Current status of molecular genetics research of goat fecundity

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Review

Current status of molecular genetics research of goat fecundity Sonika Ahlawat ∗ , Rekha Sharma, A. Maitra, M.S. Tantia National Bureau of Animal Genetic Resources, Karnal 132001, Haryana, India

a r t i c l e

i n f o

Article history: Received 6 March 2014 Received in revised form 16 January 2015 Accepted 30 January 2015 Available online xxx Keywords: Goats Fecundity Candidate genes

a b s t r a c t Reproductive traits are extremely important to the goat industry because moderate increase in litter size can lead to large profit. Traditional selection for improving litter size is difficult due to sex-limited nature and low heritability of the trait (5–10%). In addition, the lack of knowledge on the number of the genes controlling this trait and the possible gene interactions are the other limitations for this trait. Molecular genetics can overcome these limitations offering new opportunities for the improvement of reproductive traits, as it supplies tools to analyze genetic variability directly at the DNA level with the possibility of detecting the individual genes influencing the reproductive capability. For the last decade, molecular genetics has led to the discovery of individual genes or candidate genes with substantial effects on the reproductive trait viz. BMPR1B, GDF9, BMP15, FSHˇ, FSHR, POU1F1, PRLR, KiSS-1, GPR54, GH, INH, CART, GnRH, GnRHR, LHˇ, BMP4, KITLG, MT2, CYP21 and AA-NAT. Despite the progress made in goat fecundity studies, it’s hard to satisfy the actual application because the reproductive traits are complex quantitative traits involving multiple genes, loci and interactions. So it is important to analyze the combined effect of multiple genes or loci on reproductive traits. Little progress has been made on understanding interaction between genes, gene and environment, and genetic effect analysis. Thus the need of the hour is to identify more functional genes, clarify molecular mechanism of action and regulatory network and to resort to more holistic approaches like genomic selection which can tremendously accelerate the goat improvement. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Goats were among the first farm animals to be domesticated. As indicated by the archaeological evidence, they have been associated with man in a symbiotic relationship for up to 10,000 years (Ensminger and Parker, 1986). Goats disseminated all over the world because of their great adaptability to varying environmental conditions and different nutritional regimes under which they were

∗ Corresponding author at: Core Lab, NBAGR, India. Tel.: +91 9416161369; fax: +91 184 2267654. E-mail address: [email protected] (S. Ahlawat).

evolved and subsequently maintained. They have proved to be immensely useful to man due to their productivity, small size, and non-competiveness with him for food (Aziz, 2010). Rearing of goat plays a very important role in the lives of households in developing countries. This is because goats provide the easiest and most readily accessible source of credit available to meet immediate social and financial obligations. The world goat population is 861.9 million and the largest number of goats is observed in Asia, followed by Africa, representing about 59.7% and 33.8%, summing up to 93.5% out of the total number of the world, respectively (FAOSTAT, 2008). Goat meat is widely consumed in the developing countries. The total amount of goat meat

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produced in 2008 was 4.9 million metric tonnes (MT) and developing countries produced approximately 97% of this amount, reflecting the great importance of goat meat to feed millions of people in these countries (FAOSTAT, 2008). The major part of this amount is not traded as other major meats. It is usually produced and consumed locally among the poor in the developing countries. Hence the potential of goats for sustainable supply of meat for human consumption is unquestioned, and their contribution to improved nutrition of rural people is likely to increase (Aziz, 2010). Goat rearing now faces a dilemma to produce more meat for the growing human population against the reality of shrinking grazing resources, which are creating a major constraint to the further growth of goat population. There is an acute shortage of meat for domestic needs, apart from the huge demand in the international market. The gap between demand and production of meat could be bridged by augmenting the reproductive rate of low-producing goat breeds. In order to decrease the gap of demand and supply, there is dire need to identify genes responsible for more birth per conception and also in life time of the animal. Successful reproduction is the outcome of complex interactions of genes and environment to transfer the genetic ‘blueprint’ to the next generation. One goal of reproductive biology is to understand the key events that regulate the development and function of the reproductive axis (Montgomery, 2000). Primates and many ruminants typically release a single oocyte at each cycle whereas species such as mice and pigs have consistently high ovulation rates. In mammals the ovulation rate and the litter size is a result of well-regulated interactions of endocrine and paracrine mediators. How precisely the litter size is controlled remains a critical and important question in reproductive biology (Polley et al., 2009). Information about genes and their protein products, variation in genes that lead to significant physiological differences (or phenotypes), and the interaction of genes and the environment is required to achieve this understanding (Montgomery, 2000). “Fecundity” means the ability to produce live offspring, and “fertility” means the actual production of live offspring. So fecundity refers to the potential production, and fertility to actual production, of live offspring. Improvement of reproductive traits in livestock species has become of increasing interest, especially in sheep and goats, where small increase in litter size can equal large gains in profit (Ghaffari et al., 2009; Di et al., 2011). Traditional selection for improving litter size is difficult due to the sex-limited nature and low heritability of the trait (5–10%). In addition, the lack of knowledge on the number of the genes controlling this trait and the possible gene interactions are the other limitations for this trait. Molecular genetics can overcome these limitations offering new opportunities to the improvement of reproductive traits, as it supplies tools to analyze genetic variability directly at the DNA level with the possibility of detecting the individual genes influencing the reproductive capability. The identification of polymorphism and DNA markers associated with reproductive traits can lead to genetic improvement through the implementation of marker assisted selection (MAS) by the

