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Association of single nucleotide polymorphisms in the growth hormone and growth hormone receptor genes with blood serum insulin-like growth factor I concentration and growth traits in Angus cattle^1,2,3

^* Department of Animal Sciences, The Ohio State University, Columbus 43210-1095 and and Department of Animal Sciences and Interdisciplinary Concentration in Animal Molecular and Cell Biology, University of Florida, Gainesville 32611-0901

	Abstract

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This study was conducted to identify polymorphisms in the promoter and coding regions of the bovine growth hormone and growth hormone receptor genes and to study association of polymorphisms identified in these genes with growth traits and serum insulin-like growth factor-I (IGF-I) concentration. The denaturing gradient gel electrophoresis method and sequencing were utilized to identify three new single nucleotide polymorphisms in the promoter region of the growth hormone gene in Angus cattle. Polymerase chain reaction-based restriction fragment length polymorphism procedures were developed for rapid determination of the single nucleotide polymorphism genotypes in the growth hormone and the growth hormone receptor genes among Angus calves from lines divergently selected for high or low blood serum IGF-I concentration. The IGF-I concentration and growth traits were analyzed using animal models. The single nucleotide polymorphism in the promoter region of the growth hormone receptor gene was associated with serum IGF-I concentration on d 42 of the postweaning test and with mean IGF-I concentration. The associated effects of the markers need to be verified in other populations.

Key Words: Beef Cattle • Genes • Growth • Insulin-Like Growth Factor • Receptors • Somatotropin

	Introduction

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Growth hormone has proven to be the major regulator of postnatal growth and metabolism in mammals and thus affects growth rate, body composition, health, milk production, and aging by modulating the expression of many genes including that of insulin-like growth factor I (IGF-I) (Sumantran et al., 1992; Ho and Hoffman, 1993; Lincoln et al., 1995). The growth hormone receptor (GHR) mediates the biological actions of growth hormone on target cells by transducing the myogenic-stimulating signal across the cell membrane and inducing the transcription of many genes, including IGF-I (Rotwein et al., 1994; Argetsinger and Carter-Su, 1996). Mutations in the GHR gene often cause growth retardation in humans characterized as GH resistance or GH insensitivity (Rosenbloom et al., 1997). Therefore, the GH and GHR genes are important candidate genes for the identification of genetic markers for growth, carcass, and milk traits in livestock.

In farm animals, many polymorphisms have been identified in the GH gene, but only a few of these have been precisely characterized for nucleotide changes and positions in the DNA sequence. In bovine, a single nucleotide polymorphism (SNP) in exon 5 (at codon 127) changes leucine to valine (CTG to GTG) in the mature GH molecule (Lucy et al., 1991; Zhang et al., 1992). Yao et al. (1996) identified an insertion/deletion of three base pairs (TGC) in the promoter region and an A to C transversion in exon 5. In the bovine GHR gene, only a few genetic polymorphisms have been reported (Falaki et al., 1996; Lucy et al., 1998; Moisio et al., 1998). The objectives of this study were to identify and characterize polymorphisms in the promoter and coding regions of the GH gene in Angus beef cattle and to evaluate the association of the polymorphisms in the GH and GHR genes with serum IGF-I concentrations and growth traits in the Angus cattle divergently selected for serum IGF-I concentrations.

	Materials and Methods

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Purebred Angus cattle divergently selected for blood serum IGF-I concentration, beginning in 1989, were used in this study. Selection, management, measurement of growth traits, and determination of blood serum IGF-I concentration were described previously by Davis and Simmen (1997). Differences in IGF-I concentrations between the high and low IGF-I selection lines on d 28, 42, and 56 of the postweaning test and in mean IGF-I concentration were 57 ± 6, 63 ± 7, 44 ± 7, and 55 ± 6 ng/mL, respectively (P < 0.001 for each of the four measures of IGF-I).

