Potential Genetic Markers Associated with Environmental Adaptability in Herbivorous Livestock

Simple Summary

Environmental adaptation is a crucial factor for ensuring the health, survival, and productivity of herbivorous livestock. In recent years, researchers have identified several candidate genes that play a key role in climate adaptation, fundamental to the ability of herbivorous livestock to thrive under varying environmental conditions. This review aims to examine these genetic markers in detail, exploring their potential roles and impacts on various forms of environmental adaptation. The findings herein provide a scientific foundation for developing breeding strategies that can produce livestock breeds better equipped to face climate change.

Abstract

Herbivorous livestock, such as cattle, sheep, goats, horses, and donkeys, play a crucial role in agricultural production and possess remarkable resilience to extreme environmental conditions, driven by complex genetic mechanisms. Recent advancements in high-throughput sequencing, genome assembly, and environmental data integration have enabled a deeper understanding of the genetic basis of their environmental adaptation. This review identifies key genes associated with high-altitude, heat, cold, and drought adaptation, providing insights into the molecular mechanisms underlying these traits. By elucidating these genetic adaptations, our study aims to support conservation efforts, inform selective breeding programs, and enhance agricultural productivity, ultimately contributing to sustainable livestock farming and economic benefits for farmers.

1. Introduction

The climate and environment play a pivotal role in the long-term genetic evolution of species [1,2,3,4,5]. They not only act as core drivers of genetic variation but also have a profound influence on the formation and maintenance of biodiversity [6,7,8,9]. It has been well documented that environmental changes exert a wide range of effects on animal populations, which manifest not only in physical traits but also in the structure and function of tissues and organs, the regulation of physiological and biochemical processes, and gene expression [10,11,12]. Such adaptive responses enhance the ability of animal populations to thrive in changing environments, thereby reducing the risk of population extinction. Understanding how environmental factors mediate genetic variation and adaptation remains a central challenge in evolutionary genetics. Environmental changes, such as fluctuations in temperature, precipitation, and the availability of food and water, exert significant selection pressures on organisms [13,14]. These pressures drive genetic adaptations that enhance survival and reproductive success. Herbivorous livestock species, including cattle, sheep, horses, and donkeys, provide notable examples of such adaptations. Over extended evolutionary periods, these animals have developed remarkable resilience to fluctuations in environmental conditions, such as variations in oxygen levels, temperature, humidity, and water availability. Notably, these species are capable of thriving in extreme climatic conditions, including high altitudes, heat, cold, and drought. They have become essential providers of material resources for humans living in such challenging environments; for example, the goat, often referred to as the ’poor man’s cow’, is particularly known for its adaptability [15]. Investigating the genetic markers associated with these environmental adaptations is therefore critical for identifying the genes responsible for specific adaptive traits.

On the one hand, the growing emphasis on ecological and environmental conservation, combined with advancements in global climate monitoring technologies [16,17,18], has facilitated the collection and integration of extensive environmental data. These data, stored in detailed climate databases, include key climatic parameters such as temperature, humidity, water quality, and oxygen partial pressure [19,20]. These resources provide robust datasets for investigating the genetic basis of environmental adaptability in organisms [21]. On the other hand, the rapid development of next-generation sequencing technologies has enabled high-quality genome sequencing and assembly for a wide range of plant and animal species [22,23,24,25]. With the advantages of low cost, high throughput, and speed [26,27], next-generation sequencing (NGS) technologies have accelerated genomic research and laid the groundwork for identifying molecular genetic mechanisms underlying environmental adaptation in plants and animals [28]. As a result, the integration of genetic and environmental data has become a prominent area of research, attracting considerable attention from the scientific community worldwide.

By linking genetic data with environmental variables, researchers can more precisely identify genetic markers that are influenced by environmental factors. This is essential for understanding the molecular mechanisms of environmental adaptation [29,30]. Approaches commonly used for this purpose include whole-genome sequencing and the application of statistical methods to assess genetic differentiation (F_ST), nucleotide polymorphisms (π), gene frequencies (Tajima’s D, ZHp, CLR, Hp), and measures of linkage disequilibrium (EHH, iHS, XP-EHH) [31,32,33]. These methods enable the identification of specific loci or genomic regions under environmental selection pressures.

The identification of genes associated with environmental adaptation is of paramount importance, particularly for the livestock industry. Enhancing the genetic resilience of livestock can have significant benefits, improving key economic traits such as production efficiency and reproductive success. Despite significant advancements in genomic technologies, there remains a critical gap in identifying the specific genetic mechanisms that enable local livestock breeds to adapt to extreme environmental conditions. Therefore, this review aims to provide an overview of recent advancements in the identification of genetic markers linked to environmental adaptations in cattle, sheep, goats, horses, and donkeys. By synthesizing current research, this article seeks to offer valuable insights and lay a strong foundation for future genomic studies in breeding, conservation, and molecular strategies aimed at improving animal welfare and ensuring sustainable livestock production.

2. Environment-Induced Adaptations in Herbivorous Livestock

Herbivorous livestock have developed a diverse array of environmentally induced adaptations, enabling them to survive and thrive in a variety of extreme habitats. These adaptations manifest across multiple levels, including morphological changes in appearance and growth patterns, structural modifications in tissues and organs, and shifts in blood physiological and biochemical parameters. Collectively, these adaptive traits underscore the complex interplay between genetic, physiological, and environmental factors, offering critical insights into the resilience and survival mechanisms of these animals. In this section, we will systematically explore these adaptations to uncover the underlying mechanisms that facilitate their environmental adaptability.

2.1. Appearance and Growth Characteristics

Livestock raised in high-altitude environments typically exhibit smaller body sizes, dense coats, and robust physiques, all of which contribute to enhanced disease resistance and stress tolerance. These traits are essential for survival in cold and oxygen-deprived environments at elevated altitudes, where they help mitigate environmental stressors such as low temperatures and reduced atmospheric oxygen [34,35,36,37]. In contrast, animals residing in hot environments generally possess lighter-colored and shorter coats, as well as smooth, thin skin. These features are advantageous for minimizing heat absorption and promoting efficient heat dissipation, thus enhancing their ability to survive extreme temperatures [38,39,40]. However, the challenging conditions in both cold, hypoxic high-altitude environments and hot, arid regions may lead to stunted growth, heat stress, reduced fertility, and increased susceptibility to infectious diseases. These factors can significantly influence the survival and reproductive success of these populations [41,42].

2.2. Morphological Adaptations of Tissues and Organs

Adaptations to high-altitude environments are notably reflected in the size and structure of vital organs, such as the heart and lungs, which are critical for survival in hypoxic conditions. In Tibetan sheep, for example, the lung-to-body weight ratio increases significantly as the altitude rises from 3500 m to 4500 m, while the heart-to-body weight ratio also exhibits a marked increase with higher elevations (2500, 3500, and 4500 m). Additionally, Tibetan sheep exhibit several key physiological adaptations, including increased pulmonary arterial volume, pulmonary arterial wall hypertrophy, enhanced elastic fiber content [43], and elevated alveolar density [44]. Similarly, the pulmonary architecture of yaks displays distinctive structural characteristics compared to lowland cattle, including an expanded alveolar surface area, attenuated alveolar septa and blood–gas barriers, and the presence of smooth muscle within microarteriolar walls (<50 μm in diameter), which collectively enhance gas exchange efficiency under hypoxic high-altitude conditions [45]. In extreme environments, adipose tissue accumulation serves critical functions in thermoregulation and energy reserve maintenance. A notable example is the fat tail of sheep, which enables these animals to endure periods of drought, food scarcity, and harsh climatic conditions [46]. Additionally, in arid regions, the increased dermal thickness of Kazakhstan’s white-headed cattle and the higher number of sebaceous glands in Kalmyk cattle enhance their resilience to extreme weather conditions [47].

2.3. Blood Physiological and Biochemical Indices

Blood physiological and biochemical parameters are crucial indicators of an animal’s adaptive responses to environmental stress. A study examining Baruwal sheep grazing at altitudes ranging from 2431 m to 3885 m revealed a significant increase in erythrocyte count, hemoglobin concentration, and erythrocyte pressure volume with increasing altitude [48]. Comparative studies on the hematological profiles of Tibet Alpine yaks (5100 m), Gannan yaks (3585 m), and Tianzhu white yaks (2960 m) demonstrated a significant elevation in red blood cell count (RBC), hematocrit (HCT), mean corpuscular volume (MCV), hemoglobin concentration (Hb), and mean corpuscular hemoglobin concentration (MCHC) in the Tibetan Alpine yaks, relative to the lower-altitude populations. These elevated blood indices reflect the adaptive response to hypoxic conditions, which is further supported by the increased activity of lactic acid (LA) and lactic dehydrogenase (LDH) [49].

