Mutation in BMPR-IB gene is associated with litter size in Iranian Kalehkoohi sheep

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Mutation in BMPR-IB gene is associated with litter size in Iranian Kalehkoohi sheep Morteza Mahdavi a,∗ , Shahram Nanekarani a , Seyed Davood Hosseini b a b

Department of Animal Science, Faculty of Agriculture, Broujerd Branch, Islamic Azad University, Broujerd, Iran Razi Vaccine & Serum Research Institute (Arak Branch), Arak, Iran

a r t i c l e

i n f o

Article history: Received 23 January 2014 Received in revised form 2 April 2014 Accepted 4 April 2014 Available online xxx

Keywords: Bone morphogenetic protein receptor IB gene Sheep Association Litter size

a b s t r a c t The single nucleotide polymorphism of BMPR-IB gene (bone morphogenetic protein receptor type IB) was analyzed using PCR-RFLP in Iranian native Kalehkoohi sheep. BMPR-IB which affects the fecundity of Booroola Merino sheep was studied as a candidate gene associated with the prolificacy of Kalehkoohi sheep. Improving the reproductive traits in sheep could be one of the key factors in increasing farm profitability. Major genes for litter size trait provide opportunities for large and rapid increases in the efficiency of sheep production. The same FecB (Booroola) mutation occurred in the BMPR-IB gene in Kalehkoohi sheep as found in Booroola Merino. Allele frequency for B and + was 0.35 and 0.65 respectively. The BB, B+ and ++ genotypes have been identified with the 0.13, 0.446 and 0.424, respectively. The Kalehkoohi sheep with genotypes BB and B+ had 0.52 and 0.35 lambs, more than the homozygous wild-type, respectively (P < 0.01). No significant difference was observed between B+ and BB in litter size. Also the effect of parity and flock weren’t significant in this study. Results of the present study support the concept that BMPR-IB significantly affected litter size and was associated with litter size in Kalehkoohi sheep and thus it could be used for Marker-assisted selection programmers for the genetic improvement of reproductive characteristics in this breed. © 2014 Elsevier B.V. All rights reserved.

1. Introduction In livestock production, there is always great interest in improvement of reproductive traits of animals. This interest is even more extensive in the sheep industry, where a small or moderate increase in the litter size is associated with large profits for farmers. Improvement of the reproductive characteristics is more promising than feeding and housing improvements (Rothschild et al., 1996). Major genes for the litter size trait provide opportunities for large and rapid increases in the efficiency of

∗ Corresponding author. Tel.: +98 8634372273; fax: +98 8633123844. E-mail addresses: [email protected], [email protected] (M. Mahdavi), [email protected] (S. Nanekarani), [email protected] (S.D. Hosseini).

sheep production. The Booroola gene was the first major gene for prolificacy identified in sheep. In sheep, genetic variation in ovulation rate has been widely documented. Evidence shows substantial differences among breeds and in a number of cases great variation within breeds/strains (Galloway, 2000). Ovulation rate was determined by a complex exchange of endocrine signals between the pituitary gland and the ovary. Three related oocyte-derived members of the transforming growth factor-b (TGF-b) super family, namely growth differentiation factor 9 (GDF-9), bone morphogenic protein 15 (BMP15) and bone morphogenic protein-IB (BMPR-IB) have been shown to be essential for ovulation rate and follicular growth. Ovulation rate and subsequent litter size are the main factors for improving reproductive rate in sheep (Bradford, 1972). The FecB locus is situated in the region of ovine chromosome 6 that contains the bone morphogenetic protein

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Please cite this article in press as: Mahdavi, M., et al., Mutation in BMPR-IB gene is associated with litter size in Iranian Kalehkoohi sheep. Anim. Reprod. Sci. (2014), http://dx.doi.org/10.1016/j.anireprosci.2014.04.003

