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An Autosomal Recessive Mutation in SCL24A4 Causing Enamel Hypoplasia in Samoyed and Its Relationship to Breed-Wide Genetic Diversity

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An Autosomal Recessive Mutation in SCL24A4 Causing Enamel Hypoplasia in Samoyed and Its Relationship to Breed-Wide Genetic Diversity

Niels C Pedersen et al. Canine Genet Epidemiol.

Abstract

Background: Pure breeding of dogs has led to over 700 heritable disorders, of which almost 300 are Mendelian in nature. Seventy percent of the characterized mutations have an autosomal recessive mode of inheritance, indicative of positive selection during bouts of inbreeding primarily for new desired conformational traits. Samoyed suffer from several common complex genetic disorders, but up to this time only two X-linked and one autosomal dominant disorder have been identified. Previous studies based on pedigrees and SNP arrays have concluded that Samoyed breeders have done a good job in maintaining genetic diversity and avoiding excessive inbreeding. This may explain why autosomal recessive disorders have not occurred to the extent observed in many other breeds. However, an enamel hypoplasia analogous to a form of autosomal recessive amelogenesis imperfecta (ARAI) in humans has been recently characterized in Samoyed, although the causative mutation appears to have existed for three or more decades. The rise of such a mutation indicates that bouts of inbreeding for desired conformational traits are still occurring despite an old and well-defined breed standard. Therefore, the present study has two objectives: 1) measure genetic diversity in the breed using DNA and short tandem repeats (STR), and 2) identify the exact mutation responsible for enamel hypoplasia in the breed, possible explanations for its recent spread, and the effect of eliminating the mutation on existing genetic diversity.

Results: The recent discovery of an autosomal recessive amelogenesis imperfecta (ARAI) in Samoyed provides an opportunity to study the mutation as well as genetic factors that favored its occurrence and subsequent spread. The first step in the study was to use 33 short tandem repeat (STR) loci on 25/38 autosomes and seven STRs across the dog leukocyte antigen (DLA) class I and II regions on CFA12 to determine the DNA-based genetic profile of 182 individuals from North America, Europe and Australia. Samoyed from the three continents constituted a single breed with only slight genetic differences. Breed-wide genetic diversity was low, most likely from a small founder population and subsequent artificial genetic bottlenecks. Two alleles at each autosome locus occurred in 70-95% of the dogs and 54% of alleles were homozygous. The number of DLA class I and II haplotypes was also low and three class I and two class II haplotypes occurred in 80-90% of individuals. Therefore, most Samoyed belong to two lines, with most dogs possessing a minority of existing genetic diversity and a minority of dogs containing a majority of diversity. Although contemporary Samoyed lack genetic diversity, the bulk of parents are as unrelated as possible with smaller subpopulations either more inbred or outbred than the total population. A familial disorder manifested by hypocalcification of enamel has been recently identified. A genome wide association study (GWAS) on seven affected and five unrelated healthy dogs pointed to a region of extended homozygosity on Canis familiaris autosome 8 (CFA8). The region contained a gene in the solute carrier 24 family (SCL24A4) that encodes a protein involved in potassium dependent sodium/calcium exchange and transport. Mutations in this gene were recently found to cause a similar type of enamel hypoplasia in people. Sequencing of this candidate gene revealed a 21 bp duplication in exon 17. A test for the duplication was in concordance with the disease phenotype. The exact incidence of affected dogs is unknown, but 12% of the 168 healthy dogs tested were heterozygous for the mutation. This population was biased toward close relatives, so a liberal estimate of the incidence of affected dogs in the breed would be around 3.6/1000. Theoretical calculations based on the comparison of the whole population with a population devoid of carriers indicated that eliminating the trait would not affect existing genetic diversity at this time.

Conclusions: The contemporary Samoyed, like many other breeds, has retained only a small portion of the genetic diversity that exists among all dogs. This limited genetic diversity along with positive genetic selection for desirable traits has led to at least three simple non-recessive genetic disorders and a low incidence of complex genetic traits such as autoimmune disease and hip dysplasia. Unlike many other pure breeds, the Samoyed has been spared the spate of deleterious autosomal recessive traits that have plagued many other pure breeds. However, ARAI due to a mutation in the SCL24A4 gene has apparently existed in the breed for several decades but is being increasingly diagnosed. The increase in diseased dogs is most likely due to a period of intensified positive selection for some desired conformational trait. A genetic test has been developed for identifying the mutation carriers which will enable the breeders to eliminate enamel hypoplasia in Samoyed by selective breeding and it appears that this mutation can be eliminated now without loss of genetic diversity.

