1 Introduction

High-altitude plateaus, such as the Qinghai-Tibetan Plateau, possess severe environments with hypoxia, cold, intense ultraviolet radiation, and limited supply of forage. Resident animals, particularly goats, experience heavy physiological and genetic stresses from these environments. To survive these environments, goats developed particular adaptations like enhanced oxygen transport mechanisms, efficient metabolic pathways, and robust immunity. It is significant to appreciate these adaptations to improve livestock productivity and resilience in high-altitude regions (Li et al., 2023).

Goats play a crucial role in livelihoods at the community level in high-altitude regions. They constitute a principal source of meat, milk, fiber, and cash income, especially where other forms of agriculture cannot be practiced (He et al., 2018). Economically, goats play a vital role in that they contribute meaningfully to family incomes as well as food security. Goats also assist in vegetation and land use management in a manner that results in sustainable agriculture. Their ability to survive on marginal soils makes them indispensable in the socioeconomic structure of plateau societies (Jin et al., 2020; Li et al., 2022).

Investigating the genetic basis of high-altitude adaptation in goats is essential for breeding program development to enhance resilience and productivity. Advances in genome editing technologies, particularly CRISPR/Cas9, have revolutionized functional genomics research to date. CRISPR enables precise manipulation of target genes, making it possible to validate candidate genes associated with adaptation traits. Applying CRISPR technology to research goats may be fruitful in accelerating the breeding of animals with enhanced qualities for high-altitude ecosystems and hence increasing sustainable livestock production in such challenging ecosystems.

2 Adaptive Traits and Physiological Characteristics of Plateau Goats

2.1 Plateau-adapted changes in the respiratory and hematological systems

Plateau goats such as the Tibetan cashmere goat have evolved specific respiratory and hematological adaptations to sustain themselves in hypoxic high-altitude environments. Genetic differentiation exists for key oxygen-sensing genes, especially EPAS1, where a new missense mutation (Q579L) is overrepresented in high-altitude populations. This mutation is responsible for improved oxygen transportation and utilization, most likely resulting in increased red blood cell counts and hemoglobin content, which are of crucial importance in successful oxygen delivery under hypoxia (Song et al., 2016; Wang et al., 2016a).

2.2 Regulatory mechanisms of the cardiovascular and metabolic systems

Genomic analyses show that metabolic regulation genes and cardiovascular development genes are under strong selection in plateau goats. Introgressed gene PAPSS2 of wild markhor is strongly correlated with adaptability at high altitude and includes hypoxia-related pathways. Other candidate genes, such as CDK2, SOCS2, NOXA1, and ENPEP, are implicated in adaptation to hypoxia, suggesting that cardiovascular and metabolic pathways are tightly regulated to maximize blood supply, vascular development, and metabolic efficiency during hypoxic stress(Song et al., 2016; Wang et al., 2016b; Li et al., 2022).

2.3 Immune system responses to plateau environments

Adaptation to the harsh plateau environment also encompasses enhanced immune system function. Candidate genes such as CNGA4, Camk2b, and several interleukins (IL7, IL5, IL23A) have been implicated in enhanced immune response and protection from exogenous stressors. These genetic adaptations likely enhance resistance to pathogens and environmental stress, conferring overall health and viability in high-altitude regions. Additional immunity-associated genes and pathways, including the serpin cluster, INFGR1, and TLR2, have also been identified as targets of selection in plateau-adapted goat populations (Chen et al., 2020; Tian et al., 2021; Ghanatsaman et al., 2023).

2.4 Adaptive regulation in reproductive and developmental processes

Reproductive and developmental flexibility in plateau goats is regulated by complex networks of mRNAs, miRNAs, and lncRNAs that mediate ovarian function and reproductive efficiency. These key pathways involve ovarian steroidogenesis, meiosis in oocytes, and amino acid biosynthesis, which are all linked to fertility and adaptive capacity. Such molecular networks regulate the development of germ cells and oocytes and interact with immune and metabolic processes to ensure reproductive success and plasticity in unfavorable environments (Lv et al., 2024). Such adaptations are vital for population viability and productivity under plateau conditions.