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receptor IB gene, which encodes a member of the transforming growth factor receptor family. A non-conservative substitution in the BMPR-IB coding sequence was associated fully with the hyper-prolific phenotype of Booroola ewes (Mulsant et al., 2001; Souza et al., 2001; Wilson et al., 2001). Davis (2004) reported that one copy of the FecB gene increases ovulation rate in Booroola Merino by about 1.5 and two copies by 3.0. These additional ovulations in turn increase litter size by 1.0 and 1.5, respectively. Genetic improvement of reproductive traits has traditionally been restricted to use of quantitative genetic methods but reproductive gain has been limited when using these methods. Litter size is an important economic trait in sheep breeding. Variation in litter size in sheep is controlled by both genetic and environmental factors. Most breeds of domestic sheep have one or two lambs at each lambing, although a few breeds, including the Booroola Merino, Cambridge, D’Man, Finnish Landrace and Romanov, consistently have litter sizes of three or more (Bindon and Piper, 1986). Gootwine et al. (2008) reported that Awassi and Assaf ewes are prolific. Prolificacy of ++, B+ and BB Awassi ewes was 1.28, 1.90 and 1.92 lambs born/lambing, respectively. In the Assaf breed, prolificacy of ++, B+ and BB ewes was 1.68, 2.40 and 2.55, respectively. Attempts to increase litter size by selection within a breed result in slow progress, because the heritability of litter size is low (Morris, 1990). Major genes associated with reproduction traits can be utilized in breeding through marker-assisted selection (MAS). Reproductive traits are often suggested as prime targets for MAS for the low heritability and the fact that the trait can be measured only in one sex. Therefore, the discovery of major genes with large effects on ovulation rate and thus litter size has generated considerable interest among sheep breeders and scientists. The objectives of the current study were to detect the single nucleotide polymorphisms of the BMPR-IB gene using PCR-RFLP, as well as investigating the Association of BMPR-IB gene polymorphism with litter size in Iranian Kalehkoohi sheep using a suitable statistic model. 2. Material and methods 2.1. Animals and data collection Kalehkoohi sheep examined in this study were fat-tailed sheep with medium body size and white color with black spots on the face and legs. The origin of the Kalehkoohi sheep is the Kalehkoohi Nomadic tribe in Markazi province and this breed is produced primarily for meat and wool. In the present study, blood samples were collected from 92 Kalehkoohi sheep (15 Rams and 77 ewes) from three different flocks. All ewes had at least one record of litter size (1–5). Data concerning litter size were collected during the last 5 years. 2.2. Genotyping Genomic DNA was extracted of white blood cells using the genomic DNA purification kit (ProtoGene, USA) according to manufacturer’s instructions and stored at −20 ◦ C until used in assaying samples. A

spectrophotometer was used for investigating quality and quantity of DNA. Primers were designed for 5 -CCAGAGGACAATAGCAAAGCAAA-3 for forward and 5 -CAAGATGTTTTCATGCCTCATCAACAGGTC-3 for reverse assessments. The primers were synthesized based on the sequences described by Wilson et al. (2001) (Fermentas, Germany). The amplification procedure was conducted based on the method described by Davis et al. (2002). Polymerase chain reactions were conducted in a 25 ␮L reaction mixtures containing approximately 2.5 ␮L of 10× PCR buffer [50 mM KCl, 10 mM Tris–HCl (pH 8.0), 0.1% Triton X-100], 1.5 mM MgCl2 , 250 ␮M of each dNTP, 50 ng of each primer, 100 ng ovine genomic DNA, and 1.5 U Taq DNA polymerase. PCR conditions were programmed as denaturation at 94 ◦ C for 5 min, followed by 35 cycles of denaturation at 94 ◦ C for 30 s, annealing at 60 ◦ C for 30 s, extension at 72 ◦ C for 30 s, with a final extension at 72 ◦ C for 5 min. The PCR products were digested with AvaII (Fermentas, Germany). Digestion reaction contained 5 ␮L of PCR product, 5 U appropriate enzyme and 2 ␮L buffers 10× in 20 ␮L final volumes incubated for 3–6 h at 37 ◦ C. Digested products were separated on 3% agarose gel electrophoresis and visualized after staining with ethidium bromide on UV translumination. 2.3. Statistical analysis Genotypic and allelic frequencies were calculated using the Pop Gene32 program. The Hardy–Weinberg equilibrium in the mutation sites were determined by X2 test. Analysis of association between the genotypes and litter size was conducted using the general linear model (GLM) procedure (statistical analysis system SAS 9.0 software, SAS Institute Incorporation). The following model was employed for analysis of litter size in Kalehkoohi ewes and least squares mean was used for multiple comparisons in litter size among different genotypes. Yijk =  + Pi + Hj + Gk + eijk where Yijk is the phenotypic value of litter size,  is the population mean, Pi is the fixed effect of the ith parity (i = 1, 2, 3, 4,5), Hj is the fixed effect of the jth herd and Gk is the fixed effect of the kth genotype and eijk is the random residual effect of each observation. 3. Results 3.1. Genotype distribution, genotype and allele frequencies The distribution of the different genotypes for the BMPR-IB gene in all genotyped sheep studied by means of PCR-RFLP is presented in Table 1. 3.2. Association between different genotype and litter size The results of mean values and standard error concerning ewes with BB, B+ and ++ genotypes are presented in Table 2. A difference was observed in most cases

