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High amino acid variation in the intracellular domain of the pig prolactin receptor (PRLR) and its relation to ovulation rate and piglet survival traits¹

A. Tomás^*,2, J. Casellas^*, O. Ramírez^*, G. Muñoz, J. L. Noguera and A. Sánchez^*

^* Departament de Ciència Animal i dels Aliments, Universitat Autónoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; and Departamento de Mejora Genética Animal, SGIT-INIA, 28040 Madrid, Spain; and Àrea de Producció Animal, Centre UdL-IRTA, 25198 Lleida, Spain

	Abstract

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Two polymorphisms of the porcine prolactin receptor (PRLR) gene were previously related to litter size by several authors; however, the magnitude and direction of such effects varied depending on the population analyzed. We have sequenced the complete coding region of the porcine PRLR gene and found 6 nonconservative SNP: C1217T (Leu/Pro₄₀₆), C1283A (Asp/Ala₄₂₈), G1439A (Lys/Arg₄₈₀), T1528A (Met/Leu₅₁₀), G1600A (Gly/Ser₅₃₄), and G1789A (Gly/Ser₅₉₇), within exon 10 of the gene, which encodes the entire intracytoplasmic domain of the protein. Eight haplotypes were found and were segregating at different frequencies in 6 porcine breeds. The effects of each individual SNP and haplotype were evaluated in an Iberian x Meishan F₂ population using a univariate mixed-inheritance animal model. Significant effects on the number of corpora lutea were found for PRLR haplotypes (P < 0.012), confirming the previously reported associations of PRLR in this process and highlighting the importance of performing analysis of haplotypes rather than of individual SNP. Suggestive effects or tendencies were found for heart rate at birth (P < 0.10), rectal temperature (P < 0.05), and oxygen saturation (P < 0.10) 1 h after birth, and time to first suckle (P < 0.10). We found greater than expected levels of amino acid variability within the intracellular domain of the porcine PRLR, which have been associated with differences in the number of corpus lutea of sows and the preweaning survivability of piglets.

Key Words: pig prolactin receptor • piglet survival • polymorphism • reproduction

	INTRODUCTION

Top Abstract INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION IMPLICATIONS LITERATURE CITED

 
Prolactin (PRL) is an anterior pituitary hormone involved in many endocrine activities and plays an essential role in reproduction (Bole-Feysot et al., 1998). In most mammals, PRL exerts luteotrophic actions (Gibori, 1992; Ciereszko et al., 2001) and, at least in rats, also luteolytic effects (Matsuyama et al., 1996). Knockout PRLR^–/– mice are sterile due to a failure of blastocysts to implant and show multiple reproductive abnormalities, such as irregular estrous cycles, degeneration of fertilized embryos, absence of pseudo-pregnancy, and impaired maternal behavior (Kelly et al., 2001). In the fetus PRL is a physiological trigger for lung maturation (Hamosh and Hamosh, 1977) and has been related to respiratory distress syndrome (RDS) in humans (Parker et al., 1989).

In pigs, the PRLR gene has been mapped to chromosome 16 (Vincent et al., 1997). An AluI RFLP polymorphism within exon 10 of the gene has been associated with litter size in 3 out of 5 porcine lines (Vincent et al., 1998). However, the magnitude and direction of the effects differed among lines, suggesting that the polymorphism was not the true causal mutation. Further studies have revealed significant effects of PRLR genotype on other reproductive traits such as ovulation rate, ovarian weight, uterine length, and number of teats (Putnová et al., 2002; van Rens and van der Lende, 2002; van Rens et al., 2003). These studies suggest a role for PRLR on pig reproductive performance through its action on a vast number of cells and tissues, but little is known about its effects on piglet postnatal metabolism and survival.

The current study was conducted to completely sequence the coding region of the porcine PRLR gene with the aim of identifying new polymorphisms that might explain the observed differences in the reproductive performance of sows and the early postnatal survivability of piglets from an Iberian x Meishan F₂ resource population.

	MATERIALS AND METHODS

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Animal procedures followed ethical norms of IRTA.

Animal Material
The Iberian x Meishan F₂ population was created by crossing 3 Guadyerbas boars from the CIA El Dehesón del Encinar (Toledo, Spain) to 18 Meishan females from the experimental center Le Magneraud (INRA, France). Eight boars and 108 sows from the F₁ generation were mated to obtain the F₂ progeny, all of which were bred on the experimental farm Nova Genètica S. A. (Lleida, Spain). During farrowing and lactation, sows were housed in temperature-controlled rooms (24°C) with standard farrowing crates containing heating plates for the piglets (38°C). Veterinary intervention during parturition was kept to a minimum. Sows that spent more than 30 min between births were treated with an i.m. injection of 20 IU of oxytocin. To elicit farrowing, an intravulvar injection of 175 µg of cloprostenol was administered to sows that did not deliver before d 113 of gestation.

Phenotypic Measurements
Within the first hour after birth, 8 physiological and vitality variables were measured in 262 F₂ piglets. Measurements included rectal temperature, arterial oxygen saturation (OS), and heart rate (HR), all of which were monitored at birth (designated 0) and 1 h later (designated 1), time to reach the udder, and time to first suckle (TS). The procedure that was followed for data collection has been extensively described in Casellas et al. (2004). At birth, piglets were weighed, and the number of teats was determined. Three weeks later, piglets were weaned, and their weight was recorded.

Two-hundred-fifty-five F₂ sows were selected for mating, and data from 4 successive parities for each sow were recorded. After farrowing, the total number of piglets born, number of piglets born alive, number of stillbirths, and number of piglets weaned were determined. A total of 881 parities were recorded. In the fifth parity, sows were slaughtered at 30 d of gestation, and the number of corpora lutea (CL) and the number of embryos were counted.

Sequence Data
Total RNA was extracted from liver samples of 10 pigs, belonging to 5 different breeds (2 Piétrain, 2 Land-race, 2 Large White, 2 Meishan, and 2 Iberian), using the Trizol reagent (GibcoBRL, Life Technologies S.A., Barcelona, Spain). Synthesis of cDNA was performed with the Thermoscript RT-PCR kit (Invitrogen S.A., Barcelona, Spain). We designed 3 pairs of conserved primers (Table 1) based on the orthologous sequences of human (GenBank accession number AF416619), mouse (NM_011169), cattle (L02549), and rabbit (J04510) PRLR cDNA.

Polymorphisms were detected by aligning the sequences obtained with the Multalin software (Corpet, 1988). The PolyPhen software (Ramensky et al., 2002) was used to evaluate the impact of amino acid allelic variants on protein structure/function via analysis of multiple sequence alignments and protein 3D-structures.

Typing of Polymorphisms by Primer Extension Analysis
Pig-specific primers were designed (PRLR-E10F and PRLR-E10R) to amplify an 801-bp fragment corresponding to the porcine PRLR exon 10. Primer sequences and the thermal profile are described in Table 1. The PCR reaction was performed in a 15-µL final volume containing 1.5 mM MgCl₂, 100 µM of each dNTP, 0.2 µM of each primer, 0.6 U of Taq DNA polymerase (Ecogen), and 60 ng of genomic DNA. The reaction was enzymatically purified with the EXOSAP-IT kit (Amersham Biosciences Europe GMBH, Cerdanyola del Vallès, Spain), and polymorphisms were simultaneously analyzed with the SNapSHOT multiplex kit (Applied Biosystems). Extension primers were designed to allow size discrimination between different SNP (Table 1). Polymorphisms were genotyped in the F₂ resource population to implement an association study with reproductive performance and piglet survival traits. Moreover, 112 pigs from diverse breeds (10 Iberian, 17 Landrace, 25 Large White, 18 Meishan, 26 Piétrain, and 16 Duroc) were also genotyped to determine the allelic frequencies of each PRLR SNP.

Statistical Analysis
A univariate mixed-inheritance animal model was used to evaluate the effects of genotypes or haplotypes on the traits under study. The snp option of the Qxpak 2 software was used for individual SNP, whereas the ld_fix option, which allows for multiallelic markers, was used for haplotypes (Pérez-Enciso and Misztal, 2004). The assumed model for the phenotypic data of each trait was as follows:

where y_ij is a vector containing the recorded performances of the ith individual; b contains the fixed effects included in the model; X_i' is the incidence matrix that relates the performances with the elements of the b vector; _ij is a variable that indicates the number of copies (0, 1, or 2) of the jth allele presented by each individual (note that j = 1 or 2 in the analysis of biallelic SNP, and j = 1, 2, 3, 4, or 5 when considering haplotypes); a_j is the additive effect of each allele; u_i is the infinitesimal genetic effect (treated as random with covariance matrix A, where A is the numerator relationship matrix), p_i are the permanent random effects, and e_ij is the random residual term.

