Background

Analysing genomes of animal model organisms is widely used for understanding the genetic basis of complex traits and diseases, such as obesity, for which only a few mouse models exist, however, without their lean counterparts.

Objective

To analyse genetic differences in the unique mouse models of polygenic obesity (Fat line) and leanness (Lean line) originating from the same base population and established by divergent selection over more than 60 generations.

Methods

Genetic variability was analysed using WGS. Variants were identified with GATK and annotated with Ensembl VEP. g.Profiler, WebGestalt, and KEGG were used for GO and pathway enrichment analysis. miRNA seed regions were obtained with miRPathDB 2.0, LncRRIsearch was used to predict targets of identified lncRNAs, and genes influencing adipose tissue amount were searched using the IMPC database.

Results

WGS analysis revealed 6.3 million SNPs, 1.3 million were new. Thousands of potentially impactful SNPs were identified, including within 24 genes related to adipose tissue amount. SNP density was highest in pseudogenes and regulatory RNAs. The Lean line carries SNP rs248726381 in the seed region of mmu-miR-3086-3p, which may affect fatty acid metabolism. KEGG analysis showed deleterious missense variants in immune response and diabetes genes, with food perception pathways being most enriched. Gene prioritisation considering SNP GERP scores, variant consequences, and allele comparison with other mouse lines identified seven novel obesity candidate genes: 4930441H08Rik, Aff3, Fam237b, Gm36633, Pced1a, Tecrl, and Zfp536.

Conclusion

WGS revealed many genetic differences between the lines that accumulated over the selection period, including variants with potential negative impacts on gene function. Given the increasing availability of mouse strains and genetic polymorphism catalogues, the study is a valuable resource for researchers to study obesity.

中文翻译：

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对不同肥胖（FLI）和瘦瘦（FHI）选择的小鼠品系进行全基因组测序，揭示了几种作为新型肥胖基因候选的遗传变异

背景

分析动物模型生物体的基因组被广泛用于了解复杂性状和疾病的遗传基础，例如肥胖症，然而，只有少数小鼠模型存在，但没有相应的瘦模型。

客观的

分析源自相同基础群体并通过 60 多代的不同选择建立的独特多基因肥胖（Fat 系）和瘦（Lean 系）小鼠模型的遗传差异。

方法

使用全基因组测序（WGS）分析遗传变异性。使用 GATK 识别变体并使用 Ensembl VEP 进行注释。 g.Profiler、WebGestalt和KEGG用于GO和通路富集分析。使用miRPathDB 2.0获得miRNA种子区域，使用LncRRIsearch预测已识别lncRNA的靶点，并使用IMPC数据库搜索影响脂肪组织量的基因。

结果

WGS 分析显示 630 万个 SNP，其中 130 万个是新的。鉴定出数千个具有潜在影响的 SNP，其中包括与脂肪组织量相关的 24 个基因。假基因和调节 RNA 中的 SNP 密度最高。 Lean系在mmu-miR-3086-3p的种子区域携带SNP rs248726381 ，这可能影响脂肪酸代谢。 KEGG 分析显示免疫反应和糖尿病基因中存在有害的错义变异，其中食物感知途径最为丰富。考虑到 SNP GERP 评分、变异后果以及与其他小鼠品系的等位基因比较，基因优先级确定了七个新的肥胖候选基因：4930441H08Rik、Aff3、Fam237b、Gm36633、Pced1a、Tecrl和Zfp536。

结论

全基因组测序揭示了在选择期间积累的品系之间的许多遗传差异，包括对基因功能具有潜在负面影响的变异。鉴于小鼠品系和遗传多态性目录的可用性不断增加，该研究对于研究肥胖症的研究人员来说是宝贵的资源。