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Table 1 Genotype distribution, allelic and genotypic frequencies of the Booroola mutation of the BMPR-IB gene in Kalehkoohi sheep. Gene

No. of sheep

BMPR-IBa

92

a b c d

Allelic frequencyb

Genotypic frequencyc,d

B

+

BB

B+

++

0.35

0.65

0.13(12)

0.446(41)

0.424(39)

Bone morphogenetic protein receptor type IB gene. Mutant allele for BMPR-IB gene (B), wild type allele for BMPR-IB gene (+). Homozygous career of Booroola mutation (BB), heterozygous career of Booroola mutation (B+), non-career of Booroola mutation (++). Numbers in parentheses are numbers of individuals that belong to the respective genotypes.

Table 2 Least squares means and SE for litter size of different BMPR-IB genotypes in Kalehkoohi sheep. Genotype

No. of ewesa

Litter size

BB B+ ++

11 36 30

1.902 ± 0.195a 1.725 ± 0.123a 1.379 ± 0.136b

a, b means within a column with no common letter differ significantly (P < 0.01). a Number of observations for mean ± SEM shown.

examined. Specifically, for data concerning litter size for BB and B+ ewes. Mean size of litters for BB, B+ and ++ ewes were 1.902, 1.725 and 1.379 respectively (P < 0.01). Differences in litter size between BB and B+ were not significant. Also the effects of parity and flock weren’t significant in the present study.

4. Discussion The BMPR-IB gene had two alleles, A wild type nucleotide (non-carrier) and G mutant nucleotide (carrier). The presence of the A nucleotide in wild type sheep codes for glutamine amino acid but presence of G replaces this amino acid with arginine (Souza et al., 2001). As expected, the size of PCR production of BMPR-IB gene was 190 bp (Fig. 1). After digesting with restriction endonuclease Ava II, the band of wild type (++) was 190 bp while the band of heterozygote (B+) was 190 bp and 160 bp (Fig. 2). In the present study the results showed the different band pattern in some of samples, implying existence of a mutation in the

FecB locus in our sheep. The population was not found to follow the Hardy–Weinberg equilibrium. Ovulation rate and litter size have a major impact on the reproductive efficiency of sheep. Natural litter size as evaluated in the present study considered a marker of high fecundity, as it involves multiple ovulations, successful fertilization of several oocytes, and maintaining a pregnancy with multiple conceptuses. Ovulation rate is influenced by breeding season, nutritional status and genotype (Bindon and Piper, 1986). However, most of the variation in sheep fecundity is the result of variation in the number of eggs ovulated and natural genetic variation in ovulation rate has been reported to result from variation in the sensitivity of gonadotropin release to the feedback effects of gonadal steroids (Land, 1976). The BMPR-IB gene is one of the key candidate genes for genetic control of ovulation rate and consequent increase in litter size in different sheep breeds. A mutant BMRR-IB gene results in increased ovulation rate. The litter size and ovulation rate increase with number of copies of the mutation (Fabre et al., 2006). The average effects of the FecB were originally summarized by Piper et al. (1985) as one copy of the FecB (B+) increased ovulation rate by +1.0 to +1.5 ova and litter size by +0.8 to +1.2 lambs born across a range of genetic and environmental backgrounds. The effect of a second copy (BB) appeared to be additive for ovulation rate and varied from additive to dominant for litter size depending on the background genotype. This increase in ovulation rate of FecB carriers is associated with an enhanced maturation of a large number of antral follicles from which ovulation occurs at a smaller size than non-carrier follicles (McNatty et al., 1986). In the present study, litter size

Fig. 1. Image of PCR product. Representative PCR products of the 92 sheep of the experiment population. L indicates Ladder 100 bp. All lanes (190 bp) indicate polymerase Chain reaction (PCR) products.

