In other species: pig

Categories: Hearing / vestibular / ear phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600674 (trait) , 142992 (gene) , 612109 (trait)

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2020

Species-specific description: Hereditary underdevelopment of the ear

Mapping: Having genotyped 8 affected and 12 non-affected sheep each with the Illumina OvineSNP50® chip, Jawasreh et al. (2016) reported that "a single-locus analysis revealed a statistically significant association (P = 0.012, genome-wide) with a SNP at basepair 34 647 499 on OAR23. This marker is adjacent to the gene encoding transcription factor GATA-6, which has been shown to play a role in many developmental processes, including chondrogenesis. The lack of extended homozygosity in this region suggests a fairly ancient mutation, and the time of occurrence was estimated to be approximately 3000 years ago." Mastrangelo et al. (2018) obtained a strong signal on a different chromosome in the Valle del Belice breed: "A total of 40 individuals, 20 with microtia and 20 normal, were genotyped with the Illumina OvineSNP50 BeadChip. The comparison among the results from a genome-wide association study, Fisher's exact test and FST analysis revealed a single strong association signal: rs419889303 on chromosome 1, located within intron 3 of the CLRN1 gene. Our study suggests for the first time that this novel candidate gene is responsible for microtia in sheep." In the Altay breed, a GWAS by He et al. (2020) identified a region on chromosome OAR6. Klawatsch et al. (2023): "we performed genome-wide SNP genotyping and haplotype-based mapping, in a population of 340 individuals, to identify loci influencing ear length variation in ... sheep breeds from Slovenia, Croatia, Cyprus and Greece. Additionally, two previously described candidate variants were also genotyped ... . The mapping model without candidate variant genotypes revealed only one genome-wide significant signal, which was located next to HMX1 on OAR6. This region was previously described as being associated with ear length variation in the Altay and Awassi sheep breeds. The mapping model including the candidate duplication genotype near HMX1 as a fixed effect explained the phenotypic variance on OAR6 and revealed an additional genome-wide significant locus on OAR13 associated with ear length. Our results, combined with published evidence, suggest that a duplication in the evolutionarily conserved region near HMX1 is the major regulator of ear length in sheep breeds descended from a larger region from Central Asia, to the Middle East, Cyprus, Greece and to the Alps. This distribution suggests an ancient origin of the derived allele."

Molecular basis: Within the candidate region on chromosome OAR6, He et al. (2020) identified a 76-bp duplication in the HMX1 gene that was completely concordant with microtia in their sample of 129 Altay sheep, and is absent from 6 other breeds investigated.
Zhang et al. (2024) identified the same 76-bp duplication in Kazakh sheep with microtia and provided additioanl evidence for causality: "...luciferase assays confirmed that this duplication increased HMX1 gene expression, and duplication knock-in mice also exhibited shorter and narrower external ears compared to wild-type mice. Transcriptomic analysis further demonstrated that this duplication enhanced HMX1 gene expression in animal models."

Breeds: Altay Fat-Rumped, China (Sheep) (VBO_0015734), Awassi (Sheep) (VBO_0001308), Kazakh Fat-Rumped (Sheep) (VBO_0001466).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: