In other species: rabbit

Categories: Pigmentation phene

Links to MONDO diseases: No links.

Mendelian trait/disorder: unknown

Considered a defect: no

Inheritance: Deane-Coe et al. (2018): "The high proportion of blue-eyed heterozygotes in our analyses (53% of blue-eyed dogs) suggests that the duplication, if causal, is dominant in its phenotypic effect. However, the existence of 46 brown-eyed heterozygotes with similarly elevated Δ log R (P = 0.35 comparing blue and brown heterozygote distributions) suggests that one or more additional genetic factors may modify or mask the duplication’s effect on eye color (Fig 3; S8 Fig). This effect is not completely explained by an individual’s genotype at four previously characterized pigmentation genes (A, E, B, and K loci; S6 Table), although carriers of the duplication that also carry at least one copy of the dominant melanistic mask (Em) allele are significantly more likely to have brown eyes than duplication carriers without melanistic mask (P = 0.0018)."

Mapping: Via a GWAS conducted with "Embark’s custom high-density 214,661-marker platform" on 3,180 dogs comprising many breeds and mixed-breeds, and with binary phenotypic data on blue/brown eye colour gathered from owners by online survey, Deane-Coe et al. (2018) "detected two significant associations with blue eyes, one on chromosome 10 at PMEL17" (the merle locus - see OMIA OMIA 000211-9615) and "a novel association with blue eyes on chromosome 18 (P = 1.3x10-68) and used both sequence coverage and microarray probe intensity data to identify the putative causal variant: a 98.6-kb duplication directly upstream of the Homeobox gene ALX4, which plays an important role in mammalian eye development. This duplication is largely restricted to Siberian Huskies, is strongly associated with the blue-eyed phenotype (chi-square P = 5.2x10-290), and is highly, but not completely, penetrant."

Markers: Deane-Coe et al. (2018): "we discovered a haplotype containing a 98.6-kb duplication that is strongly predictive of blue eyes and heterochromia in dogs. While we cannot definitively rule out a different typed or untyped variant on this haplotype causing the trait, we feel that the duplication is a plausible causal candidate worthy of further functional investigation. . . . we have shown that this mutation is highly (but not completely) penetrant and most common in Siberian Huskies. The presence of the duplication explains at least 75% of blue-eyed cases in our discovery panel of customer dogs (81 / 108 blue-eyed dogs carried the associated haplotype and have elevated Δ log R values consistent with duplicated markers)."