breeder to increase litter size and reproduction efficiency (Caballero and Toro, 2002). For the last decade, molecular genetics has led to the discovery of individual genes or candidate genes with substantial effects on the traits of economic importance. The candidate gene approach, employed in identifying the polymorphisms in genes likely to cause phenotypic variation based on physiological and biochemical evidence, could accelerate the improvement of goat reproductive traits. Recently, the development of next generation sequencing (NGS) allowed de novo sequencing of the goat genome, which paved the way for creation of International Goat Genome Consortium (IGGC, www.goatgenome.org) in 2010, whose aims were to consolidate research efforts at the international level. The goat genome reference sequence has been published (Dong et al., 2013) and is available to the scientific community through a web interface and mirror (http://goat.kiz.ac.cn/GGD/). These approaches have proven to be valuable tools to delineate genes and mutations implicated in goat fecundity. In recent years, a number of candidate genes for prolificacy (BMPR1B, GDF9, BMP15, FSHˇ, FSHR, POU1F1, PRLR, KiSS-1, GPR54, GH, INH, CART, GnRH, GnRHR, LHˇ, BMP4, KITLG, MT2, CYP21 and AA-NAT) have been identified which might contribute towards molecular breeding to enhance productivity of goat. Hence, the aim of this article is to review the published candidate genes which have influence on fecundity in goats. 2. Bone morphogenetic protein receptor 1B (BMPR1B) FecB was the first major gene for prolificacy identified in sheep. The FecB locus is autosomal with codominant expression, which is additive for ovulation rate associated with a mutation (Q249R) in BMPR1B gene (Souza et al., 2001; Wilson et al., 2001; Davis et al., 2002). The FecB mutation is present in Booroola Merino (Australia), Garole (India), Javanese (Indonesia), Small Tail Han (China), Hu (China), and Kendrapada sheep (India) (Chu et al., 2010a). Artificial insemination and embryo transfer programmes have been used to successfully introgress the Booroola into other breeds in several countries, and these artificial breeding technologies have been particularly useful while only small numbers of progeny tested individuals have been available (Davis, 2004). Many researchers have reported absence of FecB mutation in high prolificacy as well as low prolificacy Chinese, Thai and Indian goat breeds (Hua et al., 2008; Supakorn and Pralomkarn, 2010; Chu et al., 2010a; Ahlawat et al., 2013). Contrary to these reports, BMPR1B gene was found to be polymorphic in Black Bengal goats with the predominance of heterozygous genotype AG (Polley et al., 2009). Ahlawat et al. (2014) reported two novel SNPs T(−242)C and G(−623)A in the promoter region of BMPR1B gene in a panel of nine Indian goat breeds but no association with prolificacy trait was reported. 3. Growth differentiation factor 9 (GDF9) It plays a critical role as a growth and differentiation factor during early folliculogenesis in female reproduction

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Table 1 Polymorphic sequence variations in GDF9 gene in sheep. Allele

Mutation (coding base)

Amino acid change

Founder breed

Reference

G1

G260A

R87H

Moghani, Ghezel, Garole

G8/FecGH

C1184T

S395F

Cambridge, Belclare

FecTT FecGE

A1279C T1034G

S109R F345C

Thoka Santa Ines

Barzegari et al. (2010) Polley et al. (2010) Hanrahan et al. (2004) Nicol et al. (2009) Silva et al. (2010)

in mammals. Different mutations of GDF9 gene may cause either an increased ovulation rate or infertility in sheep. Four mutations in GDF9 have been associated with fecundity in sheep (Table 1). The G8 mutation, also indicated as FecGH (high fertility), causes increased ovulation rate in heterozygous ewes, while homozygous ewes are sterile. For the FecGE allele, homozygous ewes have shown an increase in their ovulation rate and prolificacy. Different research groups working on goats have reported mutations different from the ones found in sheep (Feng et al., 2010; Wu et al., 2006; Du et al., 2008; Zhang et al., 2008; Ahlawat et al., 2012). The polymorphism of GDF9 gene was investigated in three goat breeds (Xinong Saanen, Guanzhong and Boer) and one allelic variant was found in the GDF9 gene (G4093A) which was found to have significant effect on litter size (P < 0.05) (An et al., 2012). The relationship between the genetic polymorphism of growth differentiation factor 9 (GDF9) gene and the litter size was investigated in five breeds of black goats (Big foot black goats, Jintang black goats, Hainan black goats, Guizhou black goats and Taihang black goats) by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) (Zhu et al., 2013). Three genotypes (AA, AB and BB) were observed in Big foot (BF) and Jintang (JT) black goats and sequencing results revealed that there was a single nucleotide mutation (A792G) in exon 2 of GDF9 gene in BF and JT black goats. In BF and JT black goats, the average litter size in the third parity was significantly higher in genotype AA than both genotypes of AB and BB while the average little size of genotype AB was higher than that of genotype BB in the same parity. 4. Bone morphogenetic protein 15 (BMP15) BMP15 regulates granulosa cell proliferation and differentiation by promoting granulosa cell mitosis, suppressing follicle-stimulating hormone receptor expression and stimulating kit ligand expression, all of which play a pivotal role in female fertility in mammals (Juengel et al., 2002). Six mutations, labelled FecXR , FecXH , FecXI , FecXL , FecXG and FecXB have been detected so far within the sheep BMP15 gene (Table 2). All the six mutations show the same phenotype: homozygous carrier ewes are sterile and heterozygous carriers show increased ovulation rate (Davis et al., 2006; Monteagudo et al., 2009). Tetra-primer ARMS-PCR, forced PCR-RFLP and direct sequencing based techniques have been employed to screen goats for mutations in BMP15 gene. None of the associated mutations of sheep have been found in Chinese, Indian and Iranian goat breeds (He et al., 2010; Polley et al., 2009; Tejangookeh

et al., 2009; Ahlawat et al., 2013). Contrary to all these findings, FecXB mutation was found in female goats with triplets in white goat population of Guizhou (Lin et al., 2007). Polymorphisms of BMP15 gene exon 2 and its relationship with prolificacy of goats were detected by PCR-SSCP and DNA sequencing methods in two Chinese local goat breeds (Wang et al., 2011a). Three genotypes (AA, BB and AB) were detected in Funiu white goats and two genotypes (AB and BB) were detected in Taihang black goats. Sequencing revealed that four mutations (T456G, C466G, C510T and T511C) occurred in genotype BB of Funiu white goat and no mutation was detected in Taihang black goat. The Funiu white goat with genotype BB had 0.91 or 0.82 kids more than those with AB or AA, respectively. It was concluded that the BMP15 gene may be a major gene which affects the prolificacy in Funiu white goats. The mutations in BMP15 associated with fecundity in sheep were not identified in two Pakistani goat breeds: Teddy and Beetal (Nawaz et al., 2013). Sequencing data revealed six novel polymorphic sites in Teddy breed: two intronic mutations (T982C and A5572G) and four exonic mutations (T6280G, G6353A, T6443C and A6492G). 5. Follicle stimulating hormone beta (FSHˇ) The follicle stimulating hormone (FSH) is a pituitary gonadotropin that plays a key role in the regulation of gonadal function and follicle development in mammals (Aerts and Bols, 2010). For females, the follicle stimulating hormone is required for ovarian development, follicle recruitment and oocyte maturation (Howles, 2000). Two mutations G40A and T148C in exon 2 of FSHˇ gene were found to have significant effect on litter size in Xinong and Boer goat breeds (An et al., 2010). The associations of genotypes for A2645G mutation in exon 3 of FSHˇ with litter size, gestation length as well as super-ovulation performances have been reported in low prolific Boer and high prolific Matou breeds of goat suggesting that the FSHˇ gene is a candidate gene that affects reproduction traits in goats (Zhang et al., 2011a). 6. Follicle stimulating hormone receptor (FSHR) The FSH receptor (FSHR) is a member of the rhodopsin receptor family of G protein coupled receptors. The FSH–FSHR system relays neuronal signals from the hypothalamus to the gonads and induces feedback signals to the hypothalamus and pituitary, which keeps the endocrine balance in the reproductive axis and maintains follicle growth, development, differentiation, and

