WALTHAM is at the forefront of research into the genetics of the dog, partnering with world class scientists in discoveries such as:
• Understanding the history of dog domestication.
• Showing that a single gene is a major determinant of dog size.
• Demonstrating that genetic variants are linked to stereotypical dog characteristics.
• Understanding the genetic basis of canine disease.
The dog is descended from the wolf (Vonholdt et al. 2010) and has since continued to evolve, successfully adapting to a wide range of environments.
狗起源于狼(Vonholdt et al. 2010)，并且继续进化，成功适应各种环境。
Following domestication, the dog has undergone centuries of selective breeding as people strived to accentuate the traits they wanted. Some of these were behavioural (for example herding or guarding ability) and some were morphological (to enable them to assist their owner’s hunting lifestyle).
Nowadays, there are hundreds of distinct dog breeds which differ markedly in phenotypic traits. As a species, the dog is unique with a mature body weight that varies over a huge range – from about 1 kg to over 100 kg (Burger 1994). The breeds also look very different and behaviourally fulfil a wide range of functions from companion to search and rescue dog.
如今，有成百上千种不同的犬种，其表型特征明显不同。作为一个物种，狗很独特，成年犬体重差异极大 – 从约1公斤到超过100公斤(Burger 1994)不等。外型差异也非常大，功能从陪伴到搜寻和营救不尽相同。
Although selective breeding has given us breeds to suit every purpose, it has a downside. It can result in inbreeding (Calbodi et al. 2008), and the associated consequences are seen in the disease susceptibilities that breeders are working so hard to eliminate.
虽然选择育种使我们获得适合各用途的品种，但它也有一个缺点。它可能导致同系繁殖(Calbodi et al. 2008)，相关的后果表现为易感某些疾病，这 正是育种专家们极力要消除的。
Why WALTHAM is Interested
Until recently, the genetic basis of the various dog breeds was unknown. Understanding what happened to the genes of the dog as it evolved, and the genetic differences between the breeds, will provide information that may enable intervention in some of the breed- specific health problems that continue to affect the welfare of many dogs.
Molecular techniques were used to examine the genetic variation patterns across dog breeds, how the patterns differ between wolf and dog breeds, the amount of diversity within dog breeds, and the DNA patterns linked to health conditions.
There is rich history underlying dog domestication
Previously, mitochondrial DNA analysis suggested domestic dogs originated from East Asia (Savolainen et al. 2002).
先前，线粒体DNA分析表明，驯养犬起源于东亚(Savolainen et al. 2002)。
Collaborative research between WALTHAM and scientists all over the world involved an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their ancestor, the grey wolf (Vonholdt et al. 2010). Haplotype analysis showed that the dog is descended from Middle Eastern grey wolves rather than from East Asian wolves (Vonholdt et al. 2010). Breed groupings based on phenotypic or functional similarities were generally found to share genetic characteristics, although in some cases individuals with novel phenotypes were the basis of traits (Vonholdt et al. 2010).
威豪与世界各地的科学家们进行合作研究，对犬类和其祖先-灰狼的48000多个单核苷酸多态性的基因组进行了广泛的调查(Vonholdt et al. 2010)。 单模标本显示，狗起源于中东灰狼，而非东亚狼(Vonholdt et al. 2010)。通常以表型或功能相似性进行品种分类，以共用基因特性，虽然有些情况下， 奇特的表型是某些品种的基础特征(Vonholdt et al. 2010)。
A single gene is a major determinant of dog size
The genetic origin of the great range of body size in dogs was unclear.
For this study, WALTHAM collaborated with US scientists at the National Human Genome Research Institute in Bethesda, Cornell University New York, the University of Utah, the University of California, the University of Southern California, the University of Missouri, and the Nestle Research Center in St Louis. Following a genome-wide scan, a major quantitative trait locus (QTL) was identified on chromosome 15 that influences size variation within a single dog breed (Sutter et al. 2007). By examining the genetic variation surrounding the QTL in small and giant breeds, a selective sweep spanning a single gene, encoding insulin-like growth factor 1 (IGF1), was identified (Sutter et al. 2007). A single IGF1 single-nucleotide polymorphism haplotype (SNP 5 A allele) was found to be common to all small breeds and absent from almost all giant breeds (Figure 1. Sutter et al. 2007). This study suggests that this gene is a major contributor to body size in all small dogs.