In heat-tolerant livestock, such as N’Dama cattle (African trypanosome-tolerant) and White Fulani cattle (heat-tolerant), distinct differences in blood physiological indices have been observed. The White Fulani cattle exhibit significantly higher levels of albumin, hemoglobin, and mean hemoglobin content compared to the N’Dama cattle, which is believed to contribute to their superior heat tolerance [50]. Similarly, seasonal variations in blood indices have been reported in heat- and cold-tolerant sheep breeds, including Sirohi and Barbari (heat-tolerant) and Gaddi and Chegu (cold-tolerant). In general, hemoglobin (Hb), packed cell volume (PCV), total erythrocyte count (TEC), and total leukocyte count (TLC) were found to be higher in winter and lower in summer, with heat-tolerant breeds showing a less pronounced seasonal decline than cold-tolerant breeds. Furthermore, plasma enzyme levels (e.g., aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), thyroid hormones (triiodothyronine (T3) and thyroxine (T4)), and blood glucose levels were significantly elevated in cold-tolerant breeds compared to their heat-tolerant counterparts [51]. Under drought conditions, dehydration leads to hemoconcentration and reduced blood volume in livestock, resulting in increased hemoglobin levels and erythrocyte pressure volume. Additionally, serum proteins, such as albumin, are elevated, although prolonged dehydration can cause a reduction in albumin levels and serum urea concentration [52].

3. Potential Genetic Markers Associated with Environmental Adaptation of Herbivorous Livestock

3.1. Genes Linked to Adaptations to High-Altitude Environments

High-altitude environments are characterized by hypoxic conditions, low temperatures, and increased ultraviolet radiation, all of which impose significant physiological challenges on the species inhabiting these regions [35]. The persistent selective pressures exerted by these harsh conditions have led to the evolution of specialized physiological traits in various species. These traits are often underpinned by specific genetic adaptations that enable organisms to survive and thrive in such extreme environments [53]. The adaptive mechanisms at high altitudes are primarily driven by selective genetic changes within the genome, which have been identified through studies of gene expression, polymorphisms, and molecular pathways associated with oxygen transport, thermoregulation, and cellular protection from oxidative stress.

A study examining the EPAS1 gene, a key regulator of hypoxia responses, revealed evidence of positive selection in the genomes of several Tibetan domestic animals, including Tibetan goats, Tibetan horses, Tibetan sheep, Tibetan Mastiffs, Tibetan cattle, and Tibetan pigs. These findings provide valuable insights into the molecular mechanisms underlying adaptation to high-altitude conditions [11]. Ahmad et al. [54] further demonstrated that, in comparison to low-altitude cattle, several genes related to energy metabolism, oxygen transport, and body temperature regulation exhibited signs of positive selection in the yak genome. Notable examples include CAMK2B, which encodes a calcium signaling protein, and GLUL, a gene involved in nitrogen metabolism. These adaptations suggest that yaks are able to enhance nutrient absorption efficiency and adjust their energy metabolism to thrive under low-oxygen and high-altitude conditions [54]. Additionally, Lyu et al. [55] revealed a series of key genes through genome selection analyses that are closely associated with plateau adaptation, lipid metabolism, energy metabolism, immunity, and body size. These genes, introgressed into the genome of Tibetan cattle from yaks at varying altitudes, are involved in hypoxia response, cold adaptation, DNA damage repair, and ultraviolet radiation resistance, collectively enhancing the species’ response to high-altitude environments. Consistently, Terefe et al. [56] identified three new candidate genes (CLCA2, SLC26A2, and CBFA2T3) that are strongly selected in Ethiopian mountain cattle populations, along with the previously reported ITPR2 gene. These genes are associated with the renin secretion KEGG pathway, ion channel activity, and response to hypoxia, which may play a crucial role in the adaptation of Ethiopian cattle to their high-altitude environment. The whole-genome analysis of Ladakhi cattle revealed a significant contribution from various genes to their adaptability in the high-altitude Himalayan environment. These genes primarily participate in processes related to hypoxia adaptation, energy metabolism, cold adaptation, and circadian rhythm. Notably, the interaction between genes associated with hypoxia signal transduction (HIF-1) and several enriched pathways (including PI3K, mTOR, NF-κB, ERK, and ER stress) plays a crucial role in constructing the complex adaptation mechanism of Ladakhi cattle under hypoxic stress conditions [57]. In addition, studies identified differentially expressed genes in the heart, lungs, and pulmonary vasculature of yaks and gayal, which contribute to high-altitude adaptation. Genes such as UQCRC1, COX5A, CAPS, EDN3, and CHRM2 are involved in processes like oxidative phosphorylation, pulmonary vasoconstriction, and cardiac function, providing further evidence of genetic adaptations that optimize oxygen delivery and metabolic function at high altitudes. Notably, EGLN1, a key gene in the hypoxia-sensing pathway, was found to be downregulated across various tissues in both gayal and yak compared to lowland cattle, highlighting its role in facilitating adaptation to hypoxic environments [58]. Consequently, Wang et al. [59] reported that the expression of ACSS2 in the liver of Tibetan cattle, residing at an altitude of 3600 m, was significantly higher than in Holstein cattle. This upregulation of ACSS2 is thought to enhance metabolic efficiency via the HIF pathway, further contributing to the animal’s adaptation to hypoxic conditions. Similarly, Bao et al. [60] demonstrated that mitochondria is critical for adaptation to hypoxia. They identified several genes associated with hypoxic adaptation in the lungs, muscles, and spleens, including those encoding heat shock proteins (HSPB7, HSPB2, HSPD1, HSPA1L, and HSP90AA1) and genes involved in maintaining blood vessel density, such as VEGFA. In a separate study, Ge et al. [45,61] conducted two transcriptome studies on three types of yaks from varying altitudes (3400 m, 4200 m and 5000 m) and Zaosheng cattle at low altitudes. Their results suggest that the UVSSA gene (involved in DNA repair mechanisms) may play a critical role in the lung tissue of yaks, potentially facilitating their adaptation to the high levels of ultraviolet radiation at elevated altitudes. These findings offer valuable insights into the molecular mechanisms that underlie altitude-related environmental adaptation in yaks. Similarly, Guang-Xin et al. [62] identified seven candidate copy number variations (CNVs) from yak whole-genome sequencing data, which were associated with five key genes (GRIK4, IFNLR1, GRHL3, LOC102275985, and LOC102275713) and enriched in pathways related to hypoxic adaptation. Further genomic studies on yaks from both high-altitude and low-altitude populations revealed that four potential candidate genes, those being RPS6KA6, ITPR1, GNAO1, and PDE4D, are enriched in signaling pathways related to environmental information processing and adaptability [63]. These genes may play critical roles in helping yaks maintain homeostasis and optimize physiological functions in response to altitude-related stressors. Additionally, Qi et al. [64] observed that EPAS1, encoding HIF-2α, exhibited differential expression across various tissues in yaks from different altitudes. Specifically, EPAS1 expression decreased in the heart but increased in the liver, muscle, spleen, and testes with altitude, suggesting its significant role in mediating adaptation to hypoxic environments. Whole-genome sequencing studies by Wang et al. [65] have revealed that CNVs in genes such as DCC, GSTCD, MRPS28, and MOGAT2 contribute to the adaptation of yaks to high-altitude environments. In addition, previous studies documented matrix metalloproteinase-3 (MMP3) as a potential key target gene of hypoxia-inducible factor-1α [66]. Furthermore, Ding et al. [67] studied a polymorphism in the MMP3 gene in high-altitude Pali yaks, which was present at a significantly higher frequency than in mid- and low-altitude populations. This mutation in MMP3, a target gene of HIF-1α, is believed to enhance the adaptability of yaks to the high-altitude environment by influencing extracellular matrix remodeling and vascular function.

