1 INTRODUCTION

In the past few decades, cloning of mammals from somatic cells has been achieved in mammalian species, demonstrating that the genomes of at least some somatic cells can be reprogrammed to support complete development. Before the cloning of animals from somatic cells, Briggs and King (1952) reported the first successful generation of normal frog embryos by nuclear transplantation in 1952, followed by the mouse in 1981 by Illmensee and Hoppe (1981), and many other species in the late 1980s including rabbit (Stice & Robl, 1988), sheep (Willadsen, 1986), cattle (Prather et al., 1987) and pigs (Prather, Sims, & First, 1989). Scientists, however, were uncertain whether cloning by somatic cell nuclear transfer (SCNT) would be possible at all, and cloning animals using somatic cells was considered a dream until SCNT was applied in the creation of a cloned sheep, Dolly, in 1996 (Campbell, McWhir, Ritchie, & Wilmut, 1996). Adult somatic cells were used as donor nuclei as opposed to totipotent cells, a feat which many renowned scientists initially considered impossible. Since then, SCNT has been applied to generate cloned adult animals of various other species including mice, cattle, pigs, cats, goats, rabbits and horses (Campbell et al., 2005; Edwards et al., 2003; Galli et al., 2003; Jang, Kim, & Lee, 2010). The SCNT technique allows to preserve and screen the entire genome from individuals. It also makes collection and banking of somatic cells less invasive and easier to apply to produce animals, while the collection and banking of gametes/embryos demand the specialized processes in intracytoplasmic sperm injection/in vitro fertilization techniques. For these reasons, SCNT has become a powerful tool for the genetic management of valuable individuals, breeds and species.

The cloning of dogs was thought to be close to impossible due to their unique reproductive characteristics. First, the pattern of oestrous cycle in dogs is a non‐seasonal and monoestrous, and their inter‐oestrous interval is longer compared with other animals (dogs; 6–8 months, mice; 5 days and pigs; 13–21 days) (Allen, 1922; Fahmy, Holtmann, & Baker, 1979; Wei et al., 2017). Second, oocytes of dogs are ovulated in an immature state (germinal vesicle) and undergo maturation to metaphase II in the oviduct canal during 48–72 hr (Lee et al., 2017). Third, the small amount of in vitro oocyte collection in dog is usually performed after ovarectomy by puncturing the antral follicles or by repetitive ovarian slicing (Reynaud, de Lesegno, Chebrout, Thoumire, & Chastant‐Maillard, 2009; Yamada et al., 1993), while in cows and pigs, a large quantity of in vitro oocytes can be collected from the abattoir. Moreover, there are no established protocols for in vitro maturation (IVM) of canine oocytes, and thus, the efficiency of canine IVM is low (Luvoni, Chigioni, Allievi, & Macis, 2005).

Because of these unique reproductive characteristics, the application of assisted reproductive technologies (ART) has been limited in dogs. However, finally, with the unceasing efforts (total of 1,095 reconstructed canine embryos by SCNT were transferred into 123 recipients), Snuppy, the world's first cloned dog, was successfully produced by SCNT (Lee et al., 2005). Thereafter, the applications of canine SCNT have been markedly improved in reproductive biology and biomedical research. Very recently, the world's first cloned dog, Snuppy, was successfully recloned from SCNT by using adipose‐derived mesenchymal stem cells (ASCs) (Kim et al., 2017). The pregnancy and delivery rates of Snuppy were only 2.4% (3 dogs from 123 recipients) and 0.2% (2 clones from 1,095 embryos). These numerical values were markedly increased to 42.9% (3 dogs from 7 recipients) and 4.3% (4 clones from 94 embryos), respectively, when the recloned Snuppy was produced, which suggests that the technique is now becoming more applicable to numerous research fields. In this review, we present a brief history and the present state of dog cloning.

1.1 Ethics in animal experiments The 1‐ to 3‐year‐old mixed‐breed bitches in the oestrous stage were used for research. All the dogs were without any clinical signs of disease and were continuously monitored throughout the experimental period and fed with a constant amount of commercial adult dry food and water daily. Also, all the dogs were housed in an identical manner in individual cages. All experiments were performed in accordance with recommendations described in “The Guide for the Care and Use of Laboratory Animals” published by the institutional animal care and use committee (IACUC) of Seoul National University. In this respect, dog care facilities and the procedures performed met or exceeded the standards established by the Institute of Laboratory Animal Resources at Seoul National University.

1.2 Normality assessment in growth, haematologic and reproductive parameters The growth and haematologic characteristics in three viable cloned dogs were assessed (Park et al., 2010). This study demonstrated that those growth parameters in cloned dogs, including height, body weight and bone development showed similar patterns to those of noncloned dogs. In addition, age‐related haematologic and serum biochemical parameters in cloned dogs also showed similar patterns with noncloned dogs (Park et al., 2010). These results showed that cloned dogs derived from SCNT procedures possessed similar growth and haematologic characteristics to the noncloned dogs without exhibiting any significant adverse effects. The reproductive competence of cloned dogs, including hormonal parameters and development of ovarian follicle, was also evaluated (Hong et al., 2010). The serum concentration of estradiol, luteinizing hormone, follicle‐stimulating hormone and progesterone in cloned dogs showed similar patterns with those of noncloned dogs (Hong et al., 2010). Similar morphological changes in ovarian follicles also appeared in both of cloned and noncloned dogs (Hong et al., 2010). In addition, it was demonstrated that spermatozoa derived from cloned male dogs successfully fertilized the oocytes from noncloned female dogs by artificial insemination (AI) (Park et al., 2009). After confirming fertility of cloned male and female dogs, AI was performed using fresh semen from cloned male dog. Both cloned female dogs were both diagnosed as pregnant and delivered puppies without congenital abnormalities. These results demonstrate that cloned male and female dogs have normal reproductive viability and prove the potential aspect of the cloning technology for expanding elite canine gene pools.