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The nedd-8 activating enzyme gene underlies genetic resistance to infectious pancreatic necrosis virus in Atlantic salmon
Genomics ( IF 4.4 ) Pub Date : 2021-09-20 , DOI: 10.1016/j.ygeno.2021.09.012
Jon Pavelin 1 , Ye Hwa Jin 1 , Remi L Gratacap 1 , John B Taggart 2 , Alastair Hamilton 3 , David W Verner-Jeffreys 4 , Richard K Paley 4 , Carl-Johan Rubin 5 , Stephen C Bishop 1 , James E Bron 2 , Diego Robledo 1 , Ross D Houston 1
Affiliation  

Genetic resistance to infectious pancreatic necrosis virus (IPNV) in Atlantic salmon is a rare example of a trait where a single locus (QTL) explains almost all of the genetic variation. Genetic marker tests based on this QTL on salmon chromosome 26 have been widely applied in selective breeding to markedly reduce the incidence of the disease. In the current study, whole genome sequencing and functional annotation approaches were applied to characterise genes and variants in the QTL region. This was complemented by an analysis of differential expression between salmon fry of homozygous resistant and homozygous susceptible genotypes challenged with IPNV. These analyses pointed to the NEDD-8 activating enzyme 1 (nae1) gene as a putative functional candidate underlying the QTL effect. The role of nae1 in IPN resistance was further assessed via CRISPR-Cas9 knockout of the nae1 gene and chemical inhibition of the nae1 protein activity in Atlantic salmon cell lines, both of which resulted in highly significant reduction in productive IPNV replication. In contrast, CRISPR-Cas9 knockout of a candidate gene previously purported to be a cellular receptor for the virus (cdh1) did not have a major impact on productive IPNV replication. These results suggest that nae1 is the causative gene underlying the major QTL affecting resistance to IPNV in salmon, provide further evidence for the critical role of neddylation in host-pathogen interactions, and highlight the value in combining high-throughput genomics approaches with targeted genome editing to understand the genetic basis of disease resistance.



中文翻译:

nedd-8激活酶基因是大西洋鲑鱼对传染性胰腺坏死病毒的遗传抗性的基础

大西洋鲑鱼对传染性胰腺坏死病毒(IPNV)的遗传抗性是一个罕见的例子,单基因座(QTL)解释了几乎所有的遗传变异。基于鲑鱼26号染色体上的QTL的遗传标记测试已广泛应用于选育中,以显着降低该疾病的发病率。在当前的研究中,应用全基因组测序和功能注释方法来表征QTL区域的基因和变异。通过对受到 IPNV 攻击的纯合抗性基因型和纯合易感基因型的鲑鱼鱼苗之间的差异表达分析进行了补充。这些分析指出 NEDD-8 激活酶 1 ( nae1 ) 基因是 QTL 效应的推定功能候选基因。通过 CRISPR-Cas9 敲除大西洋鲑鱼细胞系中的nae 1 基因和化学抑制 nae1 蛋白活性,进一步评估了nae 1 在 IPN 抗性中的作用,这两种方法均导致有效 IPNV 复制的显着减少。相比之下,用 CRISPR-Cas9 敲除先前被认为是病毒细胞受体的候选基因 ( cdh 1),并没有对 IPNV 的高效复制产生重大影响。这些结果表明,nae 1是影响鲑鱼IPNV抗性的主要QTL的致病基因,为neddylation在宿主-病原体相互作用中的关键作用提供了进一步的证据,并强调了将高通量基因组学方法与目标基因组相结合的价值编辑以了解抗病性的遗传基础。

更新日期:2021-09-24
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