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Abstract：
BACKGROUND: The basis for familial alcohol use disorder (AUD) remains an enigma due to various biological and societal confounds. The present study used three of the most adopted and documented rat models, combining the alcohol-preferring/non-alcohol-preferring (P/NP) lines and high alcohol-drinking/low alcohol-drinking (HAD/LAD) replicated lines, of AUD as examined through the lens of whole genomic analyses.
METHODS: We used complete genome sequencing of the P/NP lines and previously published sequences of the HAD/LAD replicates to enhance the discovery of variants associated with AUD and to remove confounding with genetic background and random genetic drift. Specifically, we used high-order statistical methods to search for genetic variants whose frequency changes in whole sets of gene ontologies corresponded with phenotypic changes in the direction of selection, that is, ethanol-drinking preference.
RESULTS: Our first finding was that in addition to variants causing translational changes, the principal genetic changes associated with drinking predisposition were silent mutations and mutations in the 3\' untranslated regions (3\'UTR) of genes. Neither of these types of mutations alters the amino acid sequence of the translated protein but they influence both the rate and conformation of gene transcription, including its stability and posttranslational events that alter gene efficacy. This finding argues for refocusing human genomic studies on changes in gene efficacy. Among the key ontologies identified were the central genes associated with the Na+ voltage-gated channels of neurons and glia (including the Scn1a, Scn2a, Scn2b, Scn3a, Scn7a, and Scn9a subtypes) and excitatory glutamatergic secretion (including Grm2 and Myo6), both of which are essential in neuroplasticity. In addition, we identified \"Nociception or Sensory Perception of Pain,\" which contained variants in nociception (Arrb1, Ccl3, Ephb1) and enlist sodium (Scn1a, Scn2a, Scn2b, Scn3a, Scn7a), pain activation (Scn9a), and potassium channel (Kcna1) genes.
CONCLUSIONS: The multi-model analyses used herein reduced the confounding effects of random drift and the \"founders\" genetic background. The most differentiated bidirectionally selected genes across all three animal models were Scn9a, Scn1a, and Kcna, all of which are annotated in the nociception ontology. The complexity of neuroplasticity and nociception adds strength to the hypothesis that neuroplasticity and pain (physical or psychological) are prominent phenotypes genetically linked to the development of AUD.
METHODS: We used complete genome sequencing of the P/NP lines and previously published sequences of the HAD/LAD replicates to enhance the discovery of variants associated with AUD and to remove confounding with genetic background and random genetic drift. Specifically, we used high-order statistical methods to search for genetic variants whose frequency changes in whole sets of gene ontologies corresponded with phenotypic changes in the direction of selection, that is, ethanol-drinking preference.
RESULTS: Our first finding was that in addition to variants causing translational changes, the principal genetic changes associated with drinking predisposition were silent mutations and mutations in the 3\' untranslated regions (3\'UTR) of genes. Neither of these types of mutations alters the amino acid sequence of the translated protein but they influence both the rate and conformation of gene transcription, including its stability and posttranslational events that alter gene efficacy. This finding argues for refocusing human genomic studies on changes in gene efficacy. Among the key ontologies identified were the central genes associated with the Na+ voltage-gated channels of neurons and glia (including the Scn1a, Scn2a, Scn2b, Scn3a, Scn7a, and Scn9a subtypes) and excitatory glutamatergic secretion (including Grm2 and Myo6), both of which are essential in neuroplasticity. In addition, we identified \"Nociception or Sensory Perception of Pain,\" which contained variants in nociception (Arrb1, Ccl3, Ephb1) and enlist sodium (Scn1a, Scn2a, Scn2b, Scn3a, Scn7a), pain activation (Scn9a), and potassium channel (Kcna1) genes.
CONCLUSIONS: The multi-model analyses used herein reduced the confounding effects of random drift and the \"founders\" genetic background. The most differentiated bidirectionally selected genes across all three animal models were Scn9a, Scn1a, and Kcna, all of which are annotated in the nociception ontology. The complexity of neuroplasticity and nociception adds strength to the hypothesis that neuroplasticity and pain (physical or psychological) are prominent phenotypes genetically linked to the development of AUD.