Moreover, a comparison of Qaidam cashmere goats and Chengdu Brown goats using θπ and Fst values identified 1277 overlapping selection regions. Within these regions, genes associated with hypoxia and responses to elevated light intensity, such as TH, ACER1, GNB1, and HIF1A, were found to be enriched. This enrichment explains the adaptability of cashmere goats to the harsh conditions of the Tibetan Plateau [68]. In a related study, Jin et al. [69] used ClueGO functional analysis and Kobas analysis to establish a comprehensive high-altitude adaptation pathway network, identifying nine key genes—LEPR, LDB1, EGFR and FGF2—as critical for the high-altitude adaptation of Tibetan goats. Belay et al. [70] utilized the HP, Fst, and XP-EHH methods to identify a set of genes (DDX28, RUNDC3B, PIK3CD, TIGAR, PTPMT1, and STXBP4) associated with adaptation to hypoxic conditions in Ethiopian goats residing at high altitudes. Notably, PTPMT1 has been identified as a key gene contributing to survival in these environments [71]. In a comparative study, Zhong et al. [72] compared low-altitude populations (Taihang goats at 600 m and Jining gray goats at 39–65 m) with high-altitude populations (Tibetan goats at 4000–4500 m). Using the Fst and XP-EHH indices, they identified the ADIRF gene as potentially beneficial for the adaptation of Tibetan goats to high altitudes. Moreover, Li et al. [73] discovered a 233 bp deletion in intron 7 of the PAPSS2 gene. The frequency of this homozygous deletion was found to be 80.25% in Tibetan goats compared to just 28.75% in low-altitude goats. This suggests that PAPSS2 may negatively affect the adaptation of Tibetan goats to the hypoxic environment of the Qinghai–Tibet Plateau. Interestingly, it was revealed that the unique allele of PAPSS2 in Tibetan goats originated from a wild caprid species. Similarly, Sasazaki et al. [36] demonstrated that the frequencies of mutant alleles for two single-nucleotide polymorphisms (FGF5 c.-253G > A, EPAS1 Q579L) in Nepalese goats increased with altitude, a trend supported by the Pearson correlation coefficient. Additionally, studies have shown that the FGF5 gene plays a critical role in hair growth [74], with long hair providing an advantage for survival in cold, high-altitude environments. The EPAS1 gene, a transcription factor involved in various hypoxic adaptation mechanisms, also contributes to this adaptability. Therefore, polymorphisms in these two genes are crucial for understanding the genetic basis of high-altitude adaptation in Nepalese goats. Through the detection of genomic structural variations in Tibetan sheep and Hu sheep, Liang et al. [75] identified three specific structural variations (EPAS1, PAPSS2, and PTPRD) that are exclusive to Tibetan sheep. Haplotype construction revealed that these three structural variations are associated with altitude, demonstrating a significant correlation among them. Additionally, the study found that the expression of several genes closely related to cardiovascular function, including BRINP3, CDH18, BDH1, and CYP2J, was upregulated in response to hypoxic conditions. This finding further substantiates the notion that Tibetan sheep have undergone adaptive adjustments to thrive in high-altitude environments [75]. Meanwhile, Li et al. [76] analyzed transcriptome data from twelve organs (including the heart, liver, spleen, lung, kidney, and muscle) of both high-altitude Tibetan sheep and low-altitude Hu sheep. Their findings revealed that at least three genes—HBBC, HBB, and EGLN1—are differentially expressed in individual organs, thereby shedding further light on the genetic foundation of high-altitude adaptation in Tibetan sheep. Moreover, Zhao et al. [77] found that mutations in HIF-1α led to a series of changes in blood gas indicators in both Tibetan sheep and Gansu Alpine Merino sheep. Specifically, hematocrit (Hct), hemoglobin (Hb) concentration, the partial pressure of oxygen (PO₂), and oxygen saturation (SaO₂) were significantly lower than those in Hu Yang sheep. Furthermore, the half-saturated oxygen partial pressure (P50) in Tibetan sheep was significantly higher compared to Hu sheep, while the glucose (Glu) concentration was notably lower, enhancing the oxygen utilization capacity of Tibetan sheep.

Continuing in this line of research, Zhang et al. [78] utilized resequencing data from three sheep breeds to identify several genes—HIF1A, ATR, SLC24A4, PPA2, and ROCK2—associated with high-altitude adaptation in Tibetan sheep through selective sweep analysis. Notably, changes in mean corpuscular hemoglobin and elevated hemoglobin concentrations further suggest an adaptation to high-altitude environments. Additionally, resequencing data from 15 Tibetan sheep populations at varying altitudes, as reported by Liu et al. [79], revealed that high-altitude Tibetan sheep with deletion variants in the HAG1 gene exhibited significantly higher body weight, body temperature, pulse interval, and levels of erythrocyte hemoglobin and globulin compared to low-elevation Qinghai Tibetan sheep lacking such variants. Furthermore, the expression of the HAG1 gene was elevated in the liver and lung tissues of high-altitude Tibetan sheep, indicating that these deletion variants in the HAG1 gene play a role in facilitating adaptation to high-altitude environments. Consistently, Wang et al. [80] identified a single-nucleotide polymorphism (SNP) downstream of the CYP17 gene in Tibetan sheep. They found that the frequency of the dominant allele of this candidate gene increased with the altitude of the habitat across five sheep breeds. This finding supports the idea that mutations in the CYP17 gene enhance the adaptive capacity of Tibetan sheep to hypoxic environments. Previous studies have also shown that the CYP17 gene regulates hemoglobin levels and red blood cell mass and is associated with high-altitude polycythemia [81].

Recent studies have significantly advanced our understanding of genetic adaptation to high-altitude environments in various equid species. For instance, Han et al. [82] identified several genes associated with high-altitude adaptation in Ganzi horses, including EPAS1, ABTB2, RHOQ, and TMEM247, through comparisons with low-altitude horses. Notably, missense mutations in EPAS1 (A > T) and OR52A1J (C > T) were found to be more prevalent in high-altitude horses, potentially contributing to the successful survival of Ganzi horses on the Tibetan Plateau. Additionally, Liu et al. [53] conducted the first comprehensive genome-wide analysis of 17 Chinese native horse breeds across varying altitude gradients. Their study revealed that EPAS1 exhibited the strongest positive selection in Tibetan horses, with two missense variants within the PAS domains of the EPAS1 gene significantly correlated with altitude. Tibetan horses residing at altitudes exceeding 4000 m showed the highest allele frequency for these variants (approximately 0.8), while the frequency in low-altitude horses (below 1000 m) was less than 0.05. These findings suggest that EPAS1 is a critical gene for high-altitude adaptation. Furthermore, Liu et al. [83] investigated the survival strategies of Tibetan wild asses in the challenging environment of the Tibetan Plateau, focusing on their gut microbiota. Their results revealed that the intestinal microbiota of Tibetan wild asses undergoes differentiation and phenotypic alterations that enhance the host’s ability to thrive on sparse, low-quality forage. Macrogenomic analyses further identified the significant enrichment of plant biomass-degrading microbiota, alongside genes (GH43, GH3, GH31, GH5, and GH10) and enzymes (β-glucosidase, xylanase, β-xylosidase, etc.) involved in carbohydrate metabolism, thereby highlighting the adaptive role of the gut microbiome in supporting the Tibetan wild ass’s high-altitude survival. Additionally, Zeng et al. [84] reassembled the genome of an individual Kiang and analyzed the genomes of five Kiangs and 93 donkeys, including 24 Tibetan donkeys. Their investigation of high-altitude adaptation mechanisms in Kiangs and Tibetan donkeys revealed that the EPAS1 locus exhibits strong selective pressure in Kiangs, while the EGLN1 gene plays a crucial role in Tibetan donkeys’ adaptation to low-oxygen environments. In a previous study, genome-wide selective signal analyses of Qinghai donkeys—inhabiting altitudes of 3000–5000 m—revealed very low ZHp values (<–7) and very high di values (top 1%). This analysis identified overlapping regions and two genes, HBB and GLDC [85,86], which have previously been associated with high-altitude adaptation, providing valuable molecular insights into the adaptation of Qinghai donkeys to low-oxygen conditions [87]. The potential genes associated with high-altitude adaptation in livestock are summarized in

Table 1. Summary of potential genes associated with high-altitude adaptation in herbivorous livestock.

