Deletion of 2.7 kb near HOXD3 in an Arabian horse with occipitoatlantoaxial malformation.
Abstract: In the horse, the term occipitoatlantoaxial malformation (OAAM) is used to describe a developmental defect in which the first cervical vertebra (atlas) resembles the base of the skull (occiput) and the second cervical vertebra (axis) resembles the atlas. Affected individuals demonstrate an abnormal posture and varying degrees of ataxia. The homeobox (HOX) gene cluster is involved in the development of both the axial and appendicular skeleton. Hoxd3-null mice demonstrate a strikingly similar phenotype to Arabian foals with OAAM. Whole-genome sequencing was performed in an OAAM-affected horse (OAAM1) and seven unaffected Arabian horses. Visual inspection of the raw reads within the region of HOXD3 identified a 2.7-kb deletion located 4.4 kb downstream of the end of HOXD4 and 8.2 kb upstream of the start of HOXD3. A genotyping assay revealed that both parents of OAAM1 were heterozygous for the deletion. Additional genotyping identified two of 162 heterozygote Arabians, and the deletion was not present in 371 horses of other breeds. Comparative genomics studies have revealed that this region is highly conserved across species and that the entire genomic region between Hoxd4 and Hoxd3 is transcribed in mice. Two additional Arabian foals diagnosed with OAAM (OAAM 2 and 3) were genotyped and did not have the 2.7-kb deletion. Closer examination of the phenotype in these cases revealed notable variation. OAAM3 also had facial malformations and a patent ductus arteriosus, and the actual malformation at the craniocervical junction differed. Genetic heterogeneity may exist across the HOXD locus in Arabian foals with OAAM.
© 2017 Stichting International Foundation for Animal Genetics.
Publication Date: 2017-01-23 PubMed ID: 28111759PubMed Central: PMC5441686DOI: 10.1111/age.12531Google Scholar: Lookup
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Summary
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The research investigates a genetic deletion linked to a developmental defect in Arabian horses called occipitoatlantoaxial malformation (OAAM). By sequencing the genome of an affected horse and comparing it to unaffected ones, the study locates a specific absence near the HOXD3 gene, highlighting possible genetic heterogeneity within the HOXD locus in Arabian horses with OAAM.
Understanding the Pathology
- Occipitoatlantoaxial malformation (OAAM) is a developmental defect observed in horses, especially Arabian horses. It is characterized by an abnormal reshaping of the first and second cervical vertebrae so they resemble the base of the skull.
- This anomaly leads to abnormal posture and varying levels of ataxia, or loss of control of body movements, in the affected horses.
About the Research
- Through whole-genome sequencing of an OAAM-affected horse (referred to as OAAM1) and seven unaffected Arabian horses, the researchers identified a deletion of 2.7 kilobases (kb) in the vicinity of the HOXD3 gene in the affected horse.
- This deletion’s location is approximately 4.4 kb downstream of the end of the HOXD4 gene and 8.2 kb upstream of the start of HOXD3.
- The researchers developed a genotyping assay that revealed the parents of OAAM1 were carriers of this deletion, each being heterozygous.
- Among other 162 Arabian horses studied, two were identified as heterozygotes for this deletion. Also, this deletion was not found in 371 horses from other breeds.
Implications of the Findings
- Comparative genomics studies showed that the specific region with this deletion is highly conserved across species and is transcribed (expressing genetic code into RNA) in mice, indicating its importance.
- Two additional Arabian foals with an OAAM diagnosis (OAAM 2 and 3) were genotyped but did not show the 2.7-kb deletion. This, coupled with variation in the manifestation of their respective OAAM conditions, signals the potential for genetic variation across the HOXD gene cluster in Arabian foals affected by OAAM.
- The study’s findings hint at the probability of different genes connected to the HOXD cluster that may contribute to the manifestation of OAAM in Arabian horses. Such genetic diversity within the HOXD locus could be key to understanding and eventually curing OAAM.
Cite This Article
APA
Bordbari MH, Penedo MCT, Aleman M, Valberg SJ, Mickelson J, Finno CJ.
(2017).
Deletion of 2.7 kb near HOXD3 in an Arabian horse with occipitoatlantoaxial malformation.
Anim Genet, 48(3), 287-294.
https://doi.org/10.1111/age.12531 Publication
Researcher Affiliations
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA.
- Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, 48824, USA.
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, 55108, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA.
MeSH Terms
- Animals
- Female
- Genes, Homeobox
- Genotype
- Homeodomain Proteins / genetics
- Horse Diseases / genetics
- Horses / genetics
- Male
- Sequence Analysis, DNA
- Sequence Deletion
Grant Funding
- K01 OD015134 / NIH HHS
- L40 TR001136 / NCATS NIH HHS
Conflict of Interest Statement
. The authors have no conflicts of interest to disclose.
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Citations
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