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Table 2 Polymorphic sequence variations in BMP15 gene in sheep. Allele

Mutation (coding base)

Amino acid change

Founder breed

Reference

FecXG FecXH FecXI FecXL FecXB FecXR

C718T C871T T896A G962A G1100T 17 bp deletion (from nucleotide 525–541)

Q239Ter Q23stop V31D C53Y S99I

Galway Hanna Inverdale Lacaune Belclare Rasa aragonesa

Hanrahan et al. (2004) Galloway et al. (2000) Galloway et al. (2000) Bodin et al. (2007) Hanrahan et al. (2004) Monteagudo et al. (2009)

maturation as well as spermatogenesis (Nieschlag et al., 1999; George et al., 2011). Single nucleotide polymorphisms of the 5 regulatory region of the FSHR gene were detected in 3 goat breeds (Jining Grey, Boer and Inner Mongolia Cashmere) by PCR-SSCP and their effects on litter size in Jining Grey goats have been evaluated (Guo et al., 2013). Three genotypes (CC, CD, and DD) were identified in the 3 goat breeds and sequencing revealed two SNPs: T70A transversion and a G130C transversion in genotype DD compared with CC. Does with genotype CC had 0.46 (P < 0.05) or 1.03 (P < 0.05) kids more than those with genotype CD or DD, respectively, while does with CD had 0.57 (P < 0.05) kids more than those with DD in Jining Grey goats. FSHR mRNA and protein expression levels have been reported to be positively correlated with fecundity in Yunling Black goats. Reduced FSHR levels may be associated with the fewer observed oocytes and, consequently, fewer follicles (Cui et al., 2009). 7. POU class 1 homeobox 1 (POU1F1) This gene is a member of the tissue-specific POUcontaining transcription factor family, which is also named PIT-1 or GHF-1 (Wollard et al., 2000). The pituitary-specific expression of POU1F1 is necessary for normal survival, differentiation and development of three adenohypophysis cell types including somatotrophs, lactotrophs and thyrotrophs (Simmons et al., 1990). An association between allele T of mutations C256T in exon 3 and G682T in exon 6 of POU1F1 gene and high litter size in Jining Grey goats has been reported (Feng et al., 2011). 8. Prolactin receptor (PRLR) Prolactin is an anterior pituitary peptide hormone involved in many different endocrine activities and is essential for reproductive performance. This action is mediated by its receptor encoded by PRLR gene which is a member of the growth hormone/prolactin receptor gene family. The mutations in intron 2 and exon 10 of PRLR gene have been associated with prolificacy in Haimen goats (Li et al., 2010) and in Boer goats (Li et al., 2011a). The prolactin receptor (PRLR) gene was studied as a candidate gene for the high prolificacy of Jining Grey goats (Di et al., 2011). Polymorphisms in intron 1 and intron 2 of PRLR gene were detected in high prolificacy (Jining Grey) and low prolificacy (Boer, Wendeng dairy, Liaoning Cashmere and Beijing) native goats using PCR-SSCP. For intron 1, five genotypes (AA, AH, AK, HH and HK) were identified in Jining Grey goats and two (AA and AK) in the other four breeds. The Jining Grey does of genotype

