zhang, K., Bhati, M., and Leonard, A. (2024). Multi-omic Analyses Shed Light on The Genetic Control of High-altitude Adaptation in Sheep. Genom. Proteom. Bioinform., 22.","DOI":"10.1093\/gpbjnl\/qzae030"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.cell.2016.10.042","article-title":"The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease","volume":"167","author":"Astle","year":"2016","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Li, Y., Yang, Y., Yu, B., Gao, R., and Wang, X. (2024). Transcriptome and Metabolome Analyses Reveal High-Altitude Adaptation Mechanism of Epididymis Sperm Maturation in Tibetan Sheep. Animals, 14.","DOI":"10.3390\/ani14213117"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2200421119","DOI":"10.1073\/pnas.2200421119","article-title":"Genetic adaptation of skin pigmentation in highland Tibetans","volume":"119","author":"Yang","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Han, B., Tian, D., Li, X., Liu, S., Tian, F., Liu, D., Wang, S., and Zhao, K. (2024). Multiomics Analyses Provide New Insight into Genetic Variation of Reproductive Adaptability in Tibetan Sheep. Mol. Biol. Evol., 41.","DOI":"10.1093\/molbev\/msae058"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e107","DOI":"10.1002\/imt2.107","article-title":"Ultrafast one-pass FASTQ data preprocessing, quality control, and deduplication using fastp","volume":"2","author":"Chen","year":"2023","journal-title":"Imeta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2824","DOI":"10.1093\/molbev\/msu211","article-title":"Selscan: An efficient multithreaded program to perform EHH-based scans for positive selection","volume":"31","author":"Szpiech","year":"2014","journal-title":"Mol. Biol. Evol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1093\/nsr\/nwz108","article-title":"Prioritizing natural-selection signals from the deep-sequencing genomic data suggests multi-variant adaptation in Tibetan highlanders","volume":"6","author":"Deng","year":"2019","journal-title":"Natl. Sci. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"D18","DOI":"10.1093\/nar\/gkad1078","article-title":"Partners, Database Resources of the National Genomics Data Center, China National Center for Bioinformation in 2024","volume":"52","author":"Members","year":"2024","journal-title":"Nucleic Acids Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/909\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:18:26Z","timestamp":1760033906000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["genes16080909"],"URL":"https:\/\/doi.org\/10.3390\/genes16080909","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,29]]}}}