在本研究中，威豪在纽约与美国康奈尔大学国家人类基因组研究所、犹他大学、加州大学、南加州大学、密苏里大学以及位于圣路易斯的雀巢研究中 心的科学家合作。经过基因组扫描后，在影响单个犬种大小变化的染色体15上确定了数量性状基因座（QTL）(Sutter et al. 2007)。通过检查小型和大 型犬种QTL周围的基因变化，确定了选择性的扫描生成单基因，以胰岛样生长因子1 (IGF1) 编码(Sutter et al. 2007)。发现在小型犬种中，单个IGF1 单核苷酸多态性单体型很普遍，而在几乎所有大型犬种中则没有(Figure 1. Sutter et al. 2007)。该研究表明，该基因是所有小型犬种体型大小的主要 决定因素。
图1：体型与SNP 5 A等位基因频率相结合(Sutter et al. 2007)。等位基因频率的 二项回归与平均犬种数量的平方根。虚线表示非参数引导重采样估计的预测方程线95%可靠区间。143个犬种中，5和109之间（中位数22）的狗为基因型。 葡萄牙水犬以红色标示，另有三种大型犬种，其平均重量比其SNP 5 等位基因频率所预测的更大。这种大型犬的SNP 5 A 等位基因与犬种平均重量呈极强 的负相关关系 (斯皮尔曼等级相关系数 ρ= −0.773; P，似然比检验 = 2882.3, X2df-1 ，等位基因频率在体型上呈逻辑回归)
Figure 1: Association of body size and frequency of the SNP 5 A allele (Sutter et al. 2007). Binomial regression of allele frequency on square root of mean breed mass. Dashed lines indicate the 95% confidence interval on the predicted equation line as estimated from nonparametric bootstrap resampling. Between 5 and 109 (median 22) dogs were genotyped for each of 143 breeds. The Portuguese water dog is highlighted in red along with three giant breeds that have larger breed average masses than is predicted by their SNP 5 allele frequency. The frequency of the SNP 5 A allele is strongly negatively correlated with breed average mass across this large sample of breeds (Spearman’s rank correlation coefficient ρ= −0.773; P
Genetic variants are linked to stereotypical dog characteristics 遗传性变型与常规的狗的特性有关
Selective breeding has resulted in traits (or phenotypic stereotypes), such as conformation and behaviours, that are special to each breed. However, the genetics underlying these traits was not known.
In a collaboration between WALTHAM, an experienced dog trainer and judge, the University of Utah, and the National Human Genome Research Institute, Bethesda, Maryland, USA, DNA samples from dogs representing 148 breeds were used to associate single nucleotide polymorphism markers with breed stereotypes (Jones et al. 2008). Significant loci linked to the shape of dogs, their weight, coat length, tail curve, and the ratio of the head, neck or leg to body size were found (Jones et al. 2008; Chase et al. 2009). Loci were also tentatively identified that affected behavioural stereotypes such as herding, pointing, boldness, and trainability (Jones et al. 2008). Four significant loci were identified for longevity, a characteristic that is inversely correlated with breed size (Jones et al. 2008).
威豪与一个经验丰富的宠物犬教练和裁判、犹他大学、以及位于美国马里兰州贝赛斯达的国家人类基金组研究协会合作，从148个犬种采取DNA样本， 用于产生具有犬种特性的单核苷酸多态性标记(Jones et al. 2008)。发现了与狗的体形、重量、皮毛长度、尾巴弯曲度以及头、颈或腿与体型的比率相 关的重要位点(Jones et al. 2008; Chase et al. 2009)。在试验中还确定了影响行为特性如放牧、定位、勇敢和可训练性的位点(Jones et al. 2008) 。确定了寿命的四个重要位点，该特性与犬种大小呈负相关 (Jones et al. 2008)。
Partnering with world class scientists WALTHAM research has contributed to the understanding of the genetic basis of canine disease.
This research showed that canine diabetes has a similar genetic basis to human diabetes. Single nucleotide polymorphisms in the canine CTLA4 gene were found to be associated with diabetes (Short et al. 2010), as they are in human type-1 diabetes mellitus. CTLA4 promoter polymorphisms were associated with diabetes in crossbreed dogs and in five pedigree breeds, including the Samoyed, miniature schnauzer, West Highland white terrier, Border terrier and Labrador retriever (Short et al. 2010).
