INTRODUCTION
Body size and reproductive performance are important traits in sheep. Economically, body size directly correlates with meat yield, while reproductive performance dictates production efficiency. Biologically, these traits have been subject to natural and artificial selection over long periods, representing the direction of adaptation and evolution. Therefore, understanding the genetic architecture of these traits is crucial for selective breeding and elucidating the underlying genetic mechanisms. Previous studies have primarily focused on single trait and have not performed functional annotations for candidate genes. Hu sheep is an indigenous breed in China, characterized by rapid growth and high fertility. However, Hu sheep is small in stature compared to other meat sheep breeds; and the molecular mechanisms underlying high fertility remain unclear.
Sheep body size and reproductive performance can be influenced by various factors, especially genetics [1]. Currently, most studies on the body size of sheep only focus on body weight, while neglecting other body size traits. Specifically, the cannon bone circumference (CBC) is an important body size trait in sheep. Increasing the CBC of sheep can improve the weight-bearing capacity of legs and gain larger body size [2]. The study of CBC will be beneficial in proposing new breeding strategies to improve the body size of sheep. Additionally, litter size (LS) is important reproductive trait that affect the production yield of sheep [3]. Teat number is important reproductive trait that directly affects the lactation rate of ewes and the survival rate of lambs [4]. Despite the importance of LS and teat number, the underlying genetic mechanisms have not been elucidated, which has hindered the effective advancement of sheep breeding.
Previous studies on economic traits in sheep use a single analytical approach to screen for relevant loci. The differences between genotypes at specific loci and the expression of candidate genes in tissues and systems have not been focused on. More recently, phenome-wide association study (PheWAS), which is a complementary approach to GWAS, has been used to associate certain genetic variants with many phenotypes to study their pleiotropy and causality among big data [5]. Orthologous genes often show similar functions across species. The use of rich GWAS data from humans to conduct a PheWAS might contribute to improve the characterization of the pleiotropic effects of candidate genes and elucidate the genetic architecture of complex traits in the target species [6]. Therefore, it is critical to use more comprehensive analytical approaches to identify relevant loci and candidate genes, and explore the underlying molecular mechanisms.
Hu sheep are renowned worldwide for prolificacy. It has the advantages of early sexual maturity, high fertility, high carcass yield, tender meat, and low fatty content. In this study, we sequenced 558 Hu sheep, and estimated the heritability of each trait as well as the correlations between body size traits. The related loci and candidate genes were screened using GWAS, PheWAS, selection signatures (Fst, ROH, ROHet, integrated haplotype score [IHS]) and functional region annotation. Furthermore, we had analysed the expression level of the candidate genes in the tissues and systems of Hu sheep and explored the potential molecular mechanisms. This study aimed to identify candidate genes influencing body size and reproductive traits in Hu sheep using integrative genomic approaches. These genes will provide valuable genetic markers for selective breeding.
MATERIALS AND METHODS
Management and phenotypic measurement
All Hu sheep (n = 558) used in this study were obtained from the Yihui Ecological Agriculture. All Hu sheep were raised under consistent feeding environment and nutritional conditions with the same commercial diets and unrestricted access to water. Each phenotype was measured by the same person to reduce measurement error. Body weight of Hu sheep was measured using an electronic scale. Body height (BH) is the vertical distance from the highest point of the withers to the ground. Body length (BL) is the straight-line distance from the anterior margin of the shoulder to the posterior margin of the rump. Chest circumference is the circumference of the torso at the posterior margin of the scapulae. Cannon bone circumference is the circumference at the one-third point of the left forelimb. The aforementioned body size traits were measured using a professional measuring stick and a measuring tape. LS and teat number were recorded. LS refers to the number of lambs born to a ewe in a single reproductive cycle. The sex, birth date, age at months, age at lambing (in months), and lambing date could be found in the supplementary materials (Phenotypic data).
DNA extraction methods
Blood samples were collected from the posterior veins of Hu sheep and stored at −80°C until DNA extraction. The CWE9600 magnetic bead Blood DNA Kit and the magnetic bead method were used for DNA extraction. The extracted DNA samples were subjected to DNA sample integrity testing using a 1.5% agarose gel, followed by DNA purity testing using the NanoDrop 2000 Nucleic Acid Protein Assay Instrument and accurate quantification using the dsDNA HS Assay Kit for Qubit.