The fixed and random effects included in the analyses of survival traits were chosen according to the model described by Casellas et al. (2004). In the analysis of teat number and piglet growth traits, the effects included in each model were the batch (fixed effect) and the random effect of the litter. The male/female ratio (covariate) was included in the model for teat number, whereas litter size (fixed), birth weight (covariate), and age at weaning (covariate) were considered in the model for weaning weight. For prolificacy traits (total number of piglets born, number of piglets born alive, number of stillbirths, and number of piglets weaned), the effects of year-season and parity number were included as fixed effects, and the permanent effect of the sow was included as a random effect. Statistical models for number of CL and embryo survival considered the batch (contemporary group) in which the sows were inseminated as a fixed effect.

The dominance effect was initially included in the model when analyzing individual SNP, but it did not reach significant values and was, therefore, eliminated from the model. Likelihood ratio tests were calculated, and nominal P values were obtained assuming a ² distribution of the likelihood ratio test. The Bonferroni-adjusted alpha for multiple comparison tests was calculated considering an average correlation of 0.62 and 0.15 for the sow and piglet sets of traits, respectively. Mean correlations were calculated based on the ones described by Zhang et al. (2000) and Casellas et al. (2004) for each set of parameters. The adjusted significance threshold for an overall alpha of P < 0.05 was 0.012 and 0.0012 for sow (42 tests) and piglet (77 tests) traits, respectively.

	RESULTS AND DISCUSSION

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Nucleotide Sequence of the Pig PRLR cDNA
The complete coding region of the porcine PRLR gene was amplified by reverse transcription-PCR in 3 overlapping fragments encompassing exon 3 (which contains the start codon) to exon 10. The PRLR cDNA consensus sequence comprised 1,934 bp (GenBank accession number DQ157757) and encoded a protein of 625 amino acid residues. An unexpected finding was that the comparison of pig vs. rabbit PRLR yielded a greater amino acid identity (77%) than the comparison of pig vs. cattle PRLR (74%). Pigs and cattle are Cetarctiodactyla species, whereas rabbits belong to the order Lagomorpha. The time of divergence between Cetartiodactyla and Lagomorpha has been estimated to be ~40 million years (Douzery et al., 2003).

The relatively low amino acid identity between pig PRLR and other mammalian orthologues was mostly attributable to amino acid substitutions clustered in the intracellular domain (ICD), entirely encoded by exon 10 of the gene. In fact, when this region was excluded from the BlastP analysis, amino acid identities of 90, 82, 77, and 76% were observed between pig and rabbit, cattle, human, and mouse PRLR protein sequences, respectively. As a reference, the pig pyruvate carboxylase, a highly conserved enzyme, which catalyzes the synthesis of acetyl-CoA, displays 92 and 91% amino acid identity with its human and mouse orthologues (Dávalos et al., 2003). A different genomic organization of the PRLR gene among rodents, ruminants, and pigs has been postulated by Bignon et al. (1997). Our results provide evidence of a different amino acid composition between porcine and other mammalian PRLR orthologues and suggest that the evolutionary history for the ICD of PRLR differed among these species.

Polymorphism of PRLR Exon 10
Alignment of PRLR cDNA sequences from 12 pigs belonging to 6 different breeds revealed 6 nonconservative SNP within exon 10 of the gene at positions C1217T (Leu/Pro₄₀₆), C1283A (Asp/Ala₄₂₈), G1439A (Lys/Arg₄₈₀), T1528A (Met/Leu₅₁₀), G1600A (Gly/Ser₅₃₄), and G1789A (Gly/Ser₅₉₇), considering the start codon of the cDNA sequence as nucleotide 1. The latter mutation, G1789A, corresponded to the one previously reported by Vincent et al. (1998). As mentioned above, high levels of variability in the intracytoplasmic tail of PRLR of several mammalian orthologues have been reported mainly due to the occurrence of alternative splicing that results in several variants differing in the length and sequence composition of the ICD (Davis and Linzer, 1989; Trott et al., 2003), thus suggesting that this particular region of the protein can accommodate high levels of sequence variation.

