Investigation of major canine diseases and quantitative traits based on estimation of genetic potential for dog breeding
Review article

Investigation of major canine diseases and quantitative traits based on estimation of genetic potential for dog breeding

임 병휘  Byeonghwi Lim1,  김 준모  Jun-Mo Kim1*
1Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea

  6(2):27-34
Received Date: 17 March 2021
Revised Date: 31 May 2022
Accepted Date: 31 May 2022
DOI: 10.12972/jabng.20220004

Abstract

In this review paper, we investigated canine diseases and quantitative traits based on estimation of genetic potential to improve the quality of the companion dog breeding industry, as dogs make up the majority of companion animal. Until now, studies on the use of DNA markers in dogs have largely been related to parentage, breed identification, genetic diseases, and quantitative traits. Testing for parentage and breed often utilizes microsatellite markers, a method which has been shown to be effective in a number of studies. Genetic diseases in dogs are often caused by single mutations which show Mendelian inheritance. Causal genes, mutation types, and inheritance types have mainly been investigated in dog genetic diseases that occur most frequently. The coat color and body size of dogs are quantitative traits and do not follow Mendelian inheritance. The coat color of dogs is determined by a complex mechanism involving the interaction of 5 loci (E, A, K, D, and B). Body size was found to be related to mutations located in 17 genes (ESR1, FGF4, STC2, SMAD2, HMGA2, GHR, R3HCM1, ADAMTS9, ACSL4, IGF1R, LCORL, IRS4, IGSF1, TBX3, MED13L, RNFT2, and IGF1) and 2 loci (ZNF608 and IGF2BP2 loci). In addition, the hair feature is controlled by combinations of alleles at 5 genes (FGF5, RSPO2, KRT71, FOXI3, and SGK3). Overseas, companies (Embark, Wisdom panel, Orivet, etc.) that provide breed identification and screening for genetic diseases through DNA analysis are already available. Typical services include breed identification covering 180 – 250 breeds and risk diagnosis of 140 – 180 genetic diseases. DNA analysis services in the Republic of Korea are relatively inferior in quality/quantity and are under publicized. Therefore, it is necessary to develop a dog DNA analysis system that is easy to access and suitable for customers.

Keyword

DNA marker, dog, dog industry, genetic disease, quantitative trait

INTRODUCTION

In the Republic of Korea, family size is gradually decreasing because of nuclear family structures becoming more common, an increase in one-person households, low fertility rates, and an aging population. The demand for companion animals and the related market are expected to grow steadily in order to alleviate alienation/loneliness and is estimated to expand to around 5.3 billion US dollars by 2020 (Hwang and Kim, 2013). Along with this growing trend, awareness of accepting companion animals as one of the family is also rising, and diversification and enhancement of companion animal related products and services is increasingly required from consumers.

Recent research has been conducted on the use of DNA markers for the identification and mapping of genetic diseases and quantitative phenotypic traits in various animals (Kim et al., 2009; Lim et al., 2018; Mealey et al., 2001; Newton et al., 2000). The development of DNA analysis technology services for these traits will contribute significantly to the development of the companion animal industry as a whole.

Therefore, we present this review on DNA research related to parentage tests, breed identification, genetic diseases, and quantitative phenotypic traits in dogs, as dogs make up the majority of companion animals, and propose ways to utilize DNA information to improve the quality of the companion dog industry by identifying trends in DNA analysis domestically and abroad.

PARENTAGE TEST AND BREED IDENTIFICATION

In the past, parentage testing and breed identification relied on visual methods, but modern developments in molecular biology mean accurate and scientific parentage testing and breed identification can be performed using DNA analysis. Microsatellites, also called short tandem repeats (STRs), are sequences found distributed across the entire genome, consisting of a variable number of repetitions of a DNA motif. Microsatellite markers are widely used in parentage testing and breed identification because they are polymorphic due to the difference in the number of repetitions in each individual (Richard et al., 2008). The effectiveness of this technique in determining dog’s parentage was verified by identifying uncertain parenthood in dogs using microsatellite markers in the Republic of Korea and abroad (Binns et al., 1995; Chae et al., 1998; Chae et al., 1999; Kim et al., 2000; Ichikawa et al., 2001; DeNise et al., 2004; Kang et al., 2009). When attempting to identify the breed of dogs, it was reported that 414 dogs belonging to 85 breeds were distinguished with 99% accuracy using 96 microsatellite markers in a study carried out outside of the Republic of Korea (Parker et al., 2004).