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Fig. 2. Image of PCR product of the FecB mutation of the BMPR-IB gene digested with Ava II. Lanes indicate representative digestive products of the 92 sheep of the experiment population. L indicates Ladder 100 bp. The wild-type allele (+) is 190 bp, and the mutant allele (B) is 160 bp. Lanes (1, 11) indicate homozygous carriers of Booroola mutation (BB genotype). Lanes (6, 16) indicate heterozygous carriers of Booroola (B+ genotype). Lanes (10, 13) indicate non-carriers homozygous (++ genotype).

was influenced by this gene and heterozygous and carrier homozygous genotypes for FecB loci had a larger litter size than the wild type genotypes. The association between the BMPR-IB genotype and litter size was analyzed statistically (Table 2). The results showed that both B+ and BB genotypes increased litter size as compared to ++ genotypes. The Kalehkoohi sheep with genotypes BB and B+ had 0.52 and 0.35 (P < 0.01) lambs, more than the homozygous wildtype, respectively. These preliminary results indicate that the mutation of BMPR-IB affected litter size and is either a major gene that influences prolificacy in Kalehkoohi sheep or a molecular genetic marker is in close linkage with this gene. The effect of BMPR-IB major gene on fecundity in sheep has been the focus of the present research. At present, no report is available relating to the effect on fecundity of a major gene in Kalehkoohi sheep. The FecB mutation was discovered in Booroola sheep initially. Polymorphisms in BMPR-IB (A746G) have been detected in Garole (Davis et al., 2002; Polley et al., 2009), Javanese (Davis et al., 2002), Small Tailed Han (Liu et al., 2003; Wang et al., 2003; Yan et al., 2005), Hu (Wang et al., 2003), DuoLang (Zhong et al., 2005), Kendrapada (Kumar et al., 2008), and Cele black (Shi et al., 2010) sheep. Moreover an association between polymorphisms in BMPR-IB and litter size has been investigated in some cases. Chu et al. (2007) reported that Mutation in BMPR-IB genes is associated with litter size in Small Tailed Han sheep. The Small Tailed Han ewes with genotypes BB and B+ had 1.40 (P < 0.01) and 1.11 (P < 0.01) more lambs, respectively, than those with genotype ++. In general, findings of the present study are similar to the reproductive effects found in the previously-mentioned prolific breeds of sheep. Allelic and genotypic frequency results of the present study are in agreement with results in Cele black sheep by Shi et al. (2010). The FecB mutation in this selected population was of moderate frequency and has not been fixed at this point in time. These results are not consistent with reports in Romanov, Finn, East Friesian, Teeswater, Blueface Leicester, D’Man, Chios, Mountain Sheep, German