Segregation analysis of the PRLR polymorphisms in the Iberian x Meishan F₂ population and other European porcine breeds revealed the existence of 8 distinct haplotypes (Table 2). Three major haplotypes, named as PRLR_A, PRLR_B, and PRLR_C, were widely distributed (Table 3). The PRLR_A and PRLR_B haplotypes were exclusively found in the European breeds, whereas PRLR_C was also present in Meishan at a moderate frequency. The remaining 5 haplotypes had a much more restricted distribution, and several of them appeared to be breed-specific, although a more extensive sampling would be needed to confirm this assertion. PRLR_D and PRLR_E were only found in the Meishan breed. The absence of these 2 haplotypes in a representative pool of 94 pigs from 5 European breeds might suggest that they have an Asian origin. However, this finding is difficult to interpret taking into account that European pig breeds were strongly introgressed with Chinese breeds in the 18th and 19th centuries. The Duroc breed displayed 2 haplotypes, PRLR_F and PRLR_G, which were virtually absent from the remaining breeds. The relatively high frequency of these 2 rare haplotypes in the Duroc population might be explained by genetic drift because this population was founded from a small number of individuals. The PRLR_H haplotype displayed a very low frequency in all breeds. Unfortunately, we did not have records of reproductive performance in the purebred European populations, and therefore, the effects of the PRLR genotypes could not be analyzed in such populations.

We could not find effects of the PRLR genotypes on litter size despite the fact that several studies have reported such effects for PRLR in different porcine populations. However, in those experiments, the direction and magnitude of the effects explained by the PRLR genotypes varied among breeds and were, in some cases, antagonistic. For instance, homozygous AA individuals from Large White or Landrace synthetic lines (Vincent et al., 1998; Putnovà et al., 2002) and from a Large White x Meishan F₂ cross (van Rens and van der Lende, 2002) had a gain of approximately 1 to 2 piglets born alive compared with the alternative BB homozygotes, whereas in Meishan (Vincent et al., 1998), and Duroc (Drogemuller et al., 2001) breeds the opposite effect was found. Furthermore, lack of associations between PRLR polymorphism and litter traits was described in German Landrace and Large White pig lines (Drogemuller et al., 2001) and in 2 lines selected for ovulation rate and litter size (Linville et al., 2001). Furthermore, several QTL have been reported to affect reproductive traits; however, none of them were found on chromosome 16 (Hu et al., 2005). Such contradictory results may very well be explained by the fact that those experiments analyzed the effect of one single SNP, thus confounding the effect of different haplotypes. Individuals considered as homozygous AA, according to genotypes described by Vincent et al. (1998), could have really been any combination of the PRLR_B, PRLR_E, PRLR_F, and PRLR_G haplotypes because all of them contain the A variant at the SNP1789 polymorphic site. In fact, according to the frequencies found in the present work, AA homozygous individuals from the Meishan breed could only have been homozygous for the PRLR_E haplotype, which has unfavorable effects on ovulation rate. That would explain why in the study performed by Vincent et al. (1998), a reduced litter size in AA homozygous Meishan pigs was found. Further studies should be performed to validate our results in other porcine populations.

Piglet Survival Traits.
Suggestive effects were found for the A₁₆₀₀ allele on rectal temperature 1 h after birth (RT-1, P < 0.05, Table 4). This allele derives from the Meishan purebred parental line and results in an increase of approximately 0.4°C compared with the alternative G₁₆₀₀ allele. Another variable affected by the A₁₆₀₀ allele was TS. The RT-1 and TS variables are highly correlated as described by Casellas et al. (2004). Hypothermic piglets are more lethargic and less competitive at the udder (Noblet et al., 1997; Herpin et al., 2002). In our study, piglets that had the A₁₆₀₀ allele, and therefore had a greater rectal temperature, tended to begin suckling 8 min earlier than their counterparts (P < 0.10, Table 4). Such effects of PRLR on RT-1 and TS were also found in the analysis of haplotypes, where the PRLR_C and PRLR_E haplotypes were favorable for RT-1 (P < 0.05) and TS (P < 0.10), respectively (Table 5). Studies performed with neonatal lambs have shown that administration of PRL (2 mg/d) causes an acute response, which results in an increase of 1°C in the colonic temperature within the first hour of life (Pearce et al., 2003).

