Introduction

BASIC AND CLINICAL GENETICS

Inherited diseases and breed predisposition

It has long been recognized that many traits, desirable and undesirable, can be passed along family lines. Darwin noted in 1868 that there is a ‘unanimity of … belief by veterinaries of all nations in the transmission of various morbid tendencies’. Inherited diseases in dogs and cats can be categorized as those associated with adherence to breed standards and those unrelated to breed standards. The brachycephalic head shape is particularly associated with a number of diseases such as brachycephalic obstructive airway syndrome, dystocia and corneal ulceration (Packer et al., 2015; O’Neill et al., 2017b, 2017c). Diseases not directly related to breed standards include many intraocular diseases, haematological and immune‐mediated diseases, and endocrine diseases (although the creation of small gene pools for a breed because of adherence to breed standards may have contributed to the prevalence of these diseases). For ease of use, the accounts in this book have been arranged by body system rather than in relation to breed standards.

It should be noted that while most conditions with breed predispositions are likely to be truly hereditary, this is not always the case. (Note that in our text, we use hereditary, genetic and inherited as synonyms.) Some conditions may arise because of the use to which the animal is commonly put, such as racing injuries in greyhounds, or to their behaviour, such as the searching behaviour of spaniels making them prone to grass awn (grass seed) foreign bodies. Nevertheless, even diseases such as these will have a genetic component, for example in influencing the behaviour of the spaniel, or giving the greyhound the athletic ability that means it is used for racing, and therefore can still be considered to have some inheritabilty.

Domestication and the canine and feline genome

Dogs are thought to be descended from a common ancestor with wolves, with estimates for the timing of the divergence ranging from 15 000 to 100 000 years ago. Domestication may have occurred more than once, and there may have been further interbreeding with wolves subsequently. At least two bottlenecks have occurred in canine genetic history, one when they diverged from wolves, and another more recently when modern dog breeds were created. Nevertheless, the dog has an enormous variation in phenotype, as shown by characteristics such as size, colour, coat type and behaviour.

It has been shown that there is more variation in functional genes in domestic dogs than in wolves (Cruz et al., 2008), and alterations in functional genes are often deleterious to welfare. Population bottlenecks and selective breeding may have exacerbated this, and natural selection against these deleterious conditions is less likely in domestic animals than in their wild counterparts. Domestic dogs may therefore be more prone to inherited diseases than wolves.

Dogs were originally bred to fulfil many different purposes, such as hunting, fighting, guarding, herding and companionship. Sighthound type hunting dogs have been noted in archaeological records dating back 4000 years, and in Ancient Roman times, Columella described the division of dog breeds into working and hunting types. However, most modern dog breeds originate in the last 150 years, with the development of dog breeding as a hobby of the middle‐ and upper‐class Victorian.

In a study (Parker et al., 2007) that examined the DNA of a large number of dogs representing 161 breeds, the authors were able to divide the breeds into ‘clades’, that is, breeds with common ancestors. This paper shows how complex the genetic history of the dog is, but certain interesting points stand out. One is that single mutations can cause recognizable changes across multiple breeds within a clade. This has the consequence that dogs in a single clade may be prone to similar inherited diseases. Since most dog breeds are young in evolutionary terms, there has been little time for new mutations to occur, and so most disease‐causing genetic mutations are thought to have occurred before the breeds were founded. It is also notable that related breeds came out of certain times and geographical locations. For example, dog fighting was popular in Ireland in the 1800s, and many mastiffs and bull terrier crosses from this location and period later developed into recognized breeds. The introduction of dogs into North America by European settlers and later Asian migrations largely replaced the indigenous domesticated canine population which had been introduced by the first American settlers over 10 000 years previously. However, this study showed that breeds related to animals brought by European settlers likely had some interbreeding with the more ancient American breeds, and so American breeds of European origin retain some of the genetic material of the previous indigenous breeds.

Phenotypic variation (e.g. conformation and behaviour) is much smaller in cats than in dogs. Cats are thought to have been domesticated later than dogs, but are probably of less direct use to humans as working animals than dogs, since they are harder to train. Deliberate breeding was therefore more limited, and domesticated cats show as much genetic diversity as the wildcat.

The canine and feline genomes have both been sequenced, and the body of research into the genome and into genetic diseases in these species is rapidly growing.

Basic genetics

All mammalian life is based on the genetic code stored within the nucleus of a cell. This genetic code is stored in a long molecule called deoxyribonucleic acid (DNA). Each DNA molecule is composed of a string of units, called bases. There are four different bases, and they attract each other in pairs – guanine to cytosine and adenine to thymine. When attached together, they form the famous double helix. The order in which these bases (or base pairs, since they always match together) occur along the molecule provides the code for the synthesis of proteins. Proteins are then responsible for most of the functions of the body, from the structure of tissues, to the biological catalysts called enzymes, to the hormones which regulate the body’s metabolic processes.

A length of DNA which codes for a particular protein is called a gene. Long strings of genes, interspersed with areas of DNA which do not code for proteins, make up chromosomes. Each nucleus of a mammalian cell contains a set number of chromosomes, except the sex cells (gametes) – sperm and ovum. For dogs this number is 78, and for cats it is 38.

When a somatic (body) cell divides, the chromosomes shorten and thicken within the nucleus, so they become visible under a microscope. They then replicate, and one copy of each chromosome separates into a new nucleus before the cell splits. This process is called mitosis. However, in the production of the gametes (the process of meiosis), the chromosomes line themselves up in the middle of the cell with a companion. This companion is always the same, and two chromosomes that associate together are called homologous pairs. These homologous pairs separate, so the gametes have half the number of chromosomes as normal cells. This means that when a sperm and ovum combine at fertilization, the newly formed cell (the zygote) has the correct number of chromosomes.

Homologous pairs code for related genes, but are not identical. The two genes, one on each chromosome, interact in different ways. Sometimes one gene is dominant to the other, the less dominant gene being termed recessive, and the expression of the gene, that is, the protein that is produced, will be determined by the dominant gene. In other cases both genes will play a role in the production of the protein, a situation called co‐dominance.

The exception to the homologous pairs are two chromosomes called the sex chromosomes (all the other chromosomes are called the autosomes). These chromosomes determine the sex of an animal. In most mammals, including dogs and cats (and humans), a female’s somatic cells contain two X chromosomes while the male’s somatic cells contain an X and a Y. At meiosis, the ova acquire a single X chromosome from the mother, whereas the sperm inherit either an X or a Y from the father. This has significance for the inheritance of conditions carried on the X chromosome, and means that some inherited diseases can be more prevalent in one sex than another.

Although any one animal will carry only up to two versions of a gene, many more can exist within a population because of mutation and natural selection. These different versions of the gene are called alleles.

In conditions and characteristics that are inherited in a simple way, that is, the conditions are autosomal dominant or recessive, a system of genetics devised by the monk Gregor Mendel (hence Mendelian genetics) can be used to predict the likely offspring of two parents, if the parents’ genetic make‐up is known. For example, the gene that codes for Labrador coat colours is dominant for black and recessive for brown. A Labrador with two alleles for black colour (call the allele B) is described as BB and hence the coat will be black. If it has one allele for black and one for brown (call the allele b), it will be described as Bb but the coat colour will still be black since this colour is...