While healthy feral dogs can successfully breed without human intervention, dog fanciers invest their time, money and endless efforts trying to manipulate some genes into passing on to the next generation and trying to prevent other genes from being passed. Once a condition is shown to be inherited (see first article in series), how can a breeder influence its existence or absence in her line?

Dogs are estimated to have >22,000 genes. Each gene can have a variety of alleles, which are different copies of the gene that have different combinations of DNA bases. The maximal variation found in an individual dog is two different alleles per gene: a maternal allele and a paternal allele. A dogs’ genotype refers tothe allelic combination the dog has for one or multiple genes. A dogs’ phenotype is the observable trait or combination of traits of an individual which is a reflection of the genotype, environmental factors and their interactions.

Genes are arranged along structures called chromosomes. There are 39 chromosome pairs in dogs: 38 autosomal chromosome pairs and two sex chromosomes; X and Y. The sex chromosomes determine the individual’s gender, an XX individual is a female and an XY individual is a male. Since the Y chromosome is very small, most sex-linked traits are carried on the X chromosome. These traits are referred to as sex-linked or X-linked, the rest of the traits, located on the autosomes are referred to as autosomal traits. The mode of inheritance is the manner in which any trait is inherited. Modes of inheritance are further classified as simple (controlled by a single gene) dominant, simple recessive, co-dominant, polygenic or multifactorial and sex-linked.

An example for simple autosomal dominant mode of inheritance is shorthair (SH) versus longhair (LH) in Weimaraners. It is sufficient to have one copy (allele) of the dominant trait in the dogs’ genotype in order to have a shorthair (SH) phenotype. This also means that a SH dog can produce LH offspring if its genotype is heterozygous for coat type. An important concept to note is that mode of inheritance is a breed-specific trait. For example: black color is dominant in Newfoundland dogs but it is recessive in German Shepherd dogs. Selection against dominant traits is relatively simple since both the homozygous and the heterozygous genotypes are exhibiting the unwanted dominant trait. When applying this type of selection, it is possible to achieve complete success or fixation of the recessive trait in one generation by only using individuals with recessive phenotype (and genotype) for breeding. Exceptions are dominant traits which show late onset of expression and may only become noticed after an individual has already been used for breeding. Other exceptions are dominant traits with incomplete penetrance (the trait may be present in an individual’s genotype but never expressed). In this case a dog that never exhibited the unwanted dominant trait will be able to produce it. An example of a dominant genetic disorder is Progressive Retinal Atrophy (PRA, a blinding disorder) in Mastiff and Bullmastiff dogs. Since there is a DNA mutation test available for PRA in these breeds (OptiGen), the selection process is determined by the test status for a breeding individual. Detailed use and analysis of DNA tests will be given in the third article in this series.

An example for autosomal recessive mode of inheritance is the Weimaraner grey color. Since grey (dilute brown) is recessive to blue (dilute black), all grey dogs are homozygous for the recessive allele and two grey Weimaraners can never produce a blue Weimaraner. Blue Weimaraners can be heterozygous for the grey color; therefore, two blue dogs may have grey offspring. The recessive LH is another example; two recessive LH Weimaraners bred to each other can only have LH offspring. Selection is always performed based on the phenotypes. When selecting against a recessive trait, breeders have several ways to find out about an individual dogs’ genotype. First it is useful to know the phenotype of the parents and littermates to the individual in question. If a SH dog has a LH parent, it must be heterozygous for LH (the LH parent can only transmit the LH allele since it is homozygous for it). This dog is a carrier for LH. If a SH dog has a LH littermate but none of the parents are LH then it may or may not be a carrier (note that both parents are carriers). It may be possible through test-breeding to determine the individual’s genotype. Expected outcomes for different genotypes and their breeding combinations are presented in Table 1.

Table 1. Expected percentages of SH, LH carrier or LH offspring from matings involving an autosomal recessive LH gene in Weimaraners.

The limitation of test-breeding is that there may be no LH pups produced by chance, yet the individual in question might be a carrier. When considering a recessive genetic disorder, the concept of test-breeding to produce carrier and affected puppies is emotionally and sometimes technically difficult. This was done in the past by breeders to study a recessive form of PRA in Irish Setters and juvenile cataracts in Miniature Schnauzers.