Keywords: Canis familiaris; Familial enamel hypoplasia; Genetic diversity; SLC24A4; Samoyed; Short tandem repeats (STRs).

Conflict of interest statement

Ethics approval

Experiments were done with DNA samples that were placed on file by the owners. No institutional animal use and care committee approval was required. All saliva and blood samples were collected in accordance with all national ethics policies and with owner permission.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Robert Peary Sr in Greenland with some of the sledge dogs used in Greenland. Source: Willy Ley The Poles New York, New York: Time Incorporated, 1962. These dogs were of the Samoyede type. However, large heavy coated dogs of varied appearance were also used. Ancestors of such dogs (Samoyede or Samoyed) became more known for their gentle demeanor around people, alert and active personalities, striking thick double coats and noteworthy solid or patterned white, biscuit or cream colors than for pulling sledges
Fig. 2
Fig. 2
PCoA plot of 182 Samoyed from North America (116 US +28 Canada), Europe (n = 32) and Australia (n = 6) based on alleles and allele frequencies at 33 genomic STR loci
Fig. 3
Fig. 3
Internal relatedness (IR) scores for 182 Samoyeds from various regions of the world (solid line). The IR scores were also adjusted (dashed line) to reflect the amount of genetic diversity present in village dogs of the world that is still retained in contemporary Samoyed. The two graphs would be superimposed if Samoyed and village dogs were totally related and completely separate if there was no genetic relationship. The light-shaded area reflects the degree of genetic relatedness of Samoyed to village dogs based on allele sharing at the 33 autosomal STR loci (43%), while thee dark shaded area is a measure of non-relatedness (57%) or potential genetic diversity lost during breed evolution
Fig. 4
Fig. 4
Samoyed with typical lesions of heritable enamel hypoplasia. The teeth are noticeably discolored; smaller, blunted, and further apart; tooth surfaces are irregular. This dog has received regular dental care and therefore dental tarter is largely absent and the gums remain in good health
Fig. 5
Fig. 5
Samoyed with enamel hypoplasia and severe discoloration of the teeth, excessive tarter accumulation, and swollen gums due to gingival disease
Fig. 6
Fig. 6
(Upper) Manhattan plot of GWAS using seven Samoyed with enamel hypoplasia five unrelated healthy controls showing a genome-wide association on CFA 8. (Lower) Allele frequency in the 12-Mb region of CFA 8 for enamel hypoplasia (solid diamond) and control (open circle) and the location of a known candidate SLC24A4 for a form of autosomal recessive amelogenesis imperfecta in humans
Fig. 7
Fig. 7
Coding sequence of SCL24A4 from a dog suffering from enamel hypoplasia. There are two synonymous nucleotide changes (indicated in parentheses), an asynonymous change (C to T) in exon 12 changing amino acid from proline to leucine, and a 21 bp insertion in exon 17
Fig. 8
Fig. 8
SLC24A4 chromatograms of ARAI affected (SM01) and its healthy sibling (SM03) and his Dam (SM02). There is a 21 bp duplication in exon 17 of SM01 that is not present his healthy sibling. SM01 also has a C to T SNP causing amino acid change in exon 12 that does not occur in his sibling. The Dam is heterozygous for both sites
Fig. 9
Fig. 9
PCoA plot of 148 normal, 11 ARAI affected, and 20 ARAI carriers based on data from the 33 genomic STRs
Fig. 10
Fig. 10
ARAI in a six-year-old girl caused by a missense mutation in SLC24A4. Reprinted with permission from: Herzog CR et al. Hypomaturation amelogenesis imperfecta caused by a novel SLC24A4 mutation. Photographs from: Oral Surg Oral Med Oral Pathol Oral Radiol. 2015 Feb;119(2):e77-e81

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