Animal Molecular Breeding, 2025, Vol.15, No.1, 1-8 http://animalscipublisher.com/index.php/amb 5 4.4 Reconstruction of regulatory networks via integration with transcriptomics, metabolomics, and other omics Coupling CRISPR-enabled functional genomics with transcriptomics, metabolomics, and other omics tools enables the reconstruction of regulatory networks underlying adaptive phenotypes. For instance, goats that have been edited for specific genes can be compared for gene expression, protein profiles, and metabolic pathways to decipher the downstream effect of specific genetic changes (Kalds et al., 2019). This systems-level approach facilitates worldwide mapping of gene function and interaction, and thus the recognition of chief regulators and pathways that shape high-altitude adaptation and additional complex traits. 5 Molecular Mechanisms of Plateau Adaptation in Goats 5.1 Central role of the HIF pathway in hypoxia response The hypoxia-inducible factor (HIF) pathway is key to goat adaptation to the high-altitude hypoxic environment. EPAS1 is a gene encoding for an essential element of the HIF pathway that shows strong selection and enrichment in high-altitude goats. A missense mutation (Q579L) of EPAS1, which is located near the HIF-1 domain, is uniquely found in high-altitude goats and highlights its central role in oxygen sensing and hypoxia adaptation (Song et al., 2016; Wu et al., 2019). In addition, the PAPSS2 gene identified by GWAS and function analysis participates in hypoxia pathways and further indicates the importance of the HIF pathway in plateau adaptation (Li et al., 2022). 5.2 Coordinated regulation of energy metabolism and redox systems Goat high-altitude adaptation requires the coordinated control of energy metabolism and redox balance. RNA editing research indicates that those genes that possess population-specific editing sites are functionally engaged in ATP binding, translation, and adaptive immune response, all of which are particularly important for energy metabolism during hypoxic stress (Li et al., 2023). Genes such as FGF2, EGFR, AKT1, PTEN, SIRT6, and CDC42, which are enriched in the VEGF pathway, also function in the regulation of metabolism and vascular adaptation to secure efficient energy utilization and redox homeostasis during plateau life (Jin et al., 2020). 5.3 Involvement of stress proteins and apoptosis mechanisms Mechanisms of apoptosis and stress proteins are involved in the cellular response to high-altitude stress. Functional analysis indicates that the genes involved in cellular stress responses, such as protein folding and apoptosis regulation, are under selection in plateau goats. For example, the DSG3 gene, by its specific non-synonymous mutations in high-altitude populations, can participate in cellular hypoxic stress tolerance and regulate apoptosis pathways for survival in extreme environments (Kumar et al., 2018). The regulation of stress and apoptotic responses can be further brought about by RNA editing events targeting protein products (Li et al., 2023). 5.4 The relationship between plateau adaptation and developmental program regulation Developmental program regulation is directly linked to plateau adaptation in goats. Multi-omics investigations have identified mRNA-miRNA-lncRNA networks that regulate ovarian function, reproductive performance, and developmental processes. They influence germ cell and oocyte development and are enriched in steroidogenesis, meiosis, and amino acid biosynthesis pathways needed for reproductive success and adaptive capacity (Lv et al., 2024). The integration of developmental regulation with immune and metabolic pathways underscores the complex molecular basis of plateau adaptation in goats (Liu et al., 2025). 6 Prospects and Challenges in the Application of CRISPR Technology 6.1 Technical optimization: off-target effects and editing efficiency issues CRISPR/Cas9 technology has made it possible to efficiently edit genes in goats, but there are issues with off-target effects and editing efficiency. Despite very high mutation rates and successful knockouts of genes, e.g., in MSTN and FGF5 genes, the success of precise knock-in events (e.g., homologous recombination) is still low, and off-target mutations must be closely followed and maintained very low to be safe and reliable for use in breeding (Wang et al., 2015; Wang et al., 2023; Lu et al., 2024). Optimization strategies include improving
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