Another way to select against carriers of a recessive disorder is by performing pedigree analysis to calculate risk factors for carrier and affected status. Assessing relative risk requires the identification of every individual in the pedigree which is a parent of affected (100% carrier risk), an offspring of affected (100% carrier risk), a full-sib to a carrier (50% carrier risk) and a non-affected full-sib to an affected (67% carrier risk). By calculating the risk down the pedigree to the individual in question, we can assess the minimal risk of this individual based on the known affected relatives in the pedigree. By limiting the number of breeding offspring from carriers or those with high-carrier risk, a breeder can decrease the risk of carriers and affected individuals produced with each generation. If the average carrier risk for the breed can be determined, breeders should aim to breed to those dogs whose carrier risk is lower than this average. This is only feasible if there is recognition, cooperation and distribution of information regarding confirmed affected and carrier dogs within the breed. Without this information, concerned breeders have no means of knowing the carrier risk of their dogs.

Another recognized mode of inheritance is co-dominant. Co-dominant mode of inheritance is exemplified by the merle pattern gene seen in Shetland Sheepdogs, Australian Shepherds and many other breeds. This trait has three distinct phenotypes: the homozygous recessive, no merle, the heterozygous, merle, and the homozygous dominant, extreme white markings and additional associated defects (such as vision and hearing abnormalities). Since the phenotype always indicates the genotype, the breeders know which alleles a dog has by simply looking. Another example for co-dominantly inherited genes is the Major Histocompatibility Complex (MHC) genes. This locus (genetic location) is responsible for some of the immune-system functions and great variability is an essence to its purpose. The co-dominant expression of the MHC alleles ensures maximal utilization of the paternal and maternal alleles in the individual. This is only effective if the individual inherited different alleles from its parents, (i.e. heterozygous). Researchers suggest that some of the immune-mediated diseases common in purebred dogs are the result of the lack of heterozygosity in the MHC locus.

Complex or polygenic mode of inheritance could be exemplified by height or size which is probably the product of multiple genes and environmental factors whose combined actions result in the adult animal size. Breeders observe that the mating of large x large dogs may result in some small offspring among other large offspring, and the mating of small x small individuals may result in large offspring. In trying to predict adult size in the litter, it is sometimes possible to follow bone density and substance, but in other litters substantial pups may mature to be small adults with a lot of substance and bone. A genetic disorder that exemplifies polygenic mode of inheritance is canine Hip Dysplasia (HD). Breeders that have attempted to control hip dysplasia by only breeding dogs with OFA certified hips have not experienced a fast improvement in the health of their dogs’ hips. The lack of a rapid response to this type of selection suggests that there is no single gene representing OFA approved hips. Additionally, not all dogs have hip dysplasia due to the same genetic factors. Polygenic disorders such as HD need to be regarded as caused by multiple genes and possibly environmental factors. A critical threshold of these factors can add up to cause the disease. In order to select against polygenic traits, breeders must identify other phenotypical traits which represent those they wish to select against. For example: genetically programmed rapid growth of young pups may cause incongruity between the bony structure and the soft tissue components of the hip joint which may lead to HD. By selecting for slowly growing individuals, breeders may reduce HD risk due to rapid growth. Another important means of applying selection against a polygenic trait is by studying the breadth of a pedigree (full-sibs to a dog and to its parents) as well as the depth of pedigree (parents and grandparents). When dealing with polygenic disorders, the littermates represent the genetic potential of the individual breeding dog for these traits. Lastly, it is known that genetically “predisposed” dysplastic hips can be protected by restricting environmental stress (i.e. by limiting body weight and by avoiding strenuous activity on sliding surfaces). This is sensible to do for pet dogs, but breeding dogs should be allowed to develop naturally to reveal their full genetic potential.

X-linked disorders are characterized by unequal numbers of affected males and females. Males are affected at higher numbers since they only have one copy of the X chromosome therefore a single recessive X-linked gene will be expressed in males. A recessive X-linked gene will be passed from unaffected mothers to their male offspring, and a dominant X-linked trait will be transmitted from affected mothers to all of their offspring. X-linked disorders can be selected against in the same manner as simple dominant or recessive traits, once the mode of inheritance is understood. Examples for X-linked disorders are PRA in Siberian Huskies and Samoyeds and severe combined immuno-deficiency (SCID) in Cardigan Welsh Corgi and Basset Hounds. Interestingly, researchers at the University of Pennsylvania have recently performed successful gene-therapy to retrieve immune function for several Basset Hound pups with X-SCID. The exciting outcome was complete restoration of the immune-system function in three out of the four pups. Is gene-therapy the future answer to canine genetic diseases, or will it be DNA based genetic tests helping breeders to identify carriers? The next article will concentrate on reviewing available DNA tests and their usefulness in performing genetic selection for breeding purposes.