3 Research Progress on Plateau Adaptation-Related Genes in Goats

3.1 Identification and screening of candidate adaptive genes

Exome sequencing and whole-genome sequencing are being used, along with high-density SNP chips, in recent research to identify candidate genes for high-altitude adaptation in goats. EPAS1, PAPSS2, LEPR, LDB1, EGFR, FGF2, ENPEP, SIRT6, and CDC42 are a few such genes that play a role in hypoxia response, cardiovascular development, and energy metabolism (Wang et al., 2016a; Song et al., 2016; Jin et al., 2020; Li et al., 2022). In addition, DSG3 was discovered to be a candidate hypoxia adaptation gene through targeted resequencing, which determined specific SNPs that distinguish highland and lowland populations (Kumar et al., 2018). Immune genes CNGA4 and Camk2b were also discovered to contribute to environmental defense and adaptation (Tian et al., 2021).

3.2 Findings from genome-wide association studies (GWAS) and selective sweep analyses

GWAS and selective sweep analysis identified genomic regions under strong selection within arms length plateau goats. For example, a region spanning PAPSS2, introgressed from markhor, exhibits strong association with adaptation to high altitudes (Li et al., 2022). Selective sweep analysis also demonstrated that genes such as CDK2, SOCS2, NOXA1, and ENPEP are selected for hypoxia adaptation (Wang et al., 2016b). VEGF pathway and its genes (e.g., FGF2, EGFR, AKT1, PTEN, KDR) are highly enriched in high-altitude humans, validating their roles in vascular and metabolic adaptation (Jin et al., 2020). The findings provide a genetic basis for phenotypic disparity between highland and lowland breeds of goats.

3.3 Regulatory roles of epigenetics and non-coding RNAs in adaptation

Epigenetic mechanisms, including RNA editing and non-coding RNAs, also play a role in adaptation to high altitudes. A-to-I and C-to-U types of RNA editing sites are variably distributed and expressed in plateau goats and affect genes involved in energy metabolism, translation, and immune response (Li et al., 2023). Multi-omics approaches have uncovered complex mRNA-miRNA-lncRNA networks that regulate ovarian function, reproductive performance, and adaptive capacity, linking reproductive traits to immune and metabolic adaptation (Lv et al., 2024). Such layers of regulation make genetic architecture of plateau adaptation complex.

3.4 Cross-species comparative analyses revealing conserved and specific adaptive mechanisms

Comparative genomics of domestic mammals (e.g., goat, sheep, horse, cattle, pig, dog) is uncovering both species-specific and conserved adaptive pathways. The convergent positive selection of the EPAS1 gene in multiple high-altitude domestic mammals suggests an emergent genetic response to hypoxia (Song et al., 2016; Wu et al., 2019). However, cross-species comparisons also show that closely related species, such as goats and sheep, utilize different genetic pathways and candidate genes for local adaptation, thereby reflecting the set of evolutionary solutions to similar environmental pressures (Figure 1) (Benjelloun et al., 2023). It reflects both the universality as well as specificity of genetic adaptation to high-altitude environments.

4 Functional Genomics Applications Based on CRISPR

4.1 Overview of CRISPR/Cas9 technology principles and advantages

The CRISPR/Cas9 system is a powerful genome editing technique that enables targeted editing through the introduction of double-strand breaks at specific genomic sites, which are then repaired by cellular mechanisms. Its major advantages are high efficiency, versatility, ease of design, and the ability to generate both knockouts and knock-ins. CRISPR/Cas9 has, in a relatively short period, become the dominant technology for genome editing in livestock, taking over from the earlier used ZFNs and TALENs, and has enabled precise genetic modifications for research and agricultural applications (Kalds et al., 2019; Yang, 2024).

4.2 Practical applications of CRISPR editing in goat somatic cells and embryos

CRISPR/Cas9 has also been utilized to edit goat genomes successfully via both somatic cell nuclear transfer (SCNT) and direct embryo microinjection. Primary goat fetal fibroblast cells, for example, have been edited to knock in or knockout genes, and the edited cells have been used to generate live goats through SCNT (Wang et al., 2023). Cas9 mRNA and sgRNAs microinjection into zygotes has enabled effective generation of gene-edited goats, such as successful editing of MSTN and FGF5 genes, and demonstrated germline transmission of edited alleles (Wang et al., 2015; Wang et al., 2018; He et al., 2018). These techniques have been used to generate goats with enhanced production traits and altered milk composition (Li et al., 2024; Singh, 2024; Zhu et al., 2025). This technique employs the CSN2 promoter to enable the specific expression of HNP1 in the mammary gland and then convert it into an antimicrobial peptide-producing bioreactor. Our research not only confirms the feasibility of generating HNP1-expressing goats but also lays a basis for the generation of novel, high-quality dairy foods using CRISPR/Cas9 technology in goats. Moreover, it indicates the promise of CRISPR/Cas9 as a valuable tool for genetic engineering in this animal (Figure 2) (Li et al., 2024).