GENETIC DISEASES

Genetic diseases in dogs have been influenced by a high preference for purebred dogs and excessive breed subdivision. As the risk of inbreeding increased, various diseases appeared and became increasingly frequent. Many of the genetic diseases known to date are caused by a single mutation in the genomic sequence, so the traits are passed on to the next generation according to Mendel’s law. On the OMIA website (https://www.omia.org/home), a total of 841 disorders have been identified and 323 disorders following Mendelian rules with causal variants are summarized (assessed in May 2022). We focused on the most frequently occurring genetic diseases in dogs, together with details about the causal mutations and inheritance types (Table 1). It consists of 16 genetic diseases separated into 9 categories: clinical, hormones, eyes, kidney & bladder, brain & spinal cord, heart, muscular, metabolic, and skeletal. Most of these diseases are known to be caused by missense point mutations or indels (insertion or deletion) leading to frameshift mutations; however, some are caused by other types of mutations. One-third of the incidences of muscular dystrophy are known to be caused by the exon 7 of DMD being skipped due to a single point mutation located at the 3′ consensus splice site of intron 6, resulting in termination of the reading frame in exon 8 (Sharp et al., 1992).

Osteogenesis imperfecta has been reported to be caused by a frameshift mutation, in which specific CTGA nucleotides located in exon 51 of COL1A2 are replaced with TGTCATTGG (Campbell et al., 2001). The majority of reported dog genetic diseases have been identified as recessive, suggesting that there are more unaffected carriers than individuals with diseases.

Table 1. The dog’s genetic diseases in which mutation is known

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QUANTITATIVE PHENOTYPIC TRAITS

The coat color and body size of dogs are examples of quantitative phenotypic traits. Table 2 indicates the genes related to the coat color and body size of dogs. Many studies have been conducted on coat color in dogs, because coat color is highly diverse in dogs relative to other animals (Schmutz and Berryere, 2007). The coat color of animals is determined through the complex interaction of allelic and non-allelic genes. In most vertebrate animals, differences in pigmentation arise from differences in two types of melanin – eumelanin and pheomelanin – which are determined by the E locus of MC1R and A locus of ASIP. However in dogs, in addition to the E locus and A locus, the K locus of CBD103 is known to have a strong effect on determining the pigment type (Candille et al., 2007). The E locus of MC1R has four alleles: Em (dominant eumelanin masked), Eg (dominant grizzle/domino), E (normal extension, no effect on phenotype), and e (recessive red), which shows dominance in the order Eg > Em > E >e (Dreger and Schmutz, 2010; Schmutz et al., 2003). The A locus of ASIP also has four alleles: ay (dominant sable), aw (dominant agouti), at (dominant tan points), and a (recessive black), and shows dominance in the order ay > aw>at>a (Berryere et al., 2005). The K locus of CBD103 has three alleles: KB (dominant black), kbr (dominant brindle), and ky (recessive non-black), and shows dominance in the order KB>kbr>ky (Candille et al., 2007). In addition, the D locus of MLPH is known to modulate the intensity of eumelanin expression through dilution caused by the recessive d allele (Drögemüller et al., 2007), and the B locus of TYRP1 induces browning by modifying the molecule of eumelanin (Schmutz et al., 2002). Because the coat color of dogs is very diverse, there are still a number of traits for which the genetic basis of is unknown; therefore, further studies are necessary.

Table 2. The dog’s quantitative traits in which the mutation is known

http://dam.zipot.com:8080/sites/jabg/images/JABG_22-004_image/Table_JABG_06_02_01_T2 .png