Library construction and genotyping
The Universal Library Construction Kit (MGI) NadPrep DNA was used for library construction. More than 1 μg of genomic DNA was randomly fragmented into pieces of approximately 300–350 bp using the Covaris crusher. Following end repair, addition of A-tail, and ligation of sequencing junctions, DNA fragments of approximately 300–350 bp were screened using NadPrep SP Beads. The polymerase chain reaction (PCR) amplification was then performed, and the resulting PCR products were purified using NadPrep SP Beads to produce a sequencing library. After library construction was completed, preliminary quantification was performed using Qubit 2.0 and the library was tested for inserts using a Bioanalyzer (Agilent).
The resequencing data were filtered and indexed based on the sheep reference genome ARS-UI_Lamb_v2.0. The BWA software was used to compare clean reads with the reference genome, and samtools was used to sort and build indexes. GATK was used to deduplicate the Bam files, and calculated the sequencing depth and genome coverage for each sample based on the Bam files, which were prepared for subsequent mutation detection. Using the VariatFilter module to strictly filter SNPs. The following SNP loci would be excluded: a minimum allele frequency of <0.05, a Hardy-Weinberg test p-value of <0.000001, and typing deletions >10%.
The chip data was genotyped using the sheep 50K chips. The chip was manufactured and designed by Beijing Compass Biotechnology. SNPs with a call rate lower than 90%, and a minor allele frequency lower than 5% were filtered out using the Plink (ver. 1.90) software [7]. The overlapping SNPs shared by both datasets was extracted and served as the basis for downstream analyses.
Heritability and correlations calculation
The following model was used to calculate the heritability and correlations between traits:
In the above equation, where y is the trait vector; b is the fixed effects (body size traits include sex, measurement year and season, and measurement age of Hu sheep; reproductive traits include year and season of lambing, age of ewes); a is a random effect and obeys normal distribution with mean 0 and variance
G σ a 2 a ~ N ( 0 , G σ a 2 ) , σ a 2 N ( 0 , I σ a 2 ) , σ a 2 h 2 = σ a 2 σ a 2 + σ e 2
Where σa1a2 and σe1e2 are the additive genetic covariance and the residual covariance between each pair of traits;
σ a 1 2 , σ a 2 2 σ e 1 2 , σ e 2 2
Genome-wide association study
The GWAS was conducted using the rMVP software [10]. The GWAS analysis uses a mixed linear model that accurately accounts for population structure and complex kinship relationships within the population [11]. The formula for this model is as follows:
Where y is the phenotype vector, Xβ is the fixed effects, including population structure, sex, measurement year and season, and measurement age of Hu sheep, Zkγk is the marker effect to be tested, ξ~N (0, Kφ2) represents the polygenic effect, and e~N (0, Iσ2) is the residual effect. K is the polygenic effect in the marker-inferred kinship matrix. The qqman package in R software was used, to plot the Manhattan and Q-Q plots [12]. The significant SNP threshold was determined using a 1,000 permutation test.
Gene annotation and QTL enrichment
The reference genome of Ovis aries (assembly ARS-UI_Ramb_v2.0) was downloaded from the ENSEMBL website, and significant SNPs were annotated to their corresponding genes using the ANNOVAR software [13]. Additionally, the Animal QTL Database (http://www.animalgenome.org/QTLdb) was used to annotate potential functions of the selected regions. The QTL annotation was performed using the GALLO package of the R software [14].
Functional region annotation and expression level analysis
The significant SNP loci were annotated to the reference genome Oar_v4.0 using LiftOver software [15]. Subsequently, functional annotations of the significant SNPs were performed in the sheep enhancer database (http://genome.ucsc.edu/s/zhypan/oviAri4_chr_state). The significant SNPs were annotated for alternative polyadenylation (APA) in the Animal-APA Database [16]. The eRNA in genes were annotated in the Animal-eRNA database [17]. The expression level of candidate genes in tissues and systems of Hu sheep were queried in the Herbivore Transcriptome Information Resource Database, and KEGG pathways enrichment analysis was conducted for the candidate genes [18]. To explore whether the orthologues of candidate genes detected for body size traits in sheep were associated with complex traits in humans, we conducted a PheWAS for these genes based on the human GWAS data in the GWASATLAS database [19].
