The yak (Bos grunniens) is native to the Qinghai–Tibet Plateau and adjacent alpine regions. As the only large domestic animal adapted to extremely high-altitude environments, it is often referred to as the “ship of the plateau” and “all-purpose livestock” (). It can efficiently utilize alpine meadow forage resources, providing local communities with meat, milk, draft power, hides, fuel, and other livelihood products (). China's yak population exceeds 15 million heads, accounting for over 95 % of the global total (). In yak production practices, nutritional regulation measures such as supplementary feeding during the cold season can improve production performance to a certain extent. However, the ultimate level of production performance achievable is fundamentally determined by the yak's genetic potential. With the rapid development of molecular genetics and sequencing technologies, molecular markers have been widely adopted. In livestock, genetic variants, including single-nucleotide polymorphisms (SNPs), small insertions and/or deletions (InDel, < 50 bp), and copy number variations (CNVs), are widespread across the genome and may contribute to phenotypic diversity and economically important traits (). As the most commonly used method for assessing genetic diversity in animal populations, SNP molecular markers are characterized by a wide distribution, high density, abundant loci, and high genetic stability within the genome ().

The insulin-like growth factor (IGF) family consists of two ligands (IGF-1 and IGF-2), corresponding receptors (IGF1R and IGF2R), and six binding proteins (IGFBP-1-IGFBP-6) (). As multifunctional bioactive peptides, IGFs directly participate in the regulation of animal growth and development; reproductive, nutrition, and metabolic processes; and fundamental cellular activities, including cell proliferation, differentiation, and apoptosis. They also mediate the growth-promoting effects of the growth hormone (GH). As a key receptor in the IGF system, IGF1R mediates its core biological functions and is widely expressed across many tissues and cell types. Therefore, genetic variations in this gene may perturb hormone-signaling pathways and thereby influence growth and reproductive traits. The IGF1R is expressed in B and T lymphocytes; in thyroid cells and osteoblasts; and in tissues including the liver, brain, stomach, kidney, heart, lung, muscle, and bone (). During embryonic and postnatal development, IGF1R participates in immune regulation, lymphocyte production, and muscle and bone development (). IGF1R is a core component of the neuroendocrine growth axis, and its function depends on the synergistic effect of GH and IGF. In addition to altering the encoded amino-acid sequence, variants in IGF1R may influence gene function by affecting pre-mRNA processing, transcript abundance, or receptor expression. Variants within exon 13 or its flanking intronic sequences may disrupt exonic or intronic splicing regulatory elements and, when located near exon–intron boundaries, canonical splice-site signals. Such alterations can affect exon recognition or splice-site selection and may consequently lead to aberrant transcripts, including exon skipping, intron retention, or cryptic splice-site activation (). Although direct functional evidence for variants in this specific IGF1R region remain limited, these potential molecular consequences provide a rationale for investigating IGF1R polymorphisms in relation to growth-related traits in yak.

Numerous studies report associations between IGF1R polymorphisms and economically important traits in livestock. In cattle, copy number variation (CNV) and insertion/deletion (InDel) polymorphism of IGF1R are significantly associated with body weight, withers height, chest girth, and body length (). Another study reported that SNPs in specific IGF1R exons are associated with the weaning weight of Angus cattle (). In addition, IGF1R CNV is associated with body weight and withers height in Jinnan cattle and with withers height and hip width in Qinchuan cattle; however, no such associations were detected in Nanyang or Xianan cattle, indicating that its genetic effect may vary by breed (). Beyond growth traits, meta-analyses and transcriptomic data indicate that IGF1R participates in the regulation of feed efficiency, AMP-activated protein kinase (AMPK)-related pathways, intramuscular fat (IMF) deposition, and fatty-acid metabolism in beef cattle and promotes muscle cell proliferation and differentiation (). In sheep, IGF1R polymorphisms are also associated with growth performance; one study reported significant associations between several SNPs and five growth traits (). In Polish Merino sheep, the IGF1R variant c.654G>A has been associated with average daily gain and foreleg weight, as well as meat quality traits including loin eye depth, intramuscular fat content, and water-holding capacity (). In pigs, IGF1R expression is associated with fecundity. It shows a distinct pattern in high-fecundity sows, with the highest hepatic expression in replacement gilts at 60 and 90 d of age, suggesting that it may be involved in the developmental regulation of reproductive traits (). Therefore, this study aimed to screen IGF1R SNPs in Qinghai Plateau yaks, identify loci associated with growth traits, and evaluate their effects through association analyses in order to provide a theoretical basis for molecular-marker-assisted breeding of yaks.