摘要：
背景：由于各种生物和社会困惑，家族性酒精使用障碍（AUD）的基础仍然是一个谜。本研究使用了三种最被采用和记录最多的大鼠模型，结合酒精偏好/非酒精偏好（P/NP）系列和高饮酒/低饮酒（HAD/LAD）复制系列，通过全基因组分析的镜头检查的AUD。
方法：我们使用了P/NP系的完整基因组测序和先前发表的HAD/LAD重复序列，以增强与AUD相关的变异的发现，并消除与遗传背景和随机遗传漂移的混淆。具体来说,我们使用高阶统计方法来搜索遗传变异，其在整个基因本体中的频率变化与选择方向的表型变化相对应，也就是说,乙醇饮用偏好。
结果：我们的第一个发现是，除了导致翻译变化的变异，与饮酒倾向相关的主要遗传变化是沉默突变和基因3'非翻译区(3'UTR)突变.这些类型的突变都不会改变翻译蛋白的氨基酸序列，但它们会影响基因转录的速率和构象。包括其稳定性和改变基因功效的翻译后事件。这一发现表明人类基因组研究的重点是基因功效的变化。确定的关键本体是与神经元和神经胶质的Na电压门控通道相关的中心基因（包括Scn1a，Scn2a,Scn2b,Scn3a,Scn7a,和Scn9a亚型）和兴奋性谷氨酸能分泌（包括Grm2和Myo6），这两者在神经可塑性中都是必不可少的。此外,我们确定了疼痛的伤害感受或感觉感知，\“在伤害感受中包含变体（Arrb1，Ccl3，Ephb1）和enlist钠（Scn1a，Scn2a,Scn2b,Scn3a,Scn7a),疼痛激活（Scn9a），和钾通道（Kcna1）基因。
结论：本文使用的多模型分析减少了随机漂移和“创始人”遗传背景的混杂效应。在所有三种动物模型中，最分化的双向选择基因是Scn9a，Scn1a,和Kcna,所有这些都在伤害感受本体中进行了注释。神经可塑性和伤害感受的复杂性增加了神经可塑性和疼痛（生理或心理）是与AUD发展遗传相关的突出表型的假设的强度。
方法：我们使用了P/NP系的完整基因组测序和先前发表的HAD/LAD重复序列，以增强与AUD相关的变异的发现，并消除与遗传背景和随机遗传漂移的混淆。具体来说,我们使用高阶统计方法来搜索遗传变异，其在整个基因本体中的频率变化与选择方向的表型变化相对应，也就是说,乙醇饮用偏好。
结果：我们的第一个发现是，除了导致翻译变化的变异，与饮酒倾向相关的主要遗传变化是沉默突变和基因3'非翻译区(3'UTR)突变.这些类型的突变都不会改变翻译蛋白的氨基酸序列，但它们会影响基因转录的速率和构象。包括其稳定性和改变基因功效的翻译后事件。这一发现表明人类基因组研究的重点是基因功效的变化。确定的关键本体是与神经元和神经胶质的Na电压门控通道相关的中心基因（包括Scn1a，Scn2a,Scn2b,Scn3a,Scn7a,和Scn9a亚型）和兴奋性谷氨酸能分泌（包括Grm2和Myo6），这两者在神经可塑性中都是必不可少的。此外,我们确定了疼痛的伤害感受或感觉感知，\“在伤害感受中包含变体（Arrb1，Ccl3，Ephb1）和enlist钠（Scn1a，Scn2a,Scn2b,Scn3a,Scn7a),疼痛激活（Scn9a），和钾通道（Kcna1）基因。
结论：本文使用的多模型分析减少了随机漂移和“创始人”遗传背景的混杂效应。在所有三种动物模型中，最分化的双向选择基因是Scn9a，Scn1a,和Kcna,所有这些都在伤害感受本体中进行了注释。神经可塑性和伤害感受的复杂性增加了神经可塑性和疼痛（生理或心理）是与AUD发展遗传相关的突出表型的假设的强度。