Selection signature analysis
We conducted ROH detection to identify regions of genetic homozygosity in Plink version 1.90 using a sliding window method with the following parameters: (1) the minimum length of the ROH was 1,000 kb, (2) each ROH had at least one SNP per 150 kb, (3) a sliding window of 25 SNPs and one heterozygous genotype was allowed in a window, and (4) each ROH contained at least 25 consecutive SNPs. The percentage of SNP occurrences in ROHs was calculated to characterize the genomic regions of ROH hotspots, and the threshold of ROH hotspots was set as the top 0.1% of SNP occurrences. Population differentiation was assessed by calculating Fst values using VCFtools software [20], the threshold was set as the top 0.1% of Fst values. The number of individuals in the high-performance group for LS is 199, while the number in the low-performance group is 229. The number of individuals in the high-performance group for teat number is 131, while the number in the low-performance group is 390. Runs of heterozygosity (ROHet) were identified and analyzed using the detectRUNS R package [21]. Additionally, IHS analysis was conducted using selscan software to detect positive selections [22]. For each analysis, the threshold was set as the top 0.1% of SNPs values.
RESULTS
Phenotypic statistics and its heritability calculation
In this study, 558 Hu sheep (36 rams and 522 ewes) were randomly selected, and their body size and reproductive traits were recorded. Body size traits included body weight, BH, BL, chest circumference (CC), and CBC. Reproductive traits included LS, teat number (TN). These traits were statistically analyzed to provide a preliminary overall characteristic. Additionally, the heritability of all traits was estimated using the GBLUP model, ranging from 2.22E-03 to 0.76. (Table 1).
Genetic and phenotypic correlations between body size traits
As shown in Table 2, in the body size traits, CBC showed high genetic correlations with BW, BH, and CC. Simultaneously, CBC also displayed high phenotypic correlations with BW, BH, and CC. The genetic and phenotypic correlations between CBC and BL were both low. The genetic and phenotypic correlations between BW and BH were both higher than the correlations between BW and BL. Furthermore, the genetic and phenotypic correlations between BH and BL were both negative.
Genome-wide association study of body size traits in Hu sheep
After quality control, 48 493 SNPs were obtained. A total of 103 significant SNPs were identified in the body size traits of Hu sheep (Figure 1A–1E and Supplement 1). The Q-Q plots demonstrated the significant association of certain loci with these traits (Figure 1F–1J). The highest number of significant SNPs was identified in the BH trait, amounting to 37. The most significant SNP among all traits, SNP1_56344040 (p = 2.69E-13), was also located in the BH trait. SNP1_56344040 was annotated to the ADGRL4 (distance = 872,910 bp), which can be considered as a candidate gene for the BH trait. In the BW and CC traits, there were three identical significant SNPs (SNP17_32588634, SNP17_32587075, and SNP17_32585911), and they were all annotated to the FAT4. Therefore, FAT4 could be a candidate gene for the BW and CC traits. Significant SNP 23_46304583 was found in BH, BL and CC traits. SNP23_46304583 was annotated to the ARK2N, and it could be a candidate gene for the BH, BL, and CC traits. The QTL annotation was performed for all significant SNPs, revealing that most significant SNPs were enriched in meat and carcass QTL, followed by production QTL and milk QTL (Supplement 2). In the production QTL, the majority were BW QTL (Supplement 3). The KEGG enrichment analysis was performed for the ADGRL4, FAT4, and ARK2N. The ADGRL4 was enriched in the G protein-coupled receptors pathway. The FAT4 was enriched in the Hippo signaling pathway-multiple species and Cell adhesion molecules pathways (Supplement 4). The ARK2N was not enriched in KEGG pathway.
SNP25_27304876 was a key locus affecting cannon bone circumference trait
In the CBC trait, 11 significant SNPs were identified. Enhancer annotations were conducted for these significant SNPs. It was found that SNP25_27304876 is annotated in enhancer regions of various tissues, including ovary, stomach, testis, muscle, and lung (Figure 2A). Additionally, through the Animal-APA Database, it was discovered that SNP25_27304876 is annotated in APA sites of multiple tissues, including rumen, spleen, and esophagus (Figure 2B). SNP25_27304876 was annotated to the CHST3. The CHST3 exhibited higher expression level in the tail fat (3.26), sternocephalicus muscle (3.23), and tail muscle (3.09) tissues, with moderate expression level in the rumen dorsal sac (2.99), uterus (2.92), ovary (2.87), rhomboid muscle (2.79), and radial extensor of wrist (2.09) tissues of Hu sheep (Figure 2C and Supplement 5). Furthermore, CHST3 showed higher expression level in the circulatory and integumentary systems, and moderate expression level in the respiratory, immune, and reproductive systems of Hu sheep (Figure 2D and Supplement 5). The CHST3 was enriched in the glycosyltransferases and glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate pathways. Through the GWASATLAS database, it was found that CHST3 is significantly associated with skeletal, immunological, metabolic and activities traits in humans, which affected immunity, metabolism and activity performances in humans (Figure 2E).