Species	Genes	Variations	Methods	Function	References
Yak	CAMK2B, GLUL	-	dN/dS, ω	Encode for key components in calcium signaling and nitrogen metabolism	[54]
Tibetan cattle	EGLN1	-	Fst, θπ, XP-EHH and Tajimas’ D	Hypoxia tolerance	[55]
Ethiopian indigenous cattle	CLCA2 SLC26A2 CBFA2T3	-	iHs, XP-CLR and PBS	Renin secretion KEGG pathway Ion channel activity Response to hypoxia	[56]
Ladakhi cattle	HIF-1A VPS13C, CPT1A DNAJA3, HSPA2, HSP90AB1 PER1, CRY1, ARNTL, CLOCK, FBXL3	-	Fst and π	Hypoxia adaptation Energy metabolism Cold adaptation Circadian rhythm	[57]
Gayal, Yak	UQCRC1, COX5A CAPS EDN3 CHRM2 EGLN1	-	edgeR	Related to the energy supply of myocardial contraction Related to pulmonary artery smooth muscle contraction Related to the tracheal epithelium and pulmonary vasoconstriction The autonomous regulation of the heart The target gene of the hypoxia-sensing pathway	[58]
Tibetan cattle	ACSS2	rs43717468 A > G, rs439295601 G > T in the 5′-flanking region	FLK, hapFLK, XP-EHH, and composite Fst	Promotes metabolic adaptation to hypoxia via the hypoxia-inducible factor (HIF) pathway	[59]
Yak	HSPB7, HSPB2, HSPD1, HSPA1L, HSP90AA1 VEGFA	-	DESeq2, WGCNA	Encode the heat shock protein (HSP) protein family Maintain the balance of blood vessel density	[60]
Yak	UVSSA	-	clusterProfiler package in R	Resistance to UV radiation	[61]
Yak	GRIK4, IFNLR1, LOC102275985, GRHL3, LOC102275713	GRIK4 (a dup CNV_202) IFNLR1 (a dup CNV_265) LOC102275985 (del CNV_199 and del CNV_200) GRHL3 (a dup CNV_265) LOC102275713 (a del CNV_201)	Fst, VST	Physiological regulation under a hypoxic environment	[62]
Yak	RPS6KA6, ITPR1, GNAO1, PDE4D	-	Fst, ZHp	Associated with environmental adaptability	[63]
Yak	EPAS1	-	voom embedded in the R package limma	Encodes hypoxia-induced-factor 2α	[64]
Yak	DCC, GSTCD, MRPS28, MOGAT2	-	CNVnator	Adaptation to hypoxia	[65]
Pali yak	MMP3	rs2381 A > G and rs4331 C > G in intron V and intron VII	Haplotype analysis	Regulates the cellular response to hypoxia	[67]
Qaidam cashmere goat	TH, ACER1, GNB1, and HIF1A	-	Fst, θπ	Hypoxic adaptation	[68]
Tibetan goat	LEPR, LDB1, EGFR and FGF2	-	Fst	Associated with high-altitude adaptation	[69]
Ethiopian indigenous goat	PTPMT1	-	Hp, Fst, XP-EHH	Associated with critical hypoxic survival gene	[70]
Tibetan goat	ADIRF	-	Fst, XP-EHH	Relates to high-altitude adaptation	[72]
Tibetan goat	PAPSS2	chr26: 42012872 G > T in intron region	Fst, XP-EHH	Adaptation to hypoxia	[73]
Nepalese goat	FGF5, EPAS1	FGF5 (c.-253G>A within 5’UTR) EPAS1 (Q579L in exon 5)	Pearson correlation coefficients	Regulated hair growth; encodes hypoxia-induced-factor 2α	[36]
Tibetan sheep	EPAS1 PAPSS2 PTPRD	EPAS1 (1 deletion SV) PAPSS2 (1 insertion SV) PTPRD (1 deletion SV)	Delly, Manta, Amoove	High-altitude adaptation Blood circulation Pulmonary hypertension	[75]
Tibetan sheep	HBBC, HBB, EGLN1	EGLN1 (Chr25:3503284 G > A in 3′UTR)	XP-EHH, XP-CLR	Relates to high-altitude adaptation	[76]
Tibetan sheep	HIF-1α	g.76805181 G > A in exon 9, g.76806025 G > A in exon 10, and g.76808146 T > A in exon 12	Haplotype analysis	Key regulator of adaptation to high-altitude hypoxia	[77]
White Tibetan sheep	HIF1A, ATR, SLC24A, PPA2, ROCK2	-	Fst, XP-EHH	Linked to high-altitude adaptation	[78]
Tibetan sheep	HAG1	C-INDEL in 5′UTR	Fst, ZHp	Relates to high-altitude adaptation	[79]
Tibetan sheep	CYP17	-	Fst, Hp	Associated with hemoglobin levels	[80]
Ganzi horse	EPAS1, ABTB2, RHOQ, TMEM247	EPAS1 (Chr15:53538574 A > T)	CLR, iHS, Fst, XP-EHH	Related to high-altitude adaptation	[82]
Tibetan Horses	EPAS1	SNP1 (R144C), SNP2 (E263D)	Fst, ZHP, θπ	Encodes hypoxia-induced-factor 2α	[53]
Equus kiang	GH43, GH3, GH31, GH5, GH10	-	metastat analysis	Associated with carbohydrate metabolism genes	[83]
Kiang	EPAS1	-	Fst, θπ	Encodes hypoxia-induced-factor 2α	[84]
Tibetan donkeys	EGLN1	-	Fst, θπ	Associated with high-altitude adaptation	[84]
Qinghai donkey	HBB, GLDC	-	ZHP	Relates to high-altitude adaptation	[87]

.

3.2. Genes Linked to Adaptations to Cold Environments in Herbivorous Livestock

The ability to withstand cold exposure is critical for the survival of herbivores in cold regions, where long, harsh winters impose significant challenges to metabolic processes, reproduction, and overall productivity. Understanding the molecular mechanisms underlying cold adaptation is essential for improving the resilience of livestock in cold climates, particularly in northern China and other regions with severe winter conditions. To gain a deeper understanding of the genetic basis of cold adaptation in livestock, various genetic approaches have been employed.

By constructing single-nucleotide polymorphism (SNP) and haplotype localization trees for the ZC3H10 gene, and by combining FLK and hapFLK analysis methods, Wang et al. [88] found that all four cattle breeds inhabiting cold zones exhibited strong positive selection signals. This finding suggests that these cattle breeds may have developed adaptations to cold environments over a long evolutionary period. To further validate the function of the ZC3H10 gene, we created a ZC3H10 knockout fibroblast cell line. The experimental results indicated that the deletion of ZC3H10 disrupted signaling pathways associated with thermogenesis and immune function, providing robust evidence for the significant role of ZC3H10 in bovine adaptation to cold environments. A genome-wide selection analysis and an in-depth study of penetrance signaling in crossbred cattle have identified several key candidate genes closely associated with adaptation to environmental changes, the maintenance of metabolic homeostasis (including TRPM8, NMUR1, OXR1, PRKAA2, and SMTNL2), and immune responses (e.g., PLCB4 and SIN3A). This research reveals the genetic mechanisms that enable crossbred cattle to adapt to cold climates [89]. While, Huang et al. [90] have newly identified a group of key candidate genes involved in heat production and energy metabolism, such as UQCR11, DNAJC18, EGR1 and STING1, on chromosome 7 by differentiating genes within the selected regions of cattle herds in southern and northern China. These findings provide valuable information for an in-depth understanding of bovine adaptation to cold environments. Correspondingly, a genome-wide scan of northern and southern cattle populations was conducted to identify candidate genes involved in thermogenesis-related pathways [91]. Furthermore, they revealed through functional analyses that a variant in the PRDM16 gene (c.2336 T > C, p.L779P) in northern cattle was involved in cold adaptation. This gene plays a crucial role in regulating the differentiation and function of brown adipocytes, influencing thermogenic capacity, and thus facilitating adaptation to cold environments [91]. Interestingly, a unique missense mutation was found in the highly conserved NRAP gene in the Yakutia breed [92]. This mutation was shared with 16 species of hibernating or cold-adapted mammals from at least six different phylogenetic orders. Furthermore, they suggested that various mammalian species may experience similar selective pressures in cold environments, leading to analogous mutations in the NRAP gene, which likely enhance adaptation to these conditions [92]. In addition, a selective scan and analysis of cold-adapted genes in Yanbian cattle was conducted by Shen et al. [93], who employed three methodologies to identify three candidate genes: CORT, associated with cold stress; FGF5, involved in hair follicle development and length; and CD36, which plays a crucial role in fat digestion and absorption. These findings provide new insights into the adaptations of Yanbian cattle [93]. Similarly, Ghoreishifar et al. [94] used de-correlated composite of multiple signal (DCMS) and adjusted p-values (FDR < 5%) from multiple testing to identify significant genomic regions. This analysis revealed genes such as AQP3, AQP7, and HSPB8, which are associated with cold adaptation in Swedish cattle. The Inner Mongolian Sanhe cattle demonstrate remarkable adaptability to extremely low temperatures, along with disease resistance and productivity. Hu et al. [95] observed significant elevations in the blood concentrations of adrenocorticotropic hormone (ACTH), triiodothyronine (T3), and thyroxine (T4) in Sanhe cattle exposed to −32 °C for 3 h [95]. Furthermore, the expression of the HSP70 gene was significantly upregulated by AQP3, AQP7, and HSPB8. They found that a total of 20 SNPs were identified in the 5′-flanking regions of the HSP70 gene in Sanhe cattle. Among these, SNP-42−, SNP-105+, SNP-181+, and SNP-205+ were significantly correlated with T3, while SNP-105+ was significantly correlated with T4. These findings suggest that the HSP70 gene may play a key role in the cold acclimatization of cattle [95]. Consequently, Weldenegodguad et al. [96] identified a range of candidate selective sweep genes in cattle breeds exposed to cold environments. Notably, genes such as DNAJC28, HSP90B1, AGTRAP, TAF7, TRIP13, NPPA, and NPPB were identified in Eastern Finncattle, while CD14, COBL, JMJD1C, KCNMA1, PLA2G4, SERPINF2, SRA1, and TAF7 were identified in Western Finncattle. Similarly, in Yakutian cattle, genes like DNAJC9, SOCS3, TRPC7, SLC8A1, GLP1R, PKLR, and TCF7L2 were identified based on whole-genome sequencing data [96]. Similarly, a candidate region on Siberian cattle chromosome 15, identified through both a genome-wide association study (GWAS) and selective sweep scans, contains the MSANTD4 and GRIA4 genes, which are functional candidates for cold stress resistance due to their roles in the cold shock response and body thermoregulation, respectively [97].

The genetic mechanisms underlying thermoregulation and adaptation to cold environments have been extensively studied in sheep. In a related study, Ji et al. investigated the mechanisms of heat production in cold-exposed Altai lambs. Their findings revealed that the activation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway, along with the calcium signaling pathway, in muscle tissues, contributed to enhanced thermogenesis [98]. In addition, this led to the upregulation of genes such as APOC3, FABP4, LPL, PCK1, PLIN1, CABP1, and CALN1. In contrast, in bearded lambs, the activation of cAMP signaling resulted in the downregulation of ADCY10 and ADORA2A. These findings highlight the different thermogenic responses to cold exposure in muscle tissues of different breeds of lambs [98]. Furthermore, five genes in muscle tissue exhibited higher expression levels in Altai lambs compared to Hu lambs, indicating that muscle contraction in colder environments aids in the maintenance of body temperature (BDNF, PVALB, TNNC1, MYL2, and ACTC1). Accordingly, Jiao et al. [99] systematically compared the liver transcriptomes of Altai lambs, which are native to cold, arid climates, with those of Hu lambs, which originate from warmer, more humid regions. Their comprehensive analysis revealed that eight genes involved in muscle shivering thermogenesis, including ACTA1, MYH1, MYH2, MYL1, MYL2, TNNC1, and TNNT3, were significantly upregulated in the Altai lambs subjected to cold exposure. Additionally, genes linked to muscle non-shivering thermogenesis, such as ATP2A1, SLN, and CKM, exhibited enhanced expression, thereby contributing an overall increase in heat production and thermoregulatory efficiency in these lambs under cold stress conditions [99]. The subsequent transcriptomic analysis of the hypothalamus, caudal fat, and perirenal adipose tissues revealed that cAMP and calcium signaling pathways were significantly activated in response to cold exposure. This activation was associated with the differential expression of key thermogenesis-related genes, such as UCP1, RYR1, ADIPOQ and LPL, which were implicated in both species (Altay and Hu ewe lambs) studied [100]. In a related study, Saravanan et al. [101] identified an SNP (rs428553319) located in the 6.5–7.0 Mb region of chromosome 1 in Changthangi sheep, a breed known for its adaptation to cold environments. This SNP is under strong natural selection and affects several genes with potential roles in thermoregulation. Among these, TRPM8, a thermoreceptor involved in both cold and heat sensation, plays a crucial role in thermoregulation, pain perception, the inflammatory response, and vascular smooth muscle function [102]. Further studies have shown that during adaptation to the cold climate of Siberia, significant selective pressure was observed in a genomic region near the ADAMTS5 gene across three sheep breeds: Kulundin, Altai Mountain, and Baikal [103]. Research has demonstrated that ADAMTS5 knockout mice exhibit increased interscapular brown adipose tissue mass, the enhanced browning of white adipose tissue, and elevated thermogenesis [104], suggesting that this gene may play a role in cold adaptation by modulating energy expenditure and thermogenesis.

Additionally, Yudin et al. [105] employed hapFLK and DCMS methods to analyze candidate regions in the genomes of native Russian cattle and sheep breeds. Their analysis identified 31 genes crucial for the adaptation of these species, as well as other mammals, to the cold Arctic environment. Notably, the NEB gene was found in positively selected regions of the genomes of cattle, sheep, mammoths, polar bears, and whales. This gene is implicated in the regulation of heat production through shivering thermogenesis, a key process for survival and reproduction in extreme cold environments. A summary of potential candidate genes associated with cold adaptation is presented in

Table 2. Potential genes associated with cold adaptation in herbivorous livestock.

Species	Genes	Variations	Methods	Function	References
Chinese native cattle	ZC3H10	-	FLK and hapFLK	Participates in thermogenesis and immune responses	[88]
Cross-bred cattle	TRPM8, NMUR1, OXR1, PRKAA2, SMTNL2 PCLB4, SIN3A	-	θπ, XP-CLR, Fst	Metabolic homeostasis Immune responses	[89]
Chinese indigenous cattle	UQCR11, DNAJC18, EGR1, STING1	UQCR11 (rs43485110 C > T and rs110122520 C > G in the 5’-flanking region) DNAJC18 (rs207746463 C > T in the 5′-flanking region) EGR1 (c.190 G > A SNP) STING1 (c.601 C > A SNP)	hapFLK, FLK	Hermogenesis and energy metabolism	[90]
Northern cattle	PRDM16	c.2336 T > C, p.L779P SNV	Fst, Pi, Tajima’s D	Maintains brown adipocyte formation	[91]
Yakut cattle	NRAP	Chr26:34131393 G > T SNP	hapFLK	Associated with myofibrillar assembly and force transmission in the heart	[92]
Yanbian Cattle	CORT FGF5 CD36	CORT (c.269C > T, p.Lys90Ile; c.251A > G, p.Glu84Gly; c.112C > T, p.Pro38Ser; c.86G > A, p.Pro29His) FGF5 (c.191C > T, p.Ser64Phe) CD36 (c.638A > G, p.Lys 213Arg)	θπ, XP-CLR, Fst	Regulate primary hormone in the hypothalamic–pituitary–adrenal (HPA) axis Linked with hair follicle and length development Affect intramuscular fat deposition	[93]
Swedish cattle	AQP3, AQP7, HSPB8	-	Tajima’s D, Pi, Fst	Associated with cold adaptation	[94]
Inner Mongolia Sanhe cattle	Hsp70	SNP-42− C > T, SNP-205 + G > T	General linear model procedure and Bonferroni t test	Cytoprotective effects by regulating pathways related to cell stress response	[95]
Eastern Finncattle	DNAJC28, HSP90B1, AGTRAP, TAF7, TRIP13, NPPA, NPPB	-	SweeD, CLR	Associated with cold adaptation	[96]
Western Finncattle	CD14, COBL, JMJD1C, KCNMA1, PLA2G4, SERPINF2, SRA1, TAF7	-	SweeD, CLR	Boost up adaptability to cold environment	[96]
Yakutian cattle	DNAJC9, SOCS3, TRPC7, SLC8A1 GLP1R, PKLR, TCF7L2	-	SweeD, CLR	Enhance resistance to cold weather	[96]
Siberian cattle	MSANTD4, GRIA4	-	H1, H12, Pi, DCMS, Tajima’s D	Indirect involvement in the cold shock response and body thermoregulation	[97]
Altay sheep, Hu lambs	APOC3, FABP4, LPL, PCK1, ADCY10, ADORA2A, MYL2	-	Pairwise comparisons	Thermoregulation and muscle contraction	[98]
Altay lambs	ACTA1, MYH1, MYH2, MYL1, MYL2, TNNC1, TNNC2, TNNT3 ATP2A1, SLN, CKM	-	DESeq2 software (https://bioconductor.org/packages/release/bioc/html/DESeq2.html (accessed on 17 January 2025))	Muscle shivering thermogenesis Muscle non-shivering thermogenesis	[99]
Altay lambs, Hu lambs	UCP1, RYR1, ADIPOQ and LPL	-	DESeq2 software	Thermogenesis	[100]
Changthangi sheep	TRPM8	-	ROH, iHS	Enhances ability of animals to tolerate cold weather	[101]
Kulundin, Altai Mountain, and Baikal sheep	ADAMTS5	-	hapFLK, p-value, DCMS, Tajima’s D, FST, Pi	Promotes adipogenesis and white adipose tissue expansion	[103]
Russia sheep and cattle	NEB	-	hapFLK, DCMS	Thermoregulation	[105]

.