Growth traits are key indicators of livestock growth, development, and economic value, playing a significant role in breeding. Animal growth and development are precisely regulated by the growth hormone GH–IGF1 axis, which plays a crucial role in body growth, development, and anabolic processes. As the core regulator of this pathway, GH biological functions are primarily mediated through the binding of IGF1 to its receptor, IGF1R (). IGF1R has a high affinity for IGF1 and is considered to be a potential quantitative trait locus (QTL) that influences traits like growth, carcass traits, and reproductive performance (). In the present study, several favorable genotypes of IGF1R were associated with yak body measurement traits. Specifically, the favorable genotypes were CC and CT at g.7383084C>T, GA at g.7383136G>A, CT at g.7383137C>T, and GG at g.7383177G>A. Individuals carrying these genotypes showed significant differences in withers height, body length, and related body measurement traits compared with individuals carrying other genotypes. This observation is consistent with previous reports in multiple Chinese yak populations, including Datong yak, Qinghai Plateau yak, Tianzhu White yak, Gannan yak, and Xinjiang yak, in which polymorphism variants located in exon 1 of the IGF1R gene were shown to exert significant effects on early postnatal growth and development (). Combined with these earlier findings, our results further support the hypothesis that sequence polymorphisms in different regions of the yak IGF1R gene, both in exons and in flanking introns, can contribute to phenotypic variation in growth traits across different developmental stages and genetic backgrounds. These marker trait associations are biologically plausible because IGF1R is a key upstream mediator of IGF1-dependent signaling that directly regulates chondrocyte proliferation, longitudinal bone growth, and systemic skeletal development, all of which are fundamental processes underlying body size and body conformation formation in yaks (). Therefore, the variants identified in the exon 13–intron 13 region of the yak IGF1R gene may be considered to be promising candidates for marker-assisted selection aiming at improving growth performance in local yak-breeding programs.