The CHST3 was a key candidate gene affecting body size traits in Hu sheep
In the CBC trait, there were three genotypes at the SNP25_ 27304876 locus: TT, TC, and CC. There was a significant difference in CBC between TT and TC genotypes, and also between TT and CC genotypes. In addition, the TT genotype had the largest CBC, while the CC genotype had the smallest (Figure 3A). Therefore, SNP25_27304876 could be a key locus, and CHST3 could be a key candidate gene for CBC trait. At the SNP25_27304876 locus, the same situation existed in the BW (Figure 3B), BH (Figure 3C), BL (Figure 3D) and CC traits (Figure 3E). In the BL trait, there was no significant difference between TT and TC genotypes, but there was a significant difference between TT and CC genotypes. Furthermore, the TT genotype had the longest BL, and the CC genotype had the shortest (Figure 3D). So, SNP25_27304876 could be a key locus for body size traits, and CHST3 could be a key candidate gene for body size traits.
The SCMH1 was a key candidate gene affecting litter size trait in Hu sheep
The genetic correlation between LS and teat number traits was 0.17, and the phenotypic correlation was 0.12. A total of eight significant SNPs were identified in LS trait (Figure 4A, 4B and Supplement 1). There were three genotypes at the significant SNP 1_15813699 locus: TT, TC and CC. The TT genotype had the highest mean LS (2.73) and the CC genotype had the lowest mean LS (2.22) (Figure 4C). There was significant difference between every two genotypes. SNP 1_15813699 was also positively selected in the Fst analysis (Figure 4D). Therefore, SNP 1_15813699 could be a candidate locus for the LS trait. The SNP 1_15813699 was annotated in the SCMH1. The SCMH1 was annotated in the Animal-eRNA database and found that the eRNA in SCMH1 was highly expressed in the ovary, fallopian tube and placentome of cotyledonary placenta of sheep (Figure 4E). Gene expression level annotation of SCMH1 in Herbivore Transcriptome Information Resource database revealed that SCMH1 was expressed at the highest level in the reproductive system of Hu sheep, followed by circulatory system, exercise system and urinary system (Figure 4F and Supplement 3). In the reproductive system, SCMH1 was expressed at high level in the ovary, oviduct and cervix bottom. In addition, it was expressed at moderate level in the uterus (Figure 4G and Supplement 3). Through the human GWASATLAS database, it was found that SCMH1 was also associated with reproductive traits in humans (Figure 4H). Among them, the most significantly associated trait was age at menarche.
The BAZ2B was a key candidate gene affecting teat number trait in Hu sheep
A total of nine significant SNPs were identified in the TN trait (Figure 5A, 5B and Supplement 1). There were three genotypes at the significant SNP 2_150294372 locus: GG, GA and AA. The AA genotype had the highest mean TN (2.65) and the GG genotype had the lowest mean TN (2.20) (Figure 5C). There was significant difference between every two genotypes. SNP 2_150294372 was also positively selected in the Fst analysis (Figure 5D). Therefore, SNP 2_150294372 could be used as a candidate locus for the TN trait. The SNP 2_150294372 was annotated in BAZ2B. The BAZ2B was annotated in the Animal-eRNA database and found that the eRNA in BAZ2B was highly expressed in mammary gland, ovary and embryo of sheep (Figure 5E). Gene expression level annotation of BAZ2B in Herbivore Transcriptome Information Resource database revealed that BAZ2B had the highest expression level in the reproductive system of Hu sheep, followed by respiratory system, endocrine system and integumentary system (Figure 5F and Supplement 3). The BAZ2B has high expression level in all tissues of the reproductive system except hypothalamus (Figure 5G and Supplement 3). Through the human GWASATLAS database, it was found that BAZ2B was also associated with reproductive traits in humans (Figure 5H). Among them, number of live births trait was of attention.
