A search for genetic diversity among Italian Greyhounds from Continental Europe and the USA and the effect of inbreeding on susceptibility to autoimmune disease

Abstract

Background: Previous studies documented the problem of inbreeding among Italian Greyhounds (IG) from the USA and its possible role in a multiple autoimmune disease syndrome. The present study is an extension of these earlier experiments and had two objectives: 1) to identify pockets of additional genetic diversity that might still exist among IG from the USA and Continental Europe, and 2) to determine how loss of genetic diversity within the genome and in the dog leukocyte antigen (DLA) complex relates to the problem of autoimmune disease in IG from the USA. Genetic testing was conducted using 33 short tandem repeat (STR) loci across 25 chromosomes and 7 STR loci that associated with specific dog leukocyte antigen (DLA) class I and II haplotypes. Standard genetic assessment tests based on allele frequencies and internal relatedness (IR) were used as measures of breed-wide and individual heterozygosity. Results: The results of these tests demonstrated that IG from the USA and Continental Europe belonged to a single breed but were genetically distinguishable by genomic allele frequencies, DLA class I and II haplotypes, and principal coordinate analysis (PCoA). In the second part of the study, 85 IG from the USA that had suffered various autoimmune disorders (case) and 104 healthy dogs (control) of comparable age were studied for genetic associations with disease. Case dogs were found to be significantly more homozygous in the DLA regions than control dogs. Principal coordinate analysis did not differentiate case from control populations. No specific STR-associated DLA-class I or II haplotype was associated with increased autoimmune disease risks. Reasons for the loss of genetic diversity and increased homozygosity among IG from the USA were studied using registration data and deep pedigrees. The breed in the USA started from a small number of founders from Europe and has remained relatively isolated and small in numbers, limiting breeding choices especially in the period before modern transportation and artificial insemination. An additional cause of lost diversity and increased homozygosity has been the influence of famous sires and their show-winning progeny. The most influential of these sires was Ch. Dasa's King of the Mountain (King) born in 1978. Virtually all contemporary IG from the USA have King at least once in 10 generation pedigrees and 18 % of the genome of contemporary IG from the USA is shared with King. Conclusions: It was concluded that artificial genetic bottlenecks have concentrated numerous genetic polymorphisms responsible for autoimmune disease and that these risk factors did not originate in a specific individual or bloodline of the breed. Rather, they were of ancestral origin in both purebred and random bred dogs and inherited by descent. Italian Greyhound breeders in the USA have several options to improve breed health: 1) breed against homozygosity within the genome and in the DLA region, 2) avoid breeding dogs that have suffered an autoimmune disorder, 3) increase diversity by incorporating the genetic differences that exist in IG from Continental Europe, or 4) outcross to other small sighthound breeds. The latter two approaches must be undertaken with care to avoid introduction of new deleterious traits and to maximize retention and dissemination of new genetic diversity. Italian Greyhounds (IG) in the USA began with a small number of founders imported from Europe, with limited introduction of new dogs in the subsequent decades resulting in narrow breeding choices. These genetic bottle-necks were enhanced by a series of popular sires and their progeny, each followed by an extended period of close linebreeding. The resultant inbreeding has reduced genetic diversity, and increased homozygosity, in contemporary dogs. This has resulted in a greater susceptibility to a wide range of autoimmune diseases and inadvertent positive selection of other complex and simple deleterious traits. This loss of genetic diversity prompted a search for dogs currently in Continental Europe, parts of which were once behind the Iron Curtain. However, Italian Greyhounds from Continental Europe also lacked genetic diversity, but were genetically distinguishable from North American IG, both across the genome, and also in the DLA region. The cause of their lost diversity was not determined, although they probably suffered some of the same types of genetic bottlenecks as IG in the USA. Italian Greyhounds from Continental Europe appear to suffer from many of the same common heritable health problems as IG from the USA, but no information was obtained pertaining to the incidence of autoimmune diseases. The incidence of auto-immune diseases in IG from the USA may decrease with a concerted effort to decrease homozygosity across the genome and especially in the DLA region. Dogs that have suffered autoimmune disorders should not be used for breeding. Italian Greyhounds from the USA and Contin-ental Europe, together with other small sight-hound breeds, could also be used to increase genetic diversity in both populations. However, care should be taken to avoid introductions of polygenic or simple recessive genetic dis-orders that may be unique to one population or the other.