A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs
A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs
复制标题
DOI：
10.1186/s12863-020-00911-w
复制
发表时间：
2020-09-07
期刊：
影响因子：
2.9
通讯作者：
Mellersh, Cathryn S.
中科院分区：
文献类型：
--
作者：
Hitti-Malin, Rebekkah J.;Burmeister, Louise M.;Mellersh, Cathryn S.
研究背景犬进行性视网膜萎缩是一组遗传性视网膜变性，其特征是视网膜感光细胞耗竭，最终导致失明。拉萨Apso（LA）犬的PRA以前没有临床特征或文献描述，但建议英国的主人每年通过英国兽医协会/养犬俱乐部/国际牧羊犬协会（BVA/KC/ISDS）眼科计划以及其他国家正在实施的类似计划对他们的狗进行检查。在排除了25个先前报道的LA PRA受影响的犬的视网膜突变后，我们试图确定该品种PRA的遗传原因。结果对3例PRA阳性LA和3例无PRA体征LA的全外显子组测序数据进行分析，未发现任何外显子或剪接位点变异，表明致病变异为非外显子变异。我们随后进行了全基因组关联研究（GWAS），在犬33号染色体上发现了一个1.3 Mb的疾病相关区域，随后进行了全基因组测序分析，发现IMPG 2基因上游有一个长的散置元件-1（LINE-1）插入。IMPG 2以前与人类视网膜疾病有关;然而，直到现在还没有犬PRA与该基因相关。这种PRA相关变体的鉴定使得能够开发针对该品种中这种形式的PRA的DNA测试（这里称为PRA 4），以将其与其他品种中描述的其他形式的PRA区分开来。该测试已用于确定超过900只LA犬的基因型。使用基因分型犬的大队列来估计UK LA人群中等位基因频率在0.07-0.1之间。结论：通过GWAS的使用和随后的PRA测序，我们已经确定了视网膜候选基因IMPG 2中的LINE-1插入，该基因与LA犬的一种PRA相关。在123个品种的447只狗中验证了该变体，确定其为LA狗所独有。我们设想，随着时间的推移，开发的DNA测试将为育种者提供机会，以避免生产受这种形式的PRA影响的狗。
Background Canine progressive retinal atrophies are a group of hereditary retinal degenerations in dogs characterised by depletion of photoreceptor cells in the retina, which ultimately leads to blindness. PRA in the Lhasa Apso (LA) dog has not previously been clinically characterised or described in the literature, but owners in the UK are advised to have their dog examined through the British Veterinary Association/ Kennel Club/ International Sheep Dog Society (BVA/KC/ISDS) eye scheme annually, and similar schemes that are in operation in other countries. After the exclusion of 25 previously reported canine retinal mutations in LA PRA-affected dogs, we sought to identify the genetic cause of PRA in this breed. Results Analysis of whole-exome sequencing data of three PRA-affected LA and three LA without signs of PRA did not identify any exonic or splice site variants, suggesting the causal variant was non-exonic. We subsequently undertook a genome-wide association study (GWAS), which identified a 1.3 Mb disease-associated region on canine chromosome 33, followed by whole-genome sequencing analysis that revealed a long interspersed element-1 (LINE-1) insertion upstream of theIMPG2gene.IMPG2has previously been implicated in human retinal disease; however, until now no canine PRAs have been associated with this gene. The identification of this PRA-associated variant has enabled the development of a DNA test for this form of PRA in the breed, here termed PRA4 to distinguish it from other forms of PRA described in other breeds. This test has been used to determine the genotypes of over 900 LA dogs. A large cohort of genotyped dogs was used to estimate the allele frequency as between 0.07-0.1 in the UK LA population. Conclusions Through the use of GWAS and subsequent sequencing of a PRA case, we have identified a LINE-1 insertion in the retinal candidate geneIMPG2that is associated with a form of PRA in the LA dog. Validation of this variant in 447 dogs of 123 breeds determined it was private to LA dogs. We envisage that, over time, the developed DNA test will offer breeders the opportunity to avoid producing dogs affected with this form of PRA.