Identification of Polymorphisms

Using PCR with primers encompassing the promoter region and exons 1 to 5, DNA fragments of the GH gene were amplified from genomic DNA from 40 calves with the highest or lowest serum IGF-I concentration. Amplified fragments were analyzed for polymorphism using the denaturing gradient gel electrophoresis (DGGE) method. Briefly, PCR amplification was performed using primers GHPM1Fgc and GHPM1R (Table 1). The 30-µL reaction mixture contained 8 pmol of each primer, 100 ng of genomic DNA, 200 -M dNTP, and 1 unit of Taq polymerase (Gibco-BRL, Grand Island, NY). After the initial denaturation at 94°C for 2 min, amplification was run through 31 cycles of 94°C for 45 s, 65°C for 30 s, and 72°C for 40 s, and was followed by a 5-min extension period at 72°C in a DNA thermal cycler (Perkin Elmer Cetus, Norwalk, CT). An additional 30-bp GC-rich fragment was added to the fragment by another PCR amplification using primers GC-clamp and GHPM1R as described by Sheffield et al. (1989). Following the initial denaturation at 94°C for 2 min, two cycles of 94°C for 60 s, 50°C for 45 s, and 72°C for 60 s were followed by 28 cycles of 94°C for 45 s, 65°C for 30 s, and 72°C for 30 s, and an extension of 5 min at 72°C. The amplified fragments were run through 6% denaturing gradient polyacrylamide gels with 20 to 50% denaturing gradient (previously determined using a perpendicular gradient gel) in 0.8 (TAE buffer at 120 V and 58°C for 4 h (16 x 20 cm gel). Gels were stained with either silver or Sybr Green I (Molecular Probes, Inc., Eugene, OR) and viewed under UV light.

One fragment amplified from the promoter region of the GH gene with primer pair GHPM1Fgc/GHPM1R showed a polymorphism among 40 calves. A total of six genotypes were observed. The DNA fragment amplified from the three homozygous calves was sequenced and analyzed for nucleotide changes. Three C to T transitions were identified in the region (GenBank accession number: AF118837). Another pair of primers, GHP1TF3 and GHPMTR0 (Table 1), was designed to introduce an XmnI and an MspI recognition site to determine the haplotypes of the first and second SNP, designated as P(12). A nested PCR amplification was performed with 36 cycles of 94°C for 45 s, 56°C for 55 s, and 72°C for 30 s, and an extension of 5 min at 72°C, using PCR product (with primers GHPM1Fgc and GHPM1R) as templates. Five microliters of PCR product was mixed with three units each of enzymes XmnI and MspI (Promega Co., Madison, WI), 2.4 µL of H₂O, 0.9 µL of 10x buffer, and 0.10 µL of BSA, and incubated in a water bath at 37°C for 2 h. The mixture was then run on an Agarose mini-gel and viewed under UV lights. The third SNP, designated as P(3), can be recognized by digestion with restriction enzyme MaeIII (Boehringer Mannheim Co., Indianapolis, IN) at 55°C for 2 h.

The previously identified polymorphism in exon 5 (at codon 127) of the GH gene (Lucy et al., 1991; Zhang et al., 1992), designated as E(5), was verified among our calves using the PCR-RFLP method. Primers GHE5F and GHE5R were used to amplify a fragment from exon 5 encompassing codon 127. Polymerase chain reaction was performed under similar conditions as described above with 31 cycles of 94°C for 60 s, 58°C for 45 s, and 72°C for 60 s. Four microliters of PCR products was mixed with three units of restriction enzyme AluI (Promega Co., Madison, WI), 4.6 µL of H₂O, 1.0 µL of 10x buffer, and 0.10 µL of BSA, and incubated in a water bath at 37°C for 2 h. The mixture was then run on an agarose mini-gel and viewed under UV light.

We previously examined the promoter region and exon 10 of the bovine GHR gene (Ge et al., 1999; 2000). In the promoter region, we identified a two-allelic DGGE polymorphism (Ge et al., 1999), designated as RP(1). The fragment that displayed the DGGE polymorphism was sequenced and an A to G transition was identified (GenBank: AF126288), with the G variant corresponding to the A allele in the DGGE polymorphism (Ge et al., 1999). Restriction enzyme NsiI (Promega Co., Madison, WI) recognized the polymorphism and was used to determine the genotypes. The primers and conditions for PCR were the same as described previously (Ge et al., 1999) and RFLP genotyping was performed as described above for the GH polymorphisms. In exon 10, we identified four SNP: a C to T transition at position 76 bp, an A to G at position 200, C to T at position 229, and A to G at position 257 (Ge et al., 2000). These SNP are designated as RE(10.1), RE(10.2), RE(10.3), and RE(10.4), respectively. Genotyping of these SNP was done by the PCR–RFLP method previously described (Ge et al., 2000). The lack of effect of the polymorphism on amino acid encoding (AATAAC, both for Asn) and the high cost of restriction enzyme MaeII (Boehringer Mannheim Co.) required for differentiation of the variants influenced our decision not to perform genotyping of RE(10.1).