Whiteheaded Mutton, Lleyn, Loa, Galician, Barbados Blackbelly (Davis et al., 2006), Mulpura (Kumar et al., 2006), Suffolk, Dorset, Charolais, Chinese Merino and Romney Hills (Guan et al., 2007), Sangsari (Kasiriyan et al., 2009), Shal (Ghaffari et al., 2009), Baluchi (Moradband et al., 2011), Dalagh (Khatam Nejhad and Ahmadi, 2012), Iraqi Breeds (Al-Barzinjil and Othman, 2013) sheep in which the FecB mutant allele does not segregate. To our knowledge, this is the first case in which FecB mutation has been detected in fat tailed sheep breeds in the Middle East. Regarding the FecB mutation, it would be very interesting to compare the local haplotype around the mutation, as well as to compare genetic distances between known FecB carrier breeds and Kalehkoohi sheep, using other markers or the mitochondrial DNA analyses. This would help to determine whether mutant animals in this breed result from a unique mutational event or whether the mutation occurred twice independently. Historically, sheep were often reared through the extensive and migrating breeding system. Moreover ewes in this system usually couldn’t support more than one lamb from a nutritional perspective. Because of this and due to environmental circumstances and great lamb mortality, greater litter size was not of economic interest to producers. Indeed the natural environment did not allow for this trait to be expressed. There have, therefore, not been defined selection programs for litter size and there has been natural selection against this trait and as a result the mutant allele has been gradually removed from the population. However as production systems changed with increased intensive production practices, rearing systems became popular where litter size was of greater economic importance. Changing management conditions may have resulted in a selection trend for litter size so that it is more probable that frequency of existence the FecB mutation has been increasing in this population. If this is not the case it may be that due to Community Development and trade in past decade this mutation has been transferred from the imported animals to the Kalehkoohi sheep population through the

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introduction of gametes and embryos via artificial insemination and embryo transfer. 5. Conclusions The Kalehkoohi sheep is a relatively prolific local sheep breed in Iran. The Kalehkoohi ewes in the present study that had the FecB mutation had greater litter size than wild type ewes. Considering the present results, marker-assisted selection focusing on the BMPR-IB gene is warranted to increase litter size in this sheep breed and will be of considerable economic value to sheep producers. Indigenous sheep are valuable gene pools for adaptive and economic traits, providing a diversified genetic pool and have many remarkable characteristics when compared with the imported breeds because of greater environmental adaption to survive and reproduce under the harsh conditions. The incorporation or fixation a major gene for prolificacy into a flock can be achieved using marker assisted selection and the source of these mutations may be progeny tested or DNA tested rams carrying major genes for prolificacy. This practice can be utilized for improvement of fat-tailed low prolific sheep breeds that have greater mothering ability in those areas where environmental conditions or intensive breeding systems allow for taking advantage of improvements in ewe prolificacy. Conflict of interest The authors report that they don’t have any known potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications, registrations, educational grants, participation in speakers’ bureaus, membership and paid expert testimony in the subject matter materials discussed in this manuscript and there has been no significant financial support for this work that could have influenced its outcome. Acknowledgments We thank the farmers for their support to the data and samples collection. This research was supported by Department of Animal Science, College of Agriculture, Islamic Azad University, Broujerd Branch (IAUB), Iran. References Al-Barzinjil, Y.M.S., Othman, G.U., 2013. Genetic polymorphism in FecB gene in Iraqi Sheep Breeds using RFLP-PCR technique. IOSR-JAVS 2, 46–48. Bindon, B.M., Piper, L.R., 1986. The reproductive biology of prolific sheep breeds. Oxford Rev. Reprod. Biol. l8, 414–451. Bradford, G.E., 1972. Genetic control of litter size in sheep. J. Reprod. Fertil. Suppl. 15, 23–41. Chu, M.X., Liu, Z.H., Jiao, C.L., He, Q.Y., Fang, L., Ye, S.C., Chen, G.H., Wang, J.Y., 2007. Mutations in BMPR-IB and BMP15 genes are associated with litter size in Small tailed Han sheep (Ovis aries). J. Anim. Sci. 85, 598–603. Davis, G.H., 2004. Fecundity genes in sheep. Anim. Reprod. Sci. 82–83, 247–253. Davis, G.H., Balakrishnan, L., Ross, I.K., Wilson, T., Galloway, S.M., Lumsden, B.M., Hanrahan, J.P., Mullen, M., Mao, X.Z., Wang, G.L., Zhao, Z.S., Zeng, Y.Q., Robinson, J.J., Mavrogenis, A.P., Papachristoforou, C., Peter, C., Baumung, R., Cardyn, P., Boujenane, I., Cockett, N.E.,

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Please cite this article in press as: Mahdavi, M., et al., Mutation in BMPR-IB gene is associated with litter size in Iranian Kalehkoohi sheep. Anim. Reprod. Sci. (2014), http://dx.doi.org/10.1016/j.anireprosci.2014.04.003