HH, HK, AH and AK delivered 0.65, 0.62, 0.59 and 0.57 more kids (P < 0.01) than those of genotype AA, respectively. For intron 2, three genotypes (CC, CD and DD) were detected in Boer goats and two (CC and CD) in the other four breeds. The Jining Grey does of genotype CD delivered 0.55 (P < 0.01) more kids than those of genotype CC. 9. Kisspeptin (KiSS-1) Kisspeptins are a family of structurally related peptides, encoded by the kisspeptin (KiSS-1) gene, with ability to bind and activate the G protein coupled receptor (GPR54) (Roseweir and Millar, 2009). This family of molecules has crucial functions in key aspects of reproductive maturation and function (Tena-Sempere, 2010). No polymorphism was detected in four goat breeds (Jining Grey, Inner Mongolia Cashmere, Angora, and Boer goats) by PCR-SSCP (Feng et al., 2009). Two mutations (G3433A and C3688A) in exon 3, three mutations (G296C, G454T and T505A) in intron 1, no mutation in exon 2 and 18 bp deletion/insertion (1960–1977) in intron 2 were observed in Jining Grey goat (Cao et al., 2010). They indicated an association between allele C of the 296 locus and allele deletion of the 1960–1977 locus in KISS-1 gene and high litter size in Jining Grey goats. A mutation T2643C and 8 bp base deletion (2677AGTTCCCC) in intron 2 of goat KISS-1 gene were detected and it was found that T2643C mutation had significant effect on litter size (P < 0.05) (Hou et al., 2011). Eleven novel SNPs (G384A, T1147C, G1417A, 1428–1429 delG, C2124T, C2270T, T2489C, G2510A, C2540T, 3864–3865 delCA and 3885–3886 insACCCC) were reported in three goat breeds: Xinong Saanen, Guanzhong and Boer. It was shown that Xinong Saanen and Guanzhong goat breeds were in Hardy–Weinberg disequilibrium at G384A locus (P < 0.05). Both G2510A and C2540T loci were closely linked in Xinong Saanen, Guanzhong and Boer goat breeds (r2 > 0.33). The G384A, T2489C, G2510A and C2540T SNPs were associated with litter size (P < 0.05) (An et al., 2013). In a recent study, comparison of KiSS1 amplified sequences of indigenous goats identified nine SNPs (intron 1: G296C, T455G, T505A, T693C, T950C and intron 2: T1125C, A2510G, C2540T, A2803G) in Indian goats, including three loci (G296C, G2510A and C2540T) reported to be associated with goat litter size (Maitra et al., 2014a). 10. G protein-coupled receptors 54 (GPR54) GPR54 is a member of the rhodopsin family of G protein-coupled receptors and the endogenous receptor of kisspeptins. G protein-coupled receptor 54 (GPR54) is also

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referred to as AXOR12, KiSS1R. KiSS-1/GPR54 system is a key regulator and a catalyst for the puberty onset, and is a fundamental gatekeeper of sexual maturation in mammals (Chu et al., 2011). Polymorphism scanning of GPR54 was done in sexual precocious and sexual late-maturing Jining grey goat breeds (Cao et al., 2011). Three mutations (G4014A, G4136A and C4152T) in exon 5 were suggested to have some correlation with sexual precocity in goats. The study also preliminarily indicated an association between allele T of the 4152 locus and high litter size in Jining Grey goats. Two novel SNPs (exon 1, C1122T and intron 1, T1830C) have been reported in Indian goats by Maitra et al (2014b). Genotyping of Black Bengal goats for the mutation C1122T indicated that CC individuals attained sexual maturity earlier than the CT individuals but this difference was not statistically significant. However, regression of age at sexual maturity on litter size was significant (P ≤ 0.05) (Ahlawat et al., 2015). 11. Growth hormone (GH) The growth hormone of mammals plays an important role in the control of reproduction, in those aspects involving cell division, ovarian folliculogenesis, oogenesis and secretory activity (Hull and Harvey, 2002; Ola et al., 2008). The effect of GH on ovary function is mainly through inducing the development of small antral follicles in the gonadotrophin-dependent stages and stimulating oocyte maturation (Silva et al., 2009). Two active mutations (A781G and A1575G) in exon 2 of GH gene are highly associated with abundant prolificacy and super-ovulation response in goat breeds (Matou and Boer) as reported using PCR-RFLP (Zhang et al., 2011b). 12. Inhibin (INH) Inhibin is a glycoprotein hormone belonging to the transforming growth factor-␤ superfamily which consists of two subunits, ␣ and ␤, linked by disulphide bonds. One SNP A651G in exon 2 of INH˛ was suggested as a useful marker for litter size of the second parity in Boer goats (Wu et al., 2009). A mutation C865T in the exon of INH˛ gene was reported in three Chinese goat breeds. The genotype distributions of INH˛ gene were significantly different between year-round estrous goat breeds and seasonal estrous goat breeds revealing the association with prolificacy in goats (He et al., 2010). A mutation A782G in exon 2 of INHˇ has been associated with higher prolificacy in Jining grey goats (Chu et al., 2012). Two novel, synonymous mutations (G693A and C840T) in exon 2 of Inhibin ␤B (INHBB) have recently been reported in Indian goats by Sharma et al. (2015a). 13. Cocaine-amphetamine-regulated transcript (CART) Cocaine-amphetamine-regulated transcript (CART) has been implicated in a wide range of behaviours, including the regulation of food intake, energy homeostasis, and reproduction (Lima et al., 2008; Derks et al., 2009). The importance of CART in the