The effective allele number, heterozygosity, and polymorphic information content are key indicators of a gene fragment’s polymorphism and the population’s genetic variation. These indicators reflect genetic similarity among individuals within a population; higher values generally indicate greater genetic variation. In family-based breeding systems, genetic loci with a large effective number of alleles, high polymorphism information content, and high heterozygosity can be used for marker-assisted selection in conjunction with association analyses of important production traits, thereby providing a genetic basis for improving livestock and poultry production performance. In the present study, four SNPs were detected in the exon 13–intron 13 region of the yak IGF1R gene, including g.7383084C>T, g.7383136G>A, g.7383137C>T, and g.7383177G>A. At the g.7383084C>T locus, 182 individuals had the CC genotype, 182 had the CT genotype, and 36 had the TT genotype. At the g.7383136G>A locus, 164, 182, and 54 individuals carried the GG, GA, and AA genotypes, respectively. At the g.7383137C>T locus, the numbers of individuals with the CC, CT, and TT genotypes were 73, 182, and 145, respectively. At the g.7383177G>A locus, 382 individuals carried the GG genotype, whereas 18 carried the GA genotype. The exonic variant g.7383084C>T was a synonymous substitution that did not alter the encoded amino acid as both alleles encoded aspartic acid. However, synonymous variants should not be regarded as functionally neutral a priori because they may influence codon usage bias, mRNA secondary structure, mRNA stability, translation efficiency, co-translational protein folding, or exonic-splicing regulatory elements (). Therefore, g.7383084C>T may affect yak growth traits by modulating IGF1R transcript processing or expression efficiency, or it may be in linkage disequilibrium with another functional variant in the IGF1R gene. The variants g.7383136G>A and g.7383137C>T were located 9 and 10 bp downstream of exon 13, respectively, suggesting that they are near-exon intronic variants positioned close to the exon–intron boundary, whereas g.7383177G>A was located within intron 13. Although intronic variants do not alter the amino acid sequence directly, variants close to exon–intron boundaries may affect pre-mRNA splicing by altering splice donor recognition, exon definition, intronic splicing enhancers, intronic splicing silencers, or other cis-regulatory elements (). In particular, intronic positions near +9 and +10 downstream of an exon may lie within regions relevant to splice-site recognition and early spliceosomal assembly, suggesting that g.7383136G>A and g.7383137C>T could potentially influence IGF1R transcript structure, transcript abundance, or isoform composition (). The intronic variant g.7383177G>A is farther from the exon–intron boundary and exhibited low polymorphism (PIC < 0.25), indicating limited genetic variability and relatively weak potential for single-locus selection; nevertheless, it may still contribute to phenotypic variation as part of a haplotype background. All four loci conformed to Hardy–Weinberg equilibrium (P>0.05), suggesting that they were in a relatively stable genetic state in the sampled yak population. By contrast, g.7383084C>T, g.7383136G>A, and g.7383137C>T showed moderate polymorphism (0.25 < PIC < 0.5), indicating that these loci retain sufficient allelic diversity for evaluating genotype–phenotype associations and may serve as useful candidate markers for marker-assisted selection of yak growth traits. Taken together, the synonymous exonic variant and near-exon intronic variants identified in this study may influence yak growth traits through regulatory mechanisms affecting IGF1R mRNA processing, expression, or linkage with causal variants.

From a quantitative genetic perspective, additive genetic effects represent an important component of heritable variation in complex traits and provide the basis for allele substitution effects and breeding-value prediction (). For a biallelic locus, a potential additive pattern is suggested when phenotypic values change progressively with the number of alternative alleles and the heterozygous genotype is approximately intermediate between the two homozygous genotypes. In the present study, formal additive–dominance models were not fitted; therefore, the observed genotype differences cannot be regarded as direct evidence of additive genetic effects. Nevertheless, some genotype means showed potential allele dose tendencies for individual traits. For example, chest circumference at g.7383084C>T increased from CC to CT and TT, suggesting a possible positive dose-related association of the T allele with chest circumference. At g.7383137C>T, body length showed an increasing tendency from CC to CT and TT, whereas chest circumference showed a decreasing tendency with increasing T-allele dosage. These trait-specific patterns suggest that some IGF1R variants may contribute to phenotypic variation through potentially additive or partially additive mechanisms. However, several traits did not follow a strictly linear genotype–phenotype pattern, and heterozygote superiority or genotype-specific effects were observed at some loci. Such patterns may reflect dominance, overdominance, linkage disequilibrium with functional variants, or differences in local haplotype background. Therefore, the present findings should be interpreted as preliminary evidence of potential allele dose tendencies (). In addition to single-locus effects, the joint inheritance of linked variants, as captured by haplotypes and diplotypes, may also contribute to phenotypic variation in animal growth traits. Previous studies have reported associations between ADIPOQ haplotype combinations and body measurements in Qinchuan cattle (), as well as associations between Dapper1 haplotypes and body weight across several cattle breeds (). Consistently with these observations, all five IGF1R diplotype combinations in the present study showed significant or highly significant associations with several growth traits. Comprehensive comparison of the measured traits suggested that the H2H6 diplotype was associated with relatively favorable growth performance in the sampled yak population.

The IGF1R gene polymorphism in yaks and all four identified polymorphic sites are all significantly associated with growth traits, with H2H6 being the superior diplotype. Therefore, IGF1R can be considered to be a candidate gene for marker-assisted selection in yaks. Incorporating these markers into breeding programs is expected to enhance selection efficiency, shorten the breeding cycle, and promote sustainable development of the yak industry.