Microphthalmia in Texel Sheep Is Associated with a Missense Mutation in the Paired-Like Homeodomain 3 (PITX3) Gene

Abstract

Microphthalmia in sheep is an autosomal recessive inherited congenital anomaly found within the Texel breed. It is characterized by extremely small or absent eyes and affected lambs are absolutely blind. For the first time, we use a genome-wide ovine SNP array for positional cloning of a Mendelian trait in sheep. Genotyping 23 cases and 23 controls using Illumina's OvineSNP50 BeadChip allowed us to localize the causative mutation for microphthalmia to a 2.4 Mb interval on sheep chromosome 22 by association and homozygosity mapping. The PITX3 gene is located within this interval and encodes a homeodomain-containing transcription factor involved in vertebrate lens formation. An abnormal development of the lens vesicle was shown to be the primary event in ovine microphthalmia. Therefore, we considered PITX3 a positional and functional candidate gene. An ovine BAC clone was sequenced, and after full-length cDNA cloning the PITX3 gene was annotated. Here we show that the ovine microphthalmia phenotype is perfectly associated with a missense mutation (c.338G>C, p.R113P) in the evolutionary conserved homeodomain of PITX3. Selection against this candidate causative mutation can now be used to eliminate microphthalmia from Texel sheep in production systems. Furthermore, the identification of a naturally occurring PITX3 mutation offers the opportunity to use the Texel as a genetically characterized large animal model for human microphthalmia.

Selection signatures in worldwide sheep populations

“…Further analysis revealed that this signature was due to the German Texel population haplotype diversity differing from the other Texel samples (results not shown). It turns out that the German Texel sample consisted of a case/control study for microphtalmia [7], although the case/control status information in this sample is not given in the Sheep HapMap dataset. The consequence of such a recruitment is to bias haplotype frequencies Table 3.…”

“…They identified 31 genome regions with extreme differentiation between breeds, which included candidate genes related to coat pigmentation, skeletal morphology, body size, growth, and reproduction. Further studies took advantage of the Sheep HapMap resource to detect genetic variants associated with pigmentation [5], fat deposition [6], or microphtalmia disease [7]. An other study [8] performed a genome scan for selection focused on American synthetic breeds, using an F ST approach similar to that in [4].…”

Congenital Abnormalities in Production Animals

“…The condition occurs as an autosomal recessive trait and has been linked to a region on chromosome 23 17 involving a missense mutation in the homeobox gene PITX3. 18 Such detailed work allows the condition to be used as a model for similar pathologic condition in man.…”

Genome-wide association and regional heritability mapping to identify loci underlying variation in nematode resistance and body weight in Scottish Blackface lambs

“…The sheep 50k SNP chip has already been demonstrated as providing the ability to map causal mutations for traits showing simple patterns of inheritance (Becker et al, 2010). However, in sheep, as well as in other species including humans, answers have not been so definitive for complex traits and GWA studies have generally failed to explain most of the known genetic variation influencing complex diseases (for example, Manolio et al, 2009;Kemper et al, 2011).…”