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hypothalamic–pituitary–gonadal axis as well as in the hypothalamic–pituitary–adrenal axis is immense, particularly in the regulation of GnRH secretion and onset of puberty (Boone et al., 2008). Association of the polymorphism C539A in intronic region with litter size was observed (Wang et al., 2011b) in three Chinese goat breeds (Chuandong White, Guizhou White and Gulin Ma breeds). 14. Gonadotropin releasing hormone (GnRH) Gonadotropin releasing hormone (GnRH) is a key regulator of reproductive functions in mammals (Schneider et al., 2006; Singh et al., 2011), which acts mainly at the level of the hypothalamo-hypophysis axis. Polymorphisms of GnRH gene in three breeds: Xinong Saanen, Guanzhong and Boer was investigated and two allelic variants were identified (A3548G and G3699A) out of which SNP A3548G had significant effect on litter size (P < 0.05) (An et al., 2012). 15. Gonadotropin-releasing hormone receptor (GnRHR) The hypothalamic gonadotropin-releasing hormone receptor (GnRHR) is a key regulator of the reproductive system, which triggers the synthesis and release of the luteinizing hormones (LH) and follicle-stimulating hormone (FSH) in the pituitary gland, that in turn regulate the production of gametes and gonadal hormones (Naor, 2009). Polymorphism of GnRHR gene in Saanen Dairy Goat was investigated and the relationship between polymorphism of GnRHR gene and the litter size trait was ascertained (Han et al., 2009). PCR-SSCP and DNA sequencing were employed to detect polymorphisms in exon 1 of GnRHR gene in two goat breeds: Xinong Saanen Dairy goat and Boer goat. Two haplotypes (A and B), two observed genotypes (AA and AB) and two single nucleotide polymorphisms (SNPs) were detected. Polymorphisms of the GnRHR gene were shown to be associated with litter size in the two goat breeds (An et al., 2009). Polymorphism in GnRHR gene was detected by PCR single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 224 Boer goats (Yang et al., 2011). Two SNPs, G891T and G757A were found in the exon 1 of the goat GnRHR gene and their associations with litter size in Boer goats were evaluated. Association analysis showed that G891T and G757A had significant effects on litter size. At locus G891T, individuals with GT genotype had significantly larger litter size compared to GG genotype in the first and third parity. At locus G757A, ewes with GG genotype had significantly higher litter size than those of GA in the fourth parity. The study primarily revealed an association between allele T at 891 locus of the GnRHR gene and high litter size in the first and third parity in Boer goats. Polymorphisms of GnRHR gene were analyzed in Shaanan goats and Boer goats (Li et al., 2011b) and two alleles (A and C), two observed genotypes (AA and AC), and SNP (T > A) in exon 2 were detected. The results showed that AA genotype was associated with better litter size in Shaanan and Boer goat breeds. Relationship between the polymorphism of GnRHR gene and litter size in Chuandong White goat, Gulin Ma goat and Guizhou White goat was determined by PCR-SSCP (Huang