Selection signature hotspots detection
The assessment of genome-wide ROH was conducted on autosomes in the Hu sheep population, resulting in the identification of 8,406 ROH (Figure 6A), and 35 genes overlapped with the ROH hotspots (Supplement 6). Additionally, 9 genes overlapped with the ROHet hotspots (Figure 6B), 19 genes overlapped with the IHS hotspots (Figure 6C, Supplement 6). Four genes were annotated in ROH and ROHet, they were ATP12A, PCDH9, OLFML2B, TUBGCP5. Four genes were annotated in ROH and IHS, they were SLC23A2, TSPAN5, STPG2, GRID2. No shared candidate genes were identified between the GWAS and selection signature (ROH, ROHet and IHS) hotspots. Through literatures reviewed, it was shown that GRID2 gene is associated with growth and development of sheep. The STPG2 gene was associated with reproductive performance of sheep.
DISCUSSION
This study estimated the heritability of body size and reproductive traits. Moreover, the genetic and phenotypic correlations between body size traits revealed that CBC had an important effect on body size. In particular, three key candidate genes were identified using GWAS, QTL, PheWAS, and functional region annotation. We revealed, for the first time, CHST3 is a key candidate gene affecting body size traits, SCMH1 and BAZ2B are key candidate genes affecting reproductive traits in Hu sheep. The findings expand our understanding of the genetic basis of economic traits in Hu sheep.
Body size is an important economic trait in sheep production, which may be strongly influenced by genetics [23]. In our study, the heritability of all body size traits was greater than 0.15. This indicates that these traits have moderate to high heritability, and can be effectively improved in future breeding. The highest heritability was found in BH trait at 0.76. This suggests that selecting sheep with higher BH during breeding, their offspring will have a high probability of possessing a higher BH. Furthermore, this study calculated the heritability of CBC trait in Hu sheep for the first time, which was 0.25, lower than that found in pigs [2]. It may be due to species differences. Among the body size traits, CBC had high genetic and phenotypic correlations with BW, BH and CC. It is reasonable to assume that selection for CBC could also significantly alter the BW, BH, and CC. The genetic and phenotypic correlations between BH and BW were higher than those between BL and BW. It can be inferred that BH has a greater influence on BW than BL. Additionally, the genetic and phenotypic correlations between BH and BL were both negative, implying that only one of these traits should be selected for breeding in the Hu sheep population. During the growth and development of sheep, the body’s resources are limited. Investing more resources in BH trait would result in fewer resources being allocated to BL trait. This resource allocation conflict could lead to negative correlations between the two traits. In the body size traits, three candidate genes were identified: ADGRL4, FAT4, and ARK2N. The ADGRL4 encodes a key regulator of angiogenesis, and the silence of ADGRL4 affects the Notch pathway, subsequently leading to influences the development of muscle in sheep [24,25]. The FAT4 could mediate mesenchymal cell clustering and villus formation in gut development [26]. Through the non-canonical Wnt signaling pathway, FAT4 plays a key role in tissue homeostasis and angiogenesis [27]. Additionally, FAT4 was enriched in the Cell adhesion molecules pathway, which mediates the development and regeneration of skeletal muscle [28]. It is reasonable to assume that FAT4 may affect energy metabolism and muscle tissue development in sheep. The ARK2N was associated with skeletal muscle function, ARK2N deficiency would lead to skeletal abnormalities and reduced body weight in mice [29].
Enhancers are distal DNA elements that regulate gene expression [30]. APA can enhance the regulatory potential of genes, and facilitate tissue-specific genes expression [31]. The CHST3 affects the proliferation of bone marrow cells, and mutations in this gene will lead to skeletal and cartilage dysplasia [32,33]. In this study, we revealed, for the first time, CHST3 is a key candidate gene affecting the body size in Hu sheep. SNP 25_27304876 was annotated in enhancers (ovary, stomach, testis, muscle, and lung) and APA regions (rumen, spleen, and esophagus). And SNP25_27304876 was annotated to CHST3. Therefore, we speculated that CHST3 may affect the reproductive, digestive, and immune performances of Hu sheep. Subsequently, CHST3 was assessed at the gene expression level. We found that CHST3 had high expression level in tissues such as rumen, ovary, and muscle of Hu sheep. Additionally, CHST3 was also highly expressed in systems such as the circulatory system, immune system, and reproductive system of Hu sheep. The above results confirmed our speculation that CHST3 can affect reproductive, digestive and immune performances of Hu sheep. In the human PheWAS data, CHST3 was also significantly associated with similar traits that affect immune, metabolic, and activity performances in humans. Comparison of the data from the sheep GWAS and human PheWAS, revealed that CHST3 shows tissue specificity and conserved functions among mammals. Furthermore, the effects of CHST3 on body size traits in Hu sheep was further verified by combining the phenotypic data. At the SNP25_ 27304876 locus, there were three genotypes: TT, TC, and CC. Among the BW, BH, BL, CC, CBC traits, individuals with the TT genotype had the highest average phenotype values, while those with the CC genotype had the lowest. There were significant differences between TT and TC, TT and CC genotypes for all traits except BL. This situation may be caused by the low genetic and phenotypic correlations between CBC and BL. These results can demonstrate that CHST3 is a key candidate gene affecting body size in Hu sheep.