Statistical Analysis

Allelic distribution of the SNP in the two selection lines was tested using a ² test. Statistical analysis of trait association was performed separately for SNP from the GH and GHR genes. Traits analyzed included blood serum IGF-I concentrations at d 28, 42, and 56 of the 140-d postweaning test, the mean IGF-I concentration of each calf, birth weight, weaning weight, on-test weight, off-test weight, off-test hip height, weight gain during the 20-d adjustment period between weaning and the beginning of the postweaning test, and postweaning gain. Each trait was analyzed using the multiple trait derivative-free restricted maximum likelihood (MTDFREML) computer programs (Boldman et al., 1993), with animal models and the additive genetic relationship matrix. Pedigrees of base population animals were traced back three generations to create the numerator relationship matrix. The A^-1 matrix included 2,163 animals. All analyses were done in two steps: first with a full animal model and then with a reduced model. The full animal model included fixed effects of marker genotypes, birth year (1995, 1996, 1997), season of birth (spring vs. fall), sex (bull vs. heifer), age of dam (2, 3, 4, 5 to 9, 10), and selection line (high vs. low), random effects of animal genetic, maternal genetic, and maternal permanent environmental effects, and a covariate for age of calf. Marker genotype effects included the P(12) marker (in promoter) genotype (AA, AB, AC, BB, BC, CC) and E(5) marker genotype (AA, AB, BB) for the GH model, and four marker genotype effects [RP(1), RE(10.2), RE(10.3), and RE(10.4)] for the GHR model. The covariate for age of calf was not included in the analysis of birth weight. Maternal genetic and/or maternal permanent environmental effects were deleted from the full animal model if the effect accounted for less than 20% of the total phenotypic variance. The reduced model was used in the final analysis. Marker-associated effect was estimated by the difference between the solutions for the homozygous groups, and allelic dominance effects were estimated by subtracting the average of the solutions for the two homozygous genotypes from the solution for the corresponding heterozygous genotype. Contrasts and tests were done as described by Boldman et al. (1993) with a Bonferroni correction of the significance levels.

	Results

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Point Mutation and Marker Genotyping

A DGGE polymorphism with six genotypes was identified in the fragment amplified from the promoter region of the GH gene with primers GHPM1Fgc/GHPM1R. Sequence analysis showed three SNP closely linked in the fragment: C/T at position 253, C/T at 303, and C/T at 313 (position corresponding to sequence by Gordon et al., 1983). Three haplotypes (A, B, C) for the first two SNP were identified among the Angus calves using the PCR–RFLP method. The three haplotypes (A, B, and C) corresponded to C₂₅₃C₃₀₃, T₂₅₃C₃₀₃, and T₂₅₃T₃₀₃, respectively, and generated six genotypes: AA, AB, AC, BB, BC, and CC. These genotypes did not correspond to the six DGGE genotypes due to the interference of the third SNP on denaturing conditions.

Using the PCR–RFLP method, 468 calves (240 in the high IGF-I line and 228 in the low IGF-I line) born in the spring and fall of 1995, 1996, and 1997 were genotyped for the first and second SNP in the promoter region of the GH gene. The genotypic frequencies were as follows: 9.8% AA, 13.7% AB, 25.4% AC, 8.3% BB, 27.1% BC, and 15.6% CC (haplotype A: 29.4%, B: 28.7%, C: 41.9%). Only 249 calves were genotyped for the third SNP in the promoter region because the polymorphism was only minimally informative among the calves (genotypic frequencies: 93.6% CC, 6.4% CT, and 0% TT). Genotypes for the SNP at codon 127 (C or G) were determined for 468 calves with 34.4% AA (CC), 55.1% AB (CG), and 10.5% BB (GG) genotypes (allele A: 62.0%, B: 38.0%). Shown in Table 2 are the haplotypic or allelic frequencies in the two selection lines. For the two polymorphisms in the promoter region of the GH gene, the genotypic frequencies, but not the haplotypic frequencies, were different between the high and low IGF-I lines (P < 0.05) as determined using a ² test.