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et al., 2012). Genotypes (AA, AG and GG) were detected in different goat breeds. Sequencing results revealed that the genotype GG had one mutation (G154A) compared to AA genotype. The goats with genotype AA had higher litter size than those with genotype GG and AG in three breeds of goats (P < 0.05). 16. Luteinizing hormone beta-subunit (LHˇ) The luteinizing hormone beta (LHˇ) plays an essential role in gametogenesis and sexual development of mammals. PCR-SSCP was used to detect single nucleotide polymorphisms in the 5 regulatory region, exon 1, exon 2 and exon 3 of ovine LHˇ gene in high prolificacy breed (Jining Grey goat), medium prolificacy breed (Boer goat) and low prolificacy breeds (Liaoning Cashmere and Angora goats) (Di et al., 2009). In exon 2, three genotypes (CC, CD and DD) were detected in Jining Grey goats; two genotypes (CC and CD) were detected in Liaoning Cashmere goats and only one genotype CC was detected in Boer and Angora goats. Sequencing revealed one single nucleotide mutation (C1124CT) in exon 2 of LHˇ gene in the DD genotype compared with the CC genotype. Jining Grey does with genotype DD or CD had 0.99 (P < 0.01) or 0.87 (P < 0.01) kids more than those with genotype CC. LHˇ gene can be regarded as an effective molecular marker for marker assisted selection programme for litter number of goat (Sun, 2009). 17. Bone morphogenetic protein 4 (BMP4) Bone morphogenetic proteins (BMPs) are members of the TGF-ˇ (transforming growth factor-beta) superfamily, of which BMP4 is the most important due to its crucial role in follicular growth and differentiation, cumulus expansion and ovulation (Shimasaki et al., 1999). PCR-SSCP of intron 2 revealed three genotypes (AA, AB and BB) in Jining Grey and Inner Mongolia Cashmere goats, two genotypes (AB and BB) in Angora goats, and only one genotype (AA) in Boer goats. Sequencing revealed one mutation (G2203GA) of BMP4 gene in the genotype BB in comparison to the genotype AA. The differences of litter size between AA, AB and BB genotypes were not significant in Jining Grey goats (Chu et al., 2010b). A pair of primer was designed to detect polymorphism in the 3 flanking region of BMP4 gene that contains dinucleotide repeated sequence (CA) in the four goat breeds by microsatellite analysis. Three genotypes (CC, CD and DD) were detected in four goat breeds. Sequencing revealed one more CA dinucleotide in genotype DD than in genotype CC. The Jining Grey does with genotype CC had 0.55 (P < 0.05) or 0.72 (P < 0.05) kids more than those with genotype CD or DD. These results preliminarily indicated that allele C of BMP4 gene is a potential DNA marker for improving litter size in goats. Nine goat breeds differing in prolificacy and geographic distribution were employed for polymorphism scanning of BMP4 gene (Sharma et al., 2013). A non-synonymous SNP (G1534A) was identified in exon 2 and G to A transition at the 1534 locus revealed two genotypes GG and GA in the nine investigated goat breeds. A microsatellite was identified in the 3 flanking region, only 20 nucleotides downstream from the termination site

of the coding region, as a short sequence with more than nineteen continuous and repeated CA dinucleotides. 18. Kit ligand (KITLG) Kit ligand encoded by the KITLG (also known as the steel) gene, is a locally produced factor that is thought to have many roles in ovarian function (Yoshida et al., 1997). In goats, the protein and mRNA for KITLG are expressed in granulosa cells during all stages of follicular development, and the KITLG/c-kit system may play an important role in various processes including folliculogenesis and luteal activity (Silva et al., 2006). Analysis of kit ligand (KITLG) gene polymorphisms was done in three goat breeds: Xinong Saanen (SN), Guanzhong (GZ), and Boer (BG) and three allelic variants were identified: T769C and G817T in SN and GZ breeds, and G9760C in the three goat breeds (An et al., 2011). The T769C and G817T loci were closely linked (r2 > 0.33). All the single nucleotide polymorphism loci were in Hardy–Weinberg disequilibrium (P < 0.05). Significant associations were found with litter size for all the three loci. 19. Melatonin receptor 1b (MT2) The neurohormone melatonin (MLT) is mainly secreted from the pineal gland in a circadian pattern with higher levels being observed during the night. MLT targets two high-affinity G protein-coupled receptors (GPCRs): melatonin receptor 1A (also known as MT1, encoded by MTNR1A) and MT2 (encoded by MTNR1B) that modulate both Gi protein/adenylyl cyclase and ERK1/2 pathways (Dubocovich et al., 2010). Lack of polymorphism in exon 2 of MT2 gene between high fertility and year-round estrous goat breeds and low fertility and seasonal estrous goat breeds has been reported (Jia et al., 2012). They went on to state that it is likely that exon 2 of MT2 gene is not associated with fertility or reproductive seasonality in goat breeds. 20. Steroid 21-hydroxylase (CYP21) CYP21 gene encodes the steroid 21-hydroxylase, the enzyme necessary in corticosteroids metabolism and involved in steroidogenesis in the adrenal cortex. Steroid 21-hydroxylase gene (CYP21) was studied as a candidate gene for prolificacy in low prolificacy goat breeds (Angora and Inner Mongolia Cashmere goats), medium prolificacy breed (Boer goat) and high prolificacy breed (Jining Grey goat) by PCR-SSCP and PAGE (Yan, 2010). By a primer pair specific for exon 10, three genotypes (AA, AB and BB) were detected in Inner Mongolia Cashmere, Boer and Jining Grey goats and two genotypes (AA and AB) were detected in Angora goats. Sequencing revealed six nucleotide mutations (A2789C, C2791A, G2818A, G2851C, G2852T and G2854A) and one deletion mutation (c.2821-2822delCG) in exon 10 of CYP21 gene in the BB genotype compared with the AA genotype. The Jining Grey goats with genotype BB and AB had 0.81 (P < 0.05) and 0.47 (P < 0.05) kids more than those with genotype AA, and the difference of the