Dogs have varied body sizes, ranging from a very small body size like the Chihuahua to very large like the Great Dane. Unlike coat color, body size of dogs has been poorly studied. Studies have found associations between some loci and body size. For example, individuals with the A allele of a SNP in intron 2 of IGF1, the A allele of a SNP leading to a missense mutation in exon 2 of IGF1R, the A allele of a SNP located 20 kb downstream from STC2, a 9.9 kb deletion located 24 kb downstream from SMAD2, the A allele of a SNP located in the 5′ UTR of HMGA2, and the A and T alleles of 2 SNPs located in exon 5 of GHR have a significantly smaller body size (Hoopes et al., 2012; Rimbault et al., 2013; Sutter et al., 2007). Recently, many candidate genes and loci for morphological phenotypes were identified through the genome-wide association study (GWAS) based on next-generation sequencing (NGS) (Plassais et al., 2017; Plassais et al., 2019). The previously reported IGF1, STC2, SMAD2, HMGA2, and GHR were also significantly associated with height or weight phenotypes. Additionally, novel 12 genes (ESR1, FGF4, R3HCM1, ADAMTS9, ACSL4, IGF1R, LCORL, IRS4, IGSF1, TBX3, MED13L, and RNFT2) or 2 loci (ZNF608 and IGF2BP2 loci) were detected in height or weight. Moreover, phenotypes related to hair were confirmed using combinations of alleles at 5 genes (FGF5, RSPO2, KRT71, FOXI3, and SGK3) (Parker et al., 2017). The FGF5 controls much of the fur length, RSPO2 controls fur growth patterns or furnishings, KRT71 contributes to hair curl, and FOXI3 and SGK3 generate hairlessness. Further studies are needed because very small or large breeds including unique features were often developed through intensive breeding and may therefore be associated with congenital genetic diseases.

Dogs have varied body sizes, ranging from a very small body size like the Chihuahua to very large like the Great Dane. Unlike coat color, body size of dogs has been poorly studied. Studies have found associations between some loci and body size. For example, individuals with the A allele of a SNP in intron 2 of IGF1, the A allele of a SNP leading to a missense mutation in exon 2 of IGF1R, the A allele of a SNP located 20 kb downstream from STC2, a 9.9 kb deletion located 24 kb downstream from SMAD2, the A allele of a SNP located in the 5′ UTR of HMGA2, and the A and T alleles of 2 SNPs located in exon 5 of GHR have a significantly smaller body size (Hoopes et al., 2012; Rimbault et al., 2013; Sutter et al., 2007). Recently, many candidate genes and loci for morphological phenotypes were identified through the genome-wide association study (GWAS) based on next-generation sequencing (NGS) (Plassais et al., 2017; Plassais et al., 2019). The previously reported IGF1, STC2, SMAD2, HMGA2, and GHR were also significantly associated with height or weight phenotypes. Additionally, novel 12 genes (ESR1, FGF4, R3HCM1, ADAMTS9, ACSL4, IGF1R, LCORL, IRS4, IGSF1, TBX3, MED13L, and RNFT2) or 2 loci (ZNF608 and IGF2BP2 loci) were detected in height or weight. Moreover, phenotypes related to hair were confirmed using combinations of alleles at 5 genes (FGF5, RSPO2, KRT71, FOXI3, and SGK3) (Parker et al., 2017). The FGF5 controls much of the fur length, RSPO2 controls fur growth patterns or furnishings, KRT71 contributes to hair curl, and FOXI3 and SGK3 generate hairlessness. Further studies are needed because very small or large breeds including unique features were often developed through intensive breeding and may therefore be associated with congenital genetic diseases.

TREND OF DOG DNA ANALYSIS

Breed identification and diagnostic services for genetic diseases in dogs using DNA analysis are offered by overseas companies such as Embark (www.embarkvet.com), Wisdom Panel (www.wisdompanel.com), and Orivet (www.orivet.com). Dog DNA analysis services initially sent consumers a swab-type kit to collect DNA from the dog’s mouth, then consumers return the collected DNA to the analysis center. After that, the results are provided to consumers after breed identification and screening for genetic diseases has taken place. Although there are differences among companies, services usually include 180 to 250 breeds for breed identification and screening for between 140 and 180 genetic diseases. Some companies also offer health consulting for dogs based on the results of genetic diseases. Overseas, systematic dog DNA analysis services are well established and consumers also show high interest in these services. However, the domestic companion dog industry in the Republic of Korea lacks the overall quality and quantity of services for breed identification and screening for genetic diseases offered by DNA analysis, and publicity is also limited.

CONCLUSION

Dogs account for more than 70 percent of domestic companion animals, hugely affecting the industry in the Republic of Korea. While the industry has improved quantitatively in terms of diversity, improvement to the quality of related products and services for consumers have been limited. Testing for parentage, breed identification, and diagnosis of genetic diseases using DNA can be a positive method for improving the quality of the companion dog industry. As the development of analysis services using DNA for dogs in the Republic of Korea is not as sufficient as it is abroad, it would be beneficial to develop and promote a DNA analysis system that is accessible to consumers and aims to enhance the quality of the companion animal industry domestically.

ACKNOWLEDGEMENTS

This work was supported by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) through High Value-added Food Technology Development Program (or Project), funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA) (321037051WT011).

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