BACKGROUND Environmental variance (VE) is partly under genetic control and has recently been proposed as a measure of resilience. Unravelling the genetic background of the VE of complex traits could help to improve resilience of livestock and stabilize their production across farming systems. The objective of this study was to identify genes and functional mutations associated with variation in VE of litter size (LS) in rabbits. To achieve this, we combined the results of a genome-wide association study (GWAS) and a whole-genome sequencing (WGS) analysis using data from two divergently selected rabbit lines for high and low VE of LS. These lines differ in terms of biomarkers of immune response and mortality. Moreover, rabbits with a lower VE of LS were found to be more resilient to infections than animals with a higher VE of LS. RESULTS By using two GWAS approaches (single-marker regression and Bayesian multiple-marker regression), we identified four genomic regions associated with VE of LS, on chromosomes 3, 7, 10, and 14. We detected 38 genes in the associated genomic regions and, using WGS, we identified 129 variants in the splicing, UTR, and coding (missense and frameshift effects) regions of 16 of these 38 genes. These genes were related to the immune system, the development of sensory structures, and stress responses. All of these variants (except one) segregated in one of the rabbit lines and were absent (n = 91) or fixed in the other one (n = 37). The fixed variants were in the HDAC9, ITGB8, MIS18A, ENSOCUG00000021276 and URB1 genes. We also identified a 1-bp deletion in the 3'UTR region of the HUNK gene that was fixed in the low VE line and absent in the high VE line. CONCLUSIONS This is the first study that combines GWAS and WGS analyses to study the genetic basis of VE. The new candidate genes and functional mutations identified in this study suggest that the VE of LS is under the control of functions related to the immune system, stress response, and the nervous system. These findings could also explain differences in resilience between rabbits with homogeneous and heterogeneous VE of litter size.

中文翻译：

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鉴定与家兔产仔数环境变化有关的功能突变。

背景技术环境差异（VE）部分地处于遗传控制之下，并且最近被提出作为弹性的量度。弄清复杂性状的VE的遗传背景可以帮助提高牲畜的复原力并稳定其在整个农业系统中的生产。这项研究的目的是鉴定与家兔产仔数（LS）VE变化有关的基因和功能突变。为了实现这一目标，我们结合了全基因组关联研究（GWAS）和全基因组测序（WGS）分析的结果，使用了两种不同选择的LS高和低VE兔系的数据。这些系在免疫反应和死亡率的生物标志物方面有所不同。此外，发现LS VE较低的兔子比LS VE较高的动物对感染的抵抗力更高。结果通过使用两种GWAS方法（单标记回归和贝叶斯多标记回归），我们在3、7、10和14号染色体上鉴定了与LS VE相关的四个基因组区域。我们在相关的基因组区域中检测到38个基因使用WGS，我们在这38个基因中的16个基因的剪接，UTR和编码（缺失和移码效应）区域中鉴定出129个变体。这些基因与免疫系统，感觉结构的发展和应激反应有关。所有这些变体（一个除外）都隔离在一个兔子系中，不存在（n = 91），或者固定在另一个兔子系中（n = 37）。固定的变体位于HDAC9，ITGB8，MIS18A，ENSOCUG00000021276和URB1基因中。我们还确定了3'中的一个1 bp缺失 HUNK基因的UTR区域在低VE系中固定，而在高VE系中不存在。结论这是首次结合GWAS和WGS分析来研究VE的遗传基础的研究。在这项研究中鉴定出的新候选基因和功能突变表明，LS的VE受与免疫系统，应激反应和神经系统有关的功能的控制。这些发现还可以解释同窝大小的同种和异种VE兔子之间的弹性差异。