3.3. Genes Linked to Adaptations to Heat Environments inHerbivorous Livestock

In the context of global warming, animal husbandry is confronting significant challenges, particularly the direct effects of elevated temperatures on animal health, survival, and productivity. As climate change intensifies, understanding the underlying molecular mechanisms that govern heat tolerance in livestock becomes crucial. Investigating the genetic, physiological, and biochemical pathways involved in heat adaptation will be essential to developing strategies for improving the resilience of animals in increasingly hot environments. Notably, Akinsola et al. [106] identified key regions of homozygosity (ROHs) associated with several genes, including RIMS1, RSAD2, CMPK2, NOTCH1, OR1J1, and SLC25A17. These genes are implicated in various biological processes, such as immune response, cellular stress mechanisms, olfactory function, and metabolism. Evidence suggests these genetic factors may confer inherent adaptability and disease resistance to extreme environmental stressors experienced by breeds in sub-Saharan Africa. Additionally, investigations revealed that the HIPK1 gene, which regulates stress responses, potentially enhances heat stress resilience in Kuri cattle. Similarly, 753 differentially expressed genes (DEGs) were identified between heat-tolerant and non-heat-tolerant buffalo [107]. Weighted gene co-expression network analysis (WGCNA) identified modules associated with heat stress indices. The turquoise module demonstrated the most significant positive correlation with respiratory rate (RR) and rectal temperature (RT) and was notably enriched. Six genes involved in cytokine–cytokine receptor interactions (IL18RAP, IL6R, CCR1, PPBP, IL1B, and IL1R1) were identified as key hub genes, providing crucial insights into heat tolerance mechanisms in buffalo [107]. In complementary research, Luo et al. [108] employed weighted single-step genome-wide association study (WssGWAS), RNA sequencing, and prior findings to identify candidate genes associated with heat stress in heat-tolerant Chinese Holstein cattle. These genes—PMAIP1, SBK1, TMEM33, GATB, CHORDC1, RTN4IP1, and BTBD7—correlated with three physiological indicators of heat stress: rectal temperature, respiration rate, and drooling score. Under thermal challenge conditions, heat-tolerant Chinese Holstein cattle exhibited significantly (p < 0.05) attenuated elevations in rectal temperature and respiration rate, with reduced milk yield decline compared to non-heat-tolerant counterparts. Conversely, plasma concentrations of heat shock proteins (HSP70 and HSP90) and cortisol were significantly (p < 0.05) elevated in heat-tolerant animals, underscoring enhanced stress response mechanisms. Furthermore, transcriptomic analysis revealed the significant enrichment of genes including OAS2, MX2, IFIT5, and TGFB2, which participate in immunomodulatory pathways contributing to thermal tolerance [109]. Additionally, Li et al. [110] conducted a study on the heat tolerance of Dehong humped cattle, a breed known for its exceptional heat resistance in Southwest China. They identified a series of candidate genes associated with heat shock response (HSF1), oxidative stress (PLCB1, PLCB4), coat color (RAB31), feed intake (ATP8A1, SHC3), and reproduction (TP63, MAP3K13, PTPN4, PPP3CC, ADAMTSL1, SS18L1, OSBPL2, TOX, RREB1, and GRK2). These genes positively influence the heat tolerance of Dehong humped cattle, enabling them to thrive in tropical climates. Consistently, Wang et al. [111] investigated the allele frequency distribution of missense mutations in the EIF2AK4 gene across various Chinese native cattle breeds with differing geographic distributions. Through correlation analyses between genotypes and environmental factors, they identified significant geographic variation in the EIF2AK4 gene variants. Specifically, the frequency of the mutant allele G showed a progressive increase from northern to southern cattle populations, with the highest frequency observed in herds from the southeastern regions, particularly those exposed to higher ambient temperatures [111]. Furthermore, a study included Angus and Simmental cattle, categorizing individuals within these breeds as either poorly adapted or well adapted to heat stress [112]. Their results indicated that respiratory rate and rectal temperature were effective indicators of heat tolerance. Additionally, the expression levels of the HSF1 and HSPA6 genes varied according to acclimatization status, with poorly acclimatized animals exhibiting elevated expression levels. These findings suggest that both genes may serve as biomarkers for heat tolerance in taurine cattle [112]. Subsequently, Pires et al. [113] assessed the expression levels of genes within the heat shock protein (HSP) family, including HSPD1, HSPA1A, and HSP90AA1, in two tropical cattle breeds, Nelore and Caracu. Their findings revealed a significantly higher expression of HSPD1 in Caracu compared to Nelore. In contrast, HSP90AA1 was more highly expressed in Nelore. No significant differences were observed in the expression of HSPA1A between the two breeds, suggesting breed-specific variations in the expression of heat shock proteins in response to thermal stress. Furthermore, a study investigated the heat stress response in a population of Gir × Holstein F2 crossbred cattle through a GWAS [114]. They employed gene-transcription factor (TF) network and Gene Ontology (GO) enrichment approaches to identify genes implicated in biological processes associated with heat stress. The candidate genes identified, including LIF, OSM, TXNRD2, and DGCR8, offer valuable insights into the molecular mechanisms underlying the response of dairy cattle to heat stress [114]. Building on prior GWAS findings, Jia et al. subsequently identified four novel SNPs in the MYO1A gene, with the frequency of these mutant alleles increasing from northern to southern Chinese cattle populations [115]. Additionally, significant correlations were observed between four annual climate indicators—temperature, relative humidity, temperature–humidity index, and average annual sunshine hours—suggesting their influence on the genetic response to heat stress [115].

In another experimental study focusing on potential heat resistance candidate genes in the skin of Santa Ines sheep, the results indicated upregulation in the expression of cell protection genes (HSPA1A and HSPA6) and immune response genes (CXCL1, CAPN14, SAA4, and IGHG4). These findings suggest that these genes may play a role in enhancing cellular protection and boosting immunity in response to heat stress [116]. Similarly, Saadatabadi et al. [117] performed a comparative analysis of whole-genome sequencing data from local sheep populations in both cold and hot regions of Iran, identifying key genes such as SIK2, FER, TLR4, ATP1A1, and CDK5RAP3, which are involved in heat stress response-related pathways. These genes are critical for immune system function and heat tolerance. Additionally, they reported genes such as CD109, CR2, EOMES, and MARCHF1, as well as HTR4, ALDH1A3, and TRHDE, which are implicated in mitigating the heat shock response through the regulation of digestion and energy metabolism. Consistently, Ibrahim et al. [118] conducted a study identifying multiple SNPs in heat resistance-related genes in Barki and Aboudeleik lambs, specifically in HSP90AB1, HSPB6, HSF1, STIP1, and ATP1A1. Furthermore, they found an association of polymorphisms in these genes with phenotypic traits such as sheep skin temperature, respiratory frequency, and red blood cell count. Similarly, a recent study by Aboul-Naga et al. [119] examined the correlation between heat stress phenotypes and genome-wide SNPs in a sample of 206 sheep from three Egyptian breeds across six distinct geographical locations. Through GWAS analysis, they identified 46 SNPs, particularly those linked to pigmentation. Notably, SNPs in four genes—MYO5A, which is associated with calmness; PRKG1, which regulates body temperature; GSTCD, related to the respiratory system; and RTN1, involved in endoplasmic reticulum stress—were significantly correlated with heat tolerance [119]. In a subsequent investigation, Afsal et al. [120] analyzed the expression patterns of HSP70 genes in several key organs of Malabari goats residing in the hot and humid regions of Southern India. Their findings indicated that heat stress significantly increased HSP70 expression in the adrenal gland, while a notable decrease was observed in the thyroid and mesenteric lymph nodes. The authors proposed that the HSP70 gene is both tissue-specific and function-specific, making it an ideal biomarker for assessing goat heat stress responses. Furthermore, Wang et al. [80] conducted a comprehensive analysis of the genetic characteristics of five local sheep breeds in China, identifying the DNAJB5 gene in Duolang sheep, which demonstrates substantial resistance to heat stress. Their discovery enhances the understanding of the genetic adaptations of sheep to hot environments and provides new molecular insights into their behavioral traits. Li et al. [121] further investigated the effects of acute heat stress on Hu Sheep, performing a transcriptome analysis of hypothalamic tissue to identify 1424 differentially expressed genes. These findings showed significant alterations in pathways related to calcium signaling, ribosome biogenesis, apoptosis, and oxidative stress responses, offering insights into potential protective measures against heat stress in livestock. A previous report conducted a comprehensive analysis of RNA sequencing data comparing a heat stress-treated sheep group with an untreated control group. This analysis revealed significant differences in key biological processes, including body temperature regulation (5-HTR4 and HTR1B), stress response (the Rap1, MAPK, and PI3K-Akt pathways), energy metabolism (NPR1, ANGPT2, and SLC13A5), and immune response (HSPA2) [122]. Pantoja et al. [123] found that the expression levels of genes such as GPX3, LOC101108817 (IGHG1), VLDLR, EVC, GPAT3, and RGS6 in the livers of heat-tolerant sheep were significantly higher than those in non-heat-tolerant sheep when exposed to heat stress conditions (i.e., 36 °C). These genes were primarily enriched in the Hedgehog signaling pathway, glutathione metabolic process, glycerolipid metabolism, and thyroid hormone biosynthetic pathways. These biological pathways contribute significantly to ameliorating the deleterious effects of thermal stress, thereby enhancing heat tolerance capabilities in sheep [123]. A comparative analysis revealed that under heat stress conditions, Katjang goats maintained significantly lower rectal temperature (RT), hemoglobin (Hb), and packed cell volume (PCV) values relative to Boer goats, concomitant with elevated HSP70 gene expression. This physiological profile strongly indicates superior thermotolerance in Katjang goats compared to their Boer counterparts [124].