4.3 Case studies of functional validation of candidate plateau adaptive genes

Functional verification using CRISPR/Cas9 has targeted genes with proven or postulated roles in adaptation and production. MSTN gene knockout, for example, has resulted in goats with increased body mass and muscle fiber diameter, confirming the function of the gene in muscle growth and metabolism (He et al., 2018; Wang et al., 2018). Simultaneously, knockout and knock-in technologies have been utilized to knock in exogenous genes (e.g., fat-1, rhBChE) into specific loci and knockout endogenous genes, demonstrating the feasibility of complex genome editing in goats (Zhang et al., 2018; Wang et al., 2023). These results provide direct evidence of gene function and form the basis for plateau adaptation-related gene validation (Xuan, 2024).

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 transfection systems, maximizing homology arm lengths, and exhaustive screening for off-target events (Bertolini et al., 2018; Wang et al., 2023).

6.2 Limitations in model construction and ethical supervision

Even with the ease of how CRISPR/Cas9 has made it possible to generate gene-edited goats for both agricultural applications and biomedical investigation, constructing strong large-animal models is complex. Issues such as mosaicism, variable editing efficiency, and health issues in edited animals (e.g., MSTN knockout-induced abnormal growth or risk to health) highlight the need for strong model verification and prolonged observation (Guo et al., 2016). In addition, there needs to be ethical regulation, considering that gene editing livestock raises animal welfare, environmental impact, and food safety concerns demanding stringent regulatory frameworks (Lu et al., 2024).

6.3 Integration trends of high-throughput screening and single-cell editing technologies

New directions in CRISPR research include the merging of high-throughput screening and single-cell editing technology. Such approaches enable systematic identification of functional genes and regulatory factors at scale, as well as cellular heterogeneity dissection in gene-edited populations. Such integration is expected to accelerate the discovery of adaptive genes and pathways, improve precision editing, and assist in developing more sophisticated breeding schemes (Kalds et al., 2019; Lu et al., 2024).

6.4 Strategic considerations for applying CRISPR to goat germplasm innovation and plateau breeding

For breeding for adaptability to plateaus and germplasm innovation, CRISPR/Cas9 can potentially introduce or enhance favorable genes, such as enhanced muscle development, fiber quality, or disease resistance (Wang et al., 2016; He et al., 2018; Wang et al., 2018). Strategic implementation includes technical feasibility, stability of traits, and biosafety and ensuring the heritability of edited alleles and the absence of unintended effects (Wang et al., 2016; Wang et al., 2018; Wang et al., 2023). Continuous research, ethical management, and coordination with omics information will be necessary for effective and responsible application of CRISPR technology in goat breeding programs (Zhong et al., 2023).

7 Concluding Remarks

Recent genetic research has significantly enhanced understanding of plateau adaptation in goats. Genome-wide examinations have identified numerous genes and pathways, such as EPAS1, PAPSS2, LEPR, FGF2, and others, which are strongly associated with hypoxia response, cardiovascular development, and high-altitude energy metabolism. Introgression of wild species, such as the markhor, has also contributed adaptive alleles (e.g., PAPSS2) to Tibetan goats for enhancing survival under severe conditions. Functional studies and expression profiling have validated the physiological adaptation functions of these genes, though other candidate immune response and stress response genes have also been discovered.

Even so, several research gaps and technical constraints still remain. For most candidate genes, functional verification is still in its infancy, and the molecular mechanisms underlying complex traits like hypoxia tolerance and immune adaptation are not yet well elucidated. Additional more comprehensive integration of multi-omics data (e.g., transcriptomics, metabolomics, epigenomics) is also needed to comprehensively reconstruct adaptive regulatory networks. Technical hurdles are improving the specificity and efficacy of the gene editing reagents, reducing off-target effects, and developing efficient large-animal models for functional analysis.

The CRISPR technology possesses vast possibilities for accelerating innovation in plateau-adapted goat germplasm. By enabling precise editing of adaptive genes, CRISPR possesses the ability to facilitate the introduction or enhancement of traits such as tolerance to hypoxia, resistance to disease, and improved production traits. Future studies should focus on refining gene editing protocols through integrating high-throughput screening and single-cell technologies and following ethical and biosafety standards. Strategic application of CRISPR, supported by advanced genomic knowledge, will facilitate sustainable breeding and conservation of high-altitude adaptable goats.

Acknowledgments

We thank the Animal Disease Research team for support and assistance in data acquisition and data collection.

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

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