Sheep LS is a low heritability trait, with an estimated heritability of approximately 0.1. In this study, we had estimated the heritability of LS in Hu sheep to be 2.22E-03. This might be due to the relatively small number of SNPs, and the limited sample size of the Hu sheep population. The LS of ewes was regulated by multiple genes, and BMPR1B had been demonstrated to affect it. However, there are many genes that influenced LS in sheep remain unknown. This study revealed SCMH1 could be a candidate gene for the LS trait in Hu sheep, and provided a reference for subsequent researches on sheep LS trait. The genetic and phenotypic correlations between LS and TN traits in Hu sheep were close to moderate. It was reasonable to speculate that these two traits might be subject to a certain degree of co-selection. In future breeding programs, Hu sheep with a greater TN may exhibit higher reproductive performance.
LS and TN are economically important reproductive traits directly related to reproductive efficiency and profitability in livestock farming. Therefore, it is crucial to identify the key candidate genes that influence reproductive traits in Hu sheep. As the markers of active enhancers, eRNAs play important roles in gene regulation and are associated with various complex traits and characteristics [17]. The SCMH1 may affect the development process of oocytes and embryos [34]. In addition, SCMH1 can regulate bone formation [35]. In this study, we revealed, for the first time, SCMH1 is a key candidate gene affecting LS in Hu sheep. The eRNA in SCMH1 was highly expressed in ovary, fallopian tube and placentome of cotyledonary placenta, suggesting that SCMH1 could affect the reproductive performance in sheep. Subsequently, the gene expression level of SCMH1 was characterized. We found that SCMH1 had the highest expression level in the reproductive system in Hu sheep. At the same time, SCMH1 was also highly expressed in tissues such as ovary and oviduct. It was further demonstrated that SCMH1 could affect the reproductive performance of Hu sheep. In the human PheWAS data, SCMH1 was significantly associated with age at menarche in humans. Maternal age at menarche influenced offspring birth weight [36]. The above results have suggested our conclusion that SCMH1 is a key candidate gene affecting LS in Hu sheep, and SCMH1 may also be a tissue-specific gene in mammals. The BAZ2B has been described as a master regulator in the reprogramming of human haematopoietic progenitors and has been associated with neurodevelopment [37,38]. Currently, there is no study showing that BAZ2B is related to reproductive performance in sheep. In this study, eRNA in BAZ2B was highly expressed in mammary gland, ovary and embryo, suggesting that BAZ2B could affect mammary gland and reproductive performance in sheep. Subsequently, the gene expression level of BAZ2B was characterized. We found that BAZ2B was expressed at the highest level in the reproductive system in Hu sheep. At the same time, BAZ2B was also highly expressed in tissues such as ovary and uterus. In the human PheWAS data, BAZ2B was significantly associated with number of live births in humans. The above results have suggested that BAZ2B not only affects the TN trait, but may also affects the LS trait in Hu sheep.
Through selection signature hotspots detection, we found two genes were related to growth and reproductive performances in sheep, including GRID2 and STPG2. The GRID2 has been identified as a candidate gene for growth traits in Akkaraman sheep [39]. The STPG2 plays a role in testicular development and spermatogenesis, and it is associated with sheep fertility [40]. These findings demonstrated that Hu sheep population were suffering selection on body size and reproductive performance. Significant differences were observed between the candidate genes identified through GWAS and selection signature hotspots detection. This could be due to the different approaches used by each analysis: GWAS detected trait-related loci, whereas selection signature hotspots detection identified positive selection loci.
CONCLUSION
We revealed, for the first time, CHST3 is a key candidate gene affecting body size traits, SCMH1 is a key candidate gene influencing LS trait, and BAZ2B is a key candidate gene impacting TN trait in Hu sheep. The findings not only contribute to the understanding of biological mechanisms involved in these traits, but also provide potential markers for selective breeding in Hu sheep.
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