The investigation of heat stress response in Brazilian horses identified significant genomic regions containing genes associated with redox processes (ADO, GRHPR, GFOD1, KLF9, PIP5K1B, RANBP9, and JMJD1C) and heat shock protein expression (HSP40, HSP70, HSP27, and HSP90) [125]. These findings elucidate the genetic mechanisms facilitating adaptation to tropical climatic conditions. Further genomic analysis utilizing whole-genome copy number variation (CNV) in Jinjiang horses, through CNVR gene annotation and quantitative PCR (q-PCR) methodology, identified and validated four pivotal genes—NFKBIA, SOCS4, HSPA1A, and IL6—that exhibit differential expression patterns under varying heat stress durations, suggesting their functional relevance in adaptation to high-temperature and high-humidity environments [126].

Table 3. Summary of potential genes linked with heat adaptation herbivorous livestock.

Species	Genes	Variations	Methods	Function	References
SSA cattle	RIMS1, RSAD2, CMPK2, NOTCH1 OR1J1 SLC25A17	-	iHS, EHH	Immune response, cellular stress mechanisms Olfactory function Metabolic efficiency	[106]
Water buffalo	IL18RAP, IL6R, CCR1, PPBP, IL1B, and IL1R1	-	WGCNA	Cytokine–cytokine receptor interaction	[107]
Chinese Holstein cattle	PMAIP1 SBK1 TMEM33, GATB, BTBD7, CHORDC1, RTN4IP1,	-	WssGWAS	Regulate diverse cellular functions in autophagic cell death and metabolism Involved in the protection of cells Heat stress/heat shock and cellular adaptive function	[108]
Chinese Holstein dairy cows	OAS2, MX2, IFIT5 and TGFB2	-	DESeq2 R package	Activate immune effector process	[109]
Dehong humped cattle	HSF1 PLCB1, PLCB4 RAB31 ATP8A1, SHC3 TP63, MAP3K13, PTPN4, PPP3CC, ADAMTSL1, SS18L1, TOX, RREB1, GRK2, OSBPL2	-	Fst, XP-EHH, XP-CLR	Heat tolerance Oxidative stress response Coat color Feed intake Reproduction	[110]
Southern Chinese cattle	EIF2AK4	g.35615224 T > G in exon 6	POPGENE software (version 7.32)	Thermal stress	[111]
Angus and Simmental cattle	HSF1, HSPA6	-	RT-qPCR	Thermotolerance indicators	[112]
Nelore and Caracu beef cattle	HSPD1, HSP90AA1	-	qPCR	Enhance immune response, stress adaptation and heat tolerance	[113]
Gir × Holstein F2 cattle	LIF, OSM, TXNRD2, DGCR8	-	GWAS	Heat stress effects	[114]
Chinese indigenous cattle	MYO1A	g.56383560G > A, g.56383565T > C, g.56383578T > C, g.56383635A > G	PCR	Heat tolerance	[115]
Santa Ines sheep	HSPA1A, HSPA6 CXCL1, CAPN14, SAA4, IGHG4	-	dgeR package	Cellular protection Promote immune response	[116]
Iranian sheep	SIK2, FER, TLR4, ATP1A1, CDK5RAP3 CD109, CR2, EOMES, MARCHF1 HTR4, ALDH1A3, TRHDE	-	Fst, θπ	Heat stress Immune response Control digestive metabolism	[117]
Barki and Aboudeleik lambs	HSP90AB1, HSPB6, HSF1, ST1P1 and ATP1A1	HSP90AB1 (3 SNPs:A118G, A478G, C232T) HSPB6 (1 SNP:C155T) HSF1 (3 SNPs:G283A, G170A, C410T) ST1P1 (4 SNPs:A177G, C336T, C491T, A457) ATP1A1 (2 SNPs:A47G, C143T)	PCR	Heat tolerance	[118]
Egyptian sheep	MYO5A PRKG1 GSTCD RTN1	MYO5A (Chr7:54927841 G > A, Chr7:54966248 A > C) PRKG1 (Chr22:8045910 G > A) GSTCD (Chr6:19441931 G > A) RTN1(Chr7:68761822 G > A)	statgenGWAS	Pigmentation Body thermoregulation Respiratory system Alleviate endoplasmic reticulum stress	[119]
Malabari goats	HSP70	-	RT-PCR	Heat stress acclimation	[120]
Duolang sheep	DNAJB5	-	Fst, Hp	Heat tolerance	[80]
Hu sheep	5-HTR4, HTR1B NPR1, ANGPT2, SLC13A5 HSPA2	-	DESeq2 software	Body thermoregulation Energy metabolism Immune response	[122]
Thermotolerant sheep	GPX3 IGHG1 VLDLR EVC GPAT3 RGS6	-	EdgeR	Protect cells from heat damage Immunoglobulin synthesis Body temperature regulation Intercellular communication Metabolic homeostasis Cellular signaling and responses to heat stress	[123]
Brazilian horse	ADO, GRHPR, GFOD1, KLF9, PIP5K1B, RANBP9, JMJD1C HSP40, HSP70, HSP27, HSP90	-	hapFLK, PCAdapt	Oxidative reduction Encode heat shock protein	[125]
Jinjiang horse	NFKBIA SOCS4 HSPA1A IL6	-	qPCR	Inhibit heat shock Negatively regulate the inflammatory response Protect cell homeostasis Regulate the immune system	[126]

presents a comprehensive overview of candidate genes implicated in heat tolerance across diverse livestock species.