研究显示，犬类的糖尿病与人类糖尿病有着类似的遗传基础。发现犬类CTLA4基因中的单核苷酸多态性与糖尿病有关 (Short et al. 2010)，而人类是 1型糖尿病。CTLA4基因启动因子区多态性与杂交犬和5个犬种，包括萨摩耶犬、迷你雪纳瑞、西高地白绠、 博德猎狐犬和拉布拉多猎犬的糖尿病有关 (Short et al. 2010)。
Major histocompatibility complex haplotypes (Kennedy et al. 2006) and cytokines (Short et al. 2009; Short et al. 2007) have also been implicated in canine diabetes.
犬类糖尿病中还涉及主要组织相容性复合体单倍型 (Kennedy et al. 2006)以及细胞因子(Short et al. 2009; Short et al. 2007)。
Anal furunculosis 肛门疖病
A genetic basis of anal furunculosis was identified. This is a chronic inflammatory disease of perianal tissues that particularly affects German shepherds. Susceptibility to anal furunculosis was found to be primarily associated with the major histocompatibility complex allele DLA-DRB1*00101 (Barnes et al. 2009; Kennedy et al. 2008).
确定了肛门疖病的基因基础。这是肛门周围组织的一种慢性炎症，德国牧羊犬尤其易感。发现易感肛门疖病主要与主要组织相容性复合体等位基因 DLA-DRB1*00101有关(Barnes et al. 2009; Kennedy et al. 2008)。
Copper accumulation 铜积聚
The mutation responsible for copper toxicosis, an autosomal recessive disorder affecting Bedlington terriers, was characterised (Forman et al. 2005). Subsequently, a genomic diagnostic test for the disease was developed (Forman et al. 2005). The heritability of copper accumulating traits in Labrador retrievers was also investigated (Hoffman et al. 2008).
确定了该变化是造成铜中毒的原因，是一种影响贝得灵顿厚毛犬的常染色体隐性遗传疾病 (Forman et al. 2005)。随后，研究出了该疾病的基因诊断 测试(Forman et al. 2005)。还研究了拉布拉多猎犬铜积聚特性的遗传可能性(Hoffman et al. 2008)。
A genetic link between dog size and hip dysplasia was identified. A major determinant of size in dogs is a single insulin-like growth factor 1 (IGF1) haplotype (Sutter et al. 2007). This was found to be significantly associated with hip dysplasia (known to be more prevalent in larger dogs) as well as patella luxation and pancreatitis (Chase et al. 2009). Subsequently, it was shown that it may be possible to predict hip dysplasia from genome data (Guo et al. 2011).
确定了狗的体型和臀部发育不良之间的基因关系。狗的体型的主要决定因素是单个的胰岛样生长因素1 (IGF1) 单模标本(Sutter et al. 2007)。研究 发现它与臀部发育不良（大型犬更普遍）和膝盖骨脱臼和胰腺炎有着明显关系(Chase et al. 2009)。后来，研究显示可从基因组数据预测臀部发育不良 (Guo et al. 2011)。
A genetic basis for chondrodysplasia was identified. This is a short-legged phenotype that defines breeds including the dachshund, corgi, and Basset hound. It is strongly associated with a recently acquired retrogene encoding fibroblast growth factor 4 (fgf4) (Parker et al. 2009).
确定了软骨发育不良的基因基础。这是一个确定包括达克斯狗、威尔士矮脚狗和矮腿猎犬在内犬种的短腿表型。这与最近获得的逆基因编码成纤维细 胞生长因子4(fgf4) 紧密相关(Parker et al. 2009)。
This research identified the genes potentially involved in the pathology of atopic dermatosis. The expression of 54 genes was found to be significantly associated with the disease, of which 12 genes were expressed only in skin lesions (Merryman-Simpson et al. 2008). The genes were associated with innate immune and inflammatory responses, cell cycle, apoptosis, barrier formation, and transcriptional regulation (Merryman-Simpson et al. 2008). Understanding which genes are activated during atopic dermatosis aids understanding of the disease and ultimately its treatment.
研究确定了特应性皮炎病理学可能涉及的基因。发现54个基因的表现与该疾病有紧密关系，其中12个基因仅表现为皮肤损伤(Merryman-Simpson et al. 2008)。这些基因与先天免疫和炎症反应、细胞周期、细胞凋亡、屏障形成和转录调节有关(Merryman-Simpson et al. 2008)。了解哪些基因导致特 应性皮炎，有助于了解该疾病以及其治疗。