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litter size between genotypes BB and AB was nonsignificant (P > 0.05).

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can allow screening the genetic variability of this valuable species and genomic selection in turn can improve molecular breeding of goats.

21. Arylalkylamine-N-acetyltransferase (AA-NAT) Conflict of interest statement AA-NAT is a key enzyme associated with melatonin (MLT) biosynthesis. AA-NAT is part of the large Gcn5related acetyltransferase (G-NAT) superfamily (Dyda et al., 2000). MLT plays a key role in regulation of the reproductive system of seasonal estrous animals. High-prolificacy Jining Grey goat, medium-prolificacy Boer goat and lowprolificacy Liaoning Cashmere, Inner Mongolia Cashmere and Angora goats have been investigated to identify polymorphisms in AA-NAT gene and to analyze their relationships with litter size by PCR-SSCP and PCR-RFLP (Chu et al., 2013). Association analysis of the three SNPs identified in AA-NAT gene (T132C, C265T and C586T) revealed that allele D at the C265T locus of AA-NAT gene may be a potential marker for improving litter size in goats since Jining Grey does with genotype CD delivered 0.56 kids (P < 0.05) more than those with CC genotype. In a recent study, two novel synonymous SNPs; C825T (exon 2) and C1249T (exon 3) were identified in Indian goats by Sharma et al. (2015b). 22. Conclusion Knowledge about possible associations of mutations in candidate genes with fecundity trait can help to increase the reproductive capability including reproductive seasonality and litter size, which will be a rapid and economic method to improve the goat breeding speed. Despite the progress made in goat fecundity studies, it’s hard to satisfy the actual application. The application of marker assisted selection in livestock also has some limitations. As most economic traits are influenced by many genes, tracking a small number of these through DNA markers will only explain a small proportion of the genetic variance. In addition, individual genes are likely to have small effects and so a large amount of data is needed to accurately estimate their effects. The reproductive traits are complex quantitative traits involving multiple genes, loci and interactions, so it is important to analyze the combined effect of multiple genes or loci on reproductive traits. The structure, function and control mechanism of important candidate genes are not completely understood. The mechanism by which mutated genes alter the growth and number of ovulatory follicles needs to be established. Little progress has been made on understanding interaction between genes, gene and environment, and genetic effect analysis. To overcome these difficulties, genomic selection can be a better alternative since it involves use of markers covering the whole genome so that potentially all the genetic variance is explained by the markers. Genomic selection or whole genome selection has been possible because of recent developments in technology such as genome sequencing, identification of large number of markers across the genome in the form of single nucleotide polymorphisms (SNPs) and cost effective high throughput genotyping of tens of thousands of such SNPs on individual animals. Goat single nucleotide polymorphism (SNP) panels i.e. SNP chips

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Please cite this article in press as: Ahlawat, S., et al., Current status of molecular genetics research of goat fecundity. Small Ruminant Res. (2015), http://dx.doi.org/10.1016/j.smallrumres.2015.01.027