3.4. Genes Linked to Adaptations to Drought Environments in Herbivorous Livestock

Arid and desert regions are characterized by extreme environmental conditions, including significant temperature fluctuations, severe water scarcity, intense ultraviolet radiation, and limited vegetation and water resources [127]. These harsh conditions pose significant challenges to the survival and productivity of organisms inhabiting such environments. To better understand how species adapt to these stresses, it is essential to investigate the molecular mechanisms underlying drought tolerance. A comprehensive understanding of these adaptive processes is critical for the conservation and sustainable management of genetic resources in endemic species, particularly those adapted to arid ecosystems. For instance, Lyu et al. [128] employed four selective scanning methods and identified several potential genes in Anxi cattle. These genes include RBFOX2, CERS3, SLC16A7, and SPATA3R, which are associated with heart development, cellular energy metabolism, enhancing the skin barrier, pancreatic endocrine function, and, reproductive capability, respectively. Collectively, these genes likely contribute to the remarkable ability of Anxi cattle to withstand extreme dry climatic conditions while maintaining normal production and reproduction. In parallel, Sukhija et al. [129] identified genes related to key physiological traits, including production performance (CACNA1D and GHRHR), reproduction (ESR1 and RBMS3), immune response (NOSTRIN and IL12B), and environmental adaptation (ADAM22 and ASL) using genome-wide selective marker analysis combined with CLR and Fst methods. These findings may contribute to better understanding the genetic characteristics of cattle breeds endemic to the arid regions of India. Consistently, Liu et al. [130] identified specific gene variants in drought-adapted Anxi cattle that are associated with several key physiological pathways, including arachidonic acid metabolism, the renin–angiotensin system, the oxytocin signaling pathway, and the pancreatic secretory pathway. These genetic adaptations may enhance the ability of cattle to survive and reproduce in conditions characterized by extreme desiccation, forage scarcity, and high soil salinity. Furthermore, Ben-Jemaa et al. [131] used SNP microarray data alongside four distinct genome selection scanning strategies to pinpoint GH1, a gene undergoing strong positive selection in North African cattle populations. This gene is strongly linked to several critical biological processes, such as nutrient-level response, the positive regulation of lactation activity, and triglyceride biosynthesis. These functions are thought to contribute to the adaptation of North African cattle to seasonal fluctuations in food resources typical of arid regions, thus enhancing their survival and reproductive success.

In the extremely arid environment of the Taklamakan Desert, native sheep exhibit body size regulation through genes such as RAPSN and CNBD2. These genes facilitate skin vasodilation for heat dissipation via KCNJ16, KCNMB2, and PLCG1, optimize renal function through BMP7, facilitate lens development for ultraviolet filtration via CELF1, and contribute to pigmentation through TECRL. Collectively, these genes may contribute to an efficient set of adaptive mechanisms, allowing these sheep to endure extreme arid conditions [31].

Similarly, Asadollahpour et al. [32] employed gene-selective scanning to show that KITLG, a gene involved in skin pigmentation, exhibits strong positive selection in Southwest Asian goats. This gene is thought to enhance adaptation to UV radiation and temperature fluctuations, thus improving the adaptive flexibility of these goats [132]. Consequently, Zhang et al. [133] identified candidate genes associated with immune response (DNTT, FEN1, POLL and PRKDC, etc.), visual correlation (MAFB, PTEN, MITF and EDN3, etc.), heat stress tolerance (F13A1), and high reproductive rates (FGF3, ARNTL, CHKA and NRG4, etc.) at a 1% threshold during a genome scan of native sheep in the Taklamakan Desert. These findings provide comprehensive information of the genetic mechanisms underlying the adaptation of sheep to desert environments. Similarly, a study investigating the genetic adaptations of three native Iranian sheep breeds to hot and arid conditions identified two key genes (CORIN and CPQ) that play significant roles in coping with extreme environmental stress [134]. The CORIN gene, which is closely involved in blood volume regulation, helps ensure adequate blood flow, thus supporting essential thermoregulatory processes critical for survival under heat stress [135]. Additionally, the CPQ gene, which contributes to protein hydrolysis, was found to be stable in these breeds, suggesting that drought conditions may not adversely affect the activity of protein-hydrolyzing enzymes. This stability could potentially enhance drought resistance in sheep by maintaining efficient protein turnover in the face of water scarcity [136]. Moreover, Chebii et al. [137] detected genomic selection signals in the Nubian ibex through a comparative analysis of protein-coding genes. The ABCA12 and ASCL4 genes, which are involved in skin barrier development, along with the DNA repair gene UVSSA, exhibited positive selection signals. This indicates that the Nubian ibex inhabiting hot desert environments have evolved skin protection strategies to minimize water loss and damage from solar radiation by enhancing the epidermal barrier system.

Furthermore, a genome-wide selection scan investigating the genetic basis of drought adaptation in Liangzhou donkeys revealed a significant selection signal for the CYP4A11 gene, located on chromosome 5. This finding suggests that CYP4A11 plays a crucial role in the adaptation of Liangzhou donkeys to arid conditions [138]. The CYP4A11 gene encodes an enzyme involved in the conversion of arachidonic acid to 19(S)-HETE, a metabolite that is essential for promoting water reabsorption in the renal tubules [139]. By enhancing renal water retention, this mechanism helps Liangzhou donkeys minimize water loss during periods of drought, thus contributing to their physiological adaptation and survival in harsh, water-scarce environments.

Table 4. Summary of potential genes associated with drought adaptation in livestock.

Species	Genes	Variations	Methods	Function	References
Anxi cattle	RBFOX2 CERS3 SLC16A7 SPATA3	SPATA3 (c. 184G>A, rs43347904)	CLR, FST, θπ, XP-CLR	Cardiac development Involved in regulating skin permeability and antimicrobial functions Regulation of pancreatic endocrine function Reproduction	[128]
Indian cattle	CACNA1D, GHRHR ESR1, RBMS3 NOSTRIN, IL12B ADAM22, ASL	-	CLR, FST	Production traits Reproduction Immunity Environmental adaptation	[129]
Zhangmu cattle, Qaidam cattle, Anxi cattle, Kazakh cattle, Mongolian cattle	PLA2G4B	-	θπ, FST, Tajima’s D	Regulates water retention and reabsorption	[130]
North African cattle	GH1	-	iHS, Rsb, XP-EHH, FST	Responds to nutrient levels, positive regulation of lactation and triglyceride biosynthetic process	[131]
Taklamakan Desert sheep	RAPSN, CNBD2 KCNJ16, KCNMB2 PLCG1, BMP7 CELF1 TECRL	-	XP-EHH, iHS, FST	Body sizes Facilitate heat dissipation Kidney function and development Lens development Pigment deposition	[31]
Southwest Asia goats	KITLG	-	θπ, FST, Tajima’s D	Pigmentation	[32]
Taklamakan Desert sheep	DNTT, FEN1, POLL PRKDC MAFB, PTEN, MITF EDN3 F13A1 FGF3, ARNTL, CHKA NRG4	-	FST, XP-EHH, Rsb, iHS	Immunity Vision Heat stress tolerance High reproduction rate	[133]
Iranian sheep	CORIN, CPQ	-	FST, Pi	Maintain the proper volume of blood and proteolytic functions	[134]
Nubian ibex	ABCA12, ASCL4, UVSSA	-	comparative analysis of protein-coding genes	Skin barrier development and DNA repairing	[13]
Liangzhou donkey	CYP4A11	-	FST, θπ, CLR, XP-EHH	Promotes water reabsorption	[138]

provides a detailed summary of potential candidate genes associated with drought adaptation in livestock.

4. Suggestion and Recommendations

Based on the presented contents, we would like to offer some recommendations and suggestions. The practical application of these genetic markers offers significant benefits for farmers and government agencies. Farmers could implement marker-assisted selection programs to develop more resilient herds while maintaining productivity, potentially through the strategic crossbreeding of adapted indigenous breeds with high-producing commercial varieties. Governments should establish conservation programs for valuable indigenous genetic resources, subsidize genetic testing for small-scale farmers, and develop regional breeding centers focused on location-specific adaptations. These approaches would yield economic benefits through reduced mortality, enhanced productivity under stress conditions, lower management costs, and potential market premiums for climate-resilient livestock. These strategies collectively support sustainable livestock production amid increasing environmental challenges.

5. Conclusions

Climate change poses significant threats to livestock productivity and reproduction, driven by resource scarcity, disease prevalence, heat stress, and biodiversity loss, which collectively result in substantial economic losses [140,141,142,143]. While traditional breeding has prioritized production traits, the integration of genetic markers related to environmental resilience—such as those identified in our study—can accelerate the development of robust breeds through advanced techniques like whole-genome selection. Our findings highlight key genetic markers associated with environmental adaptation in herbivorous livestock, particularly in understudied species like horses and donkeys. These markers, linked to traits such as cold and heat tolerance, drought resistance, and high-altitude adaptation, provide a foundation for future breeding programs. However, the functional validation of these candidate genes remains a critical gap that must be addressed to fully harness their potential. In conclusion, our study underscores the importance of genetic research in enhancing livestock resilience to climate change. By leveraging genome-wide selection and focusing on candidate genes, we can develop sustainable breeding strategies that support both animal welfare and agricultural productivity. Future research should expand the scope of genetic studies across diverse species and environments while also emphasizing the functional validation of adaptive traits. Such efforts will be essential for ensuring the sustainability of global livestock production in the face of escalating environmental challenges.