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Title: Genome-wide association identifies SLC2A9 and NLN gene regions as associated with entropion in domestic sheep

item Mousel, Michelle
item Reynolds, James
item White, Stephen

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/11/2015
Publication Date: 6/22/2015
Citation: Mousel, M.R., Reynolds, J.O., White, S.N. 2015. Genome-wide association identifies SLC2A9 and NLN gene regions as associated with entropion in domestic sheep PLoS One. 10(6):e0128909.

Interpretive Summary: Modern genetics can be used to improve the health and welfare of lambs. Improved lamb health and welfare will increase the efficiency of producing human foods. Thus, studies are underway to identify genes associated with health and fitness traits. This is the first report, in any species, to associate specific genes with entropion, an ailment in which the eyelid rolls inward causing hair and potentially eyelashes to rub the eye. Infections of the eye and blindness can occur if entropion is not corrected. Results of the study found more than one gene was associated with entropion. Specifically, solute carrier family 2 C 9 and neurolysin were associated with congenital entropion in sheep. This is the first time these genes have been implicated in eyelid development. This is the first step in developing a test for marker-assisted selection, and additional studies will need to be done in other sheep breeds to confirm these genes play a role in the development of entropion in sheep. Once validated, sheep producers can use this information to make significant improvements in the health of their lambs. In other mammalian species, including humans, this information may be used to identify differences in genes that are associated with entropion and improve the health of those species.

Technical Abstract: Background: Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component. We used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. Methodology/Principal Findings: A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 5.6%, with all breeds represented. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P=0.024) and near NLN (empirical P=0.026). Four additional genome-wide suggestive SNP (nominal P<1x10-5) were identified including markers in or near PIK3CB (P=2.22x10-6), KCNB1 (P=2.93x10-6), and MYO3B (P=5.74x10-6). Conclusions/Significance: This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. Functional hypotheses for how these genes may be involved with entropion were developed with information from other species. A hexose transporter, SLC2A9, has differential isoform expression on alternate surfaces of polarized cells, and it may have a role in eyelid development pathways. A regulator of neurotensin, NLN, may play a role in eyelid development through regulation of epidermal growth factor. These results represent the first genome-wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection.