High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model.
High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model.
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DOI：
10.1371/journal.pgen.1006178
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发表时间：
2016-08
期刊：
影响因子：
4.5
通讯作者：
Muir WM
中科院分区：
文献类型：
--
作者：
Lo CL;Lossie AC;Liang T;Liu Y;Xuei X;Lumeng L;Zhou FC;Muir WM
关于先天与后天对人类酒精中毒（酒精使用障碍）的影响的调查尚未对潜在的基因组病因提供明确的观点。为了解决这个问题，我们对一个复制的动物模型系统进行了测序，该系统根据酒精偏好（AP）进行双向选择。该模型特别适合于以高重现性和分辨率绘制遗传效应。大鼠品系的起源（8向杂交）导致具有相应高水平分辨率的小单倍型块（HB）。我们对40个样本（每个重复10个）的DNA进行测序，以确定等位基因频率和HB。我们实现了每条线和重复约46倍的覆盖率。根据基因和区域对品系之间、重复之间的基因组结构的过度分化（称为选择特征（SS））进行分类。我们在930个与AP相关的基因中鉴定了SS。大多数（50%）的SS局限于单基因区域，其中最大数量的启动子（284）和内含子区域（169），最少的外显子（4），这表明AP的差异主要是由于调节区域的改变。我们证实了先前鉴定的基因，并发现了许多与AP相关的新基因。在这些新发现的基因中，有几个显示出参与突触记忆和奖励行为的神经元功能，例如离子通道（Kcnf1，Kcnn3，Scn5a），兴奋性受体（Grin2a，Gria3，Grip 1），神经递质（Pomc）和突触（Snap 29）。这项研究不仅揭示了AP的多基因结构，而且强调了调控元件的重要性，与其他复杂性状一致。酒精使用障碍（AUD）或酒精中毒在人类痛苦方面提取了巨大的社会成本。了解遗传基础对于理解，治疗和预防这种疾病至关重要，但在人类中很难，因为选择受到先天和后天的影响。为了发现其遗传基础，我们使用了一种动物模型系统，该系统通过随机化、研究重复、长期趋异选择和受控环境来控制遗传和非遗传因素。我们对强迫性过度饮酒或完全戒酒的品种进行了全基因组测序。我们发现了一些基因和神经通路的一致性改变，这些基因和神经通路以前与酗酒无关。这些结果加强了我们对酒精中毒遗传基础的理解，并揭示了潜在的遗传和神经学治疗方法。
Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon's (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits. Alcohol Used Disorder (AUD) or Alcoholism extracts a great societal cost in terms of human suffering. Understanding the genetic basis is critical to comprehend, treat and prevent this disease, but difficult in humans, as choice is influenced by nature and nurture. To discover its genetic basis, we used an animal model system that controlled for genetic and non-genetic factors through randomization, study replication, long-term divergent selection, and a controlled environment. We conducted whole genome sequencing in breeds that were either compulsive excessive drinkers or completely abstinent. We discovered consistent alterations in several genes and neurological pathways previously unassociated with alcoholism. These results strengthened our understanding of the genetic basis of alcoholism and revealed potential genetic- and neurological-based treatments.