Other effects were found for the C₁₂₈₃ and A₁₆₀₀ alleles, which tended to be associated with HR at birth, resulting in an increase of 8.43 and 12.88 beats per minute, respectively. Additionally, the A₁₅₂₈ allele was favorable for OS 1 h after birth, producing a 1% increase (P < 0.10, Table 4). In the analysis of haplotypes, however, such effects could not be confirmed (Table 5). Despite the fact that no significant P values were reached, the PRLR_E haplotype, which contains the 3 favorable variants, tended to have greater HR at birth and OS 1 h after birth simultaneously (Table 5). In humans, low levels of prolactin in serum at 31.5 to 37 wk of gestation have been associated with increased risk of RDS (Parker et al., 1989). The RDS disease predominantly affects immature infants and is associated with underdevelopment of the biochemical pathways that lead to an adequate synthesis of surfactant.

We found particularly relevant the fact that 5 of the 6 amino acid substitutions identified in our work are nonconservative, involving the replacement of a nonpolar amino acid by a polar neutral residue (Gly Ser at SNP1600 and 1789), a polar negatively charged residue (Ala Asp at SNP1283), a sulfur containing residue (Leu Met at SNP1528), or a cyclic amino acid (Leu Pro at SNP1217). These amino acid substitutions may affect the 3 dimensional structure of the ICD individually or through the interaction among them or even with other surrounding residues. In fact, SNP1217 (Leu Pro406) and SNP1528 (LeuMet510) are in close vicinity with 2 tyrosine residues (Tyr407 and Tyr512), which are able to undergo phosphorylation, thus influencing receptor signaling. We made an in silico prediction of the biological significance of the 6 amino acid replacements using the polyPhen software (Ramensky et al., 2002). Polyphen makes functional predictions based on a profile analysis of homologous sequences, the mapping of the relevant substitution to 3D structures, and the sequence-based characterization of the specific substitution site. This analysis showed that the 6 mutations we have found are not deleterious or damaging. As a consequence, we anticipate that the 8 PRLR haplotypes described in this work encode functional receptors. Further studies will be needed to elucidate if these 6 polymorphisms, which do not imply a loss of function, have more subtle effects on the biological properties of PRLR.

Our study indicates that the ICD domain of the PRLR molecule displays a much greater degree of amino acid variability than previously suspected, with at least 8 different genetic variants. The polymorphism of the pig PRLR gene was significantly associated with ovulation rate, whereas suggestive associations were found for traits related to the early postnatal metabolism and suckling behavior of piglets. These pleiotropic effects might be attributed to the multiple functional roles of prolactin or because the SNP analyzed in this experiment are in linkage disequilibrium with several QTL.

	IMPLICATIONS

Top Abstract INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION IMPLICATIONS LITERATURE CITED

 
We have identified 6 nonsynonymous substitutions within exon 10 of the porcine prolactin receptor gene (PRLR), which encodes the intracytoplasmic domain of the protein. Six amino acid polymorphisms determine the existence of 8 haplotypes differentially distributed among several porcine breeds. These high levels of amino acid variation at the intracellular domain were not contemplated in previous studies; this feature might be in part responsible for the contradictory effects found by several authors when performing association analyses in different porcine breeds. Our results yield insights into the effect of PRLR on ovulation rate in pigs and suggest a role for this gene in the metabolism, suckling behavior, and viability of newborn pigs. In the next years, the identification of genes that are involved in postnatal survivability will be essential, given the high economic losses produced by an elevated mortality of piglets within the first days of life.

	Footnotes

 
¹ The authors are grateful to Marcel Amills for his critical review of the manuscript. The authors are indebted to Luis Varona, M. Arqué, J. Tarrés, M. Fina, and the staff of Nova Genètica, in particular to E. Ramells, F. Márquez, R. Malé, F. Rovira, and I. Riart, for cooperating in the experimental protocol. Financial support was provided by MCYT, Spain (Grant AGL2000-1229-C03). The authors gratefully acknowledge the contributions of the INRA (France) and the CIA El Dehesón del Encinar (Spain) for providing the purebred Meishan sows and Iberian boars, respectively.

² Corresponding author: anna.tomas.sangenis{at}uab.es

Received for publication November 15, 2005. Accepted for publication March 3, 2006.

	LITERATURE CITED

Top Abstract INTRODUCTION MATERIALS AND METHODS RESULTS AND DISCUSSION IMPLICATIONS LITERATURE CITED

 


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