Association Analyses

Estimates of association for the polymorphism in the GH gene are shown in Table 3. With Bonferroni correction, where P-values were divided by the number of comparisons, no significant trait association was identified with the SNP in the GH gene among the Angus cattle. However, SNP RP(1) in the promoter region of the GHR gene showed significant association with serum IGF-I concentration on d 42 of the postweaning test and with mean serum IGF-I concentration (Table 4). This SNP also tended to be associated with serum IGF-I concentrations on d 28 and 56 of the postweaning test.

	Discussion

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Association analyses failed to reveal any significant association of these SNP in the GH gene with serum IGF-I concentrations or growth traits. The SNP at position 253 is located next to a binding site of transcription factor PEA3 (Roth et al., 1990), and the SNP at position 303 is the first nucleotide of the 6-bp binding site of transcription factor TRE (Theill and Karin, 1993). However, a search against a repeat database revealed that these three SNP were located in a SINE/BovA2 repeat element. This may explain the high variability in this small region, and this region may not really be the functional promoter for the bovine GH gene. Therefore, variations in such repeat elements cannot have a direct effect on GH gene expression or be closely associated with traits affected by loci in the nearby region.

Association studies between the GH gene and performance traits in livestock often yielded inconsistent results in previous studies. Eppard et al. (1992) reported that cows given exogenous bovine GH with valine at residue 127 produced 2 kg/d more milk than did cows given the leucine variant. Schlee et al. (1994) reported that the leucine homozygous genotype (CTG/CTG) was associated with a higher GH concentration and the heterozygous genotype (CTG/GTG) was associated with higher IGF-I concentration. Vukasinovic et al. (1999) found a significant allele substitution effect of the polymorphism on milk protein percentage in Holstein cows. However, Yao et al. (1996) did not find significant effects associated with the polymorphism at codon 127. Recent studies showed that the polymorphism was not significantly associated with thyrotropin releasing hormone-induced GH release in Friesian cattle (Grochowska et al., 1999) or with reproductive traits of dairy bulls (Lechniak et al., 1999). In addition to error, the inconsistent results may have arisen from differences in the number of animals analyzed and statistical approaches taken (Vukasinovic et al., 1999), or more importantly, the genetic backgrounds of the populations.

In this study, we used an animal model that took into account other polygenic effects and relationships among individuals included in the study. The fixed effect of line was included in the animal model to account for genetic drift between selection lines in the analysis of data including both selection lines. The significance levels were corrected using Bonferroni correction, which takes into account the number of tests and controls type I error. This approach should yield reliable results unbiased by relationships among individuals, or by selection (Kennedy et al., 1992). Calves used in this study had been divergently selected for approximately three generations, and thus, the two selection lines may have had different frequencies of various alleles in the genome. Quantitative traits are regulated by many genes and affected by interactions among them, and thus, a candidate gene associated with a trait in one population may have a different effect, or show no effect at all, in another population due to negative effects of other genes and epistatic interactions of the candidate gene with other genes in the population (Pomp, 1994). This theory is supported by many association studies, in which a polymorphism was significantly associated with performance traits in one family or breed, but not in another family or breed (Casas et al., 1995; Feng et al., 1997; Knorr et al., 1997). A more complex system must be developed to model QTL effects before a genetic marker can be broadly applied to breeding schemes in different populations.

	Implications

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The polymorphism we have identified in the promoter region of the bovine growth hormone receptor gene could be a potential genetic marker for serum insulin-like growth factor I concentration in Angus beef cattle. Differences in trait association of the genetic markers may exist among different populations. More tests are needed in other populations of calves to verify the associated effects of the genetic marker, as well as the effects of the other polymorphisms in the growth hormone and growth hormone receptor genes.

	Footnotes

 
¹ We are thankful to D. VanVleck for his prompt and generous help with statistical analyses and MTDFREML computer programs. Gratitude is also expressed to S. St. Martin for his advice on statistical analyses.

² Salaries and research support were provided by state and federal funds appropriated to the Ohio Agric. Res. and Dev. Center, The Ohio State University, and by USDA 95-37206-2317 (RCMS). This is publication no. R-07731 from the Florida Agric. Exp. Stn.

³ The experiment was a contributing project to North Central Regional Projects NC-196, "The Genetics of Body Composition in Beef Cattle," and NC-209, "Genetic Improvement of Cattle Using Molecular Genetic Information."

⁴ Current address: 1545 17th St., Santa Monica, CA 90404.

Received for publication January 23, 2002. Accepted for publication November 26, 2002.

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