Genome-wide analysis reveals a complex pattern of genomic imprinting in mice.
Genome-wide analysis reveals a complex pattern of genomic imprinting in mice.
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DOI：
10.1371/journal.pgen.1000091
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发表时间：
2008-06-06
期刊：
影响因子：
4.5
通讯作者：
Hager R
中科院分区：
文献类型：
--
作者：
Wolf JB;Cheverud JM;Roseman C;Hager R
由基因组印记引起的来源于父母的基因表达在调节从发育过程到认知能力和相关疾病的复杂性状中起着重要作用。然而，虽然基因打靶技术已经允许识别的印记位点，很少有人知道的印记的贡献，在复杂的性状的数量变化。此外，大多数研究都假设了一种简单的印记模式，导致父亲或母亲的基因表达;然而，也存在更复杂的影响模式。因此，基因组中不同印记模式的分布和数量在很大程度上仍未被探索。我们使用一种新的三代设计，对影响小鼠体重和生长的印记数量性状基因座（iQTL）进行全基因组扫描，以解决这些未解决的问题。我们确定了10个iQTL，显示更复杂和多样化的影响模式比以前假设的，包括四个位点的影响相似的callipyge突变在绵羊中发现。三个基因座显示了一种新的表型模式，我们称之为双极显性，其中两个杂合子彼此不同，而两个纯合子彼此相同。我们的研究进一步检测到一个父系表达的iQTL在染色体7上的一个区域包含一个已知的印记集群与许多父系表达的基因。令人惊讶的是，iQTL的影响主要限于断奶后表达的性状。我们的研究结果表明，在一个位点上的印记等位基因的数量效应取决于它的起源和等位基因的父母与它配对。我们的研究结果还表明，一个基因座的印记模式可以是可变的个体发育的时间，并在目前的观点相反，可能往往是在生命的后期阶段更强。对于某些基因，个体只表达他们从母亲（"母系表达"基因）或父亲（"父系表达"基因）继承的基因拷贝。这种"起源依赖于亲本"的基因表达模式被称为基因组印记，并已被证明在调节从发育过程到认知能力和相关疾病的各种性状中发挥重要作用。虽然各种分子技术已经允许许多印记基因的鉴定，很少有人知道的印记的贡献，在连续变化的性状，如身体大小的个体之间看到的变化。在这里，我们通过使用全基因组分析来解决这个问题，目的是找到基因组中显示印记对小鼠体重和生长的影响的区域。我们确定了10个基因座，显示复杂和多样的模式的影响，包括四个基因座的影响类似于不寻常的callipyge突变中发现的绵羊和三个，显示一个新的表型模式，我们称之为双极优势。令人惊讶的是，大多数印记的影响是最强的断奶后期间，许多人表现出转移的模式在个体发育的时间印记。
Parent-of-origin–dependent gene expression resulting from genomic imprinting plays an important role in modulating complex traits ranging from developmental processes to cognitive abilities and associated disorders. However, while gene-targeting techniques have allowed for the identification of imprinted loci, very little is known about the contribution of imprinting to quantitative variation in complex traits. Most studies, furthermore, assume a simple pattern of imprinting, resulting in either paternal or maternal gene expression; yet, more complex patterns of effects also exist. As a result, the distribution and number of different imprinting patterns across the genome remain largely unexplored. We address these unresolved issues using a genome-wide scan for imprinted quantitative trait loci (iQTL) affecting body weight and growth in mice using a novel three-generation design. We identified ten iQTL that display much more complex and diverse effect patterns than previously assumed, including four loci with effects similar to the callipyge mutation found in sheep. Three loci display a new phenotypic pattern that we refer to as bipolar dominance, where the two heterozygotes are different from each other while the two homozygotes are identical to each other. Our study furthermore detected a paternally expressed iQTL on Chromosome 7 in a region containing a known imprinting cluster with many paternally expressed genes. Surprisingly, the effects of the iQTL were mostly restricted to traits expressed after weaning. Our results imply that the quantitative effects of an imprinted allele at a locus depend both on its parent of origin and the allele it is paired with. Our findings also show that the imprinting pattern of a locus can be variable over ontogenetic time and, in contrast to current views, may often be stronger at later stages in life. For certain genes, individuals express only the copy of the gene they inherit from either their mother (“maternally expressed” genes) or their father (“paternally expressed” genes). This “parent-of-origin–dependent” pattern of gene expression is known as genomic imprinting and has been shown to play an important role in modulating a variety of traits ranging from developmental processes to cognitive abilities and associated disorders. While various molecular techniques have allowed for the identification of many imprinted genes, very little is known about the contribution of imprinting to variation seen among individuals in continuously varying traits such as body size. Here we address this issue by using a genome-wide analysis aimed at finding regions of the genome that show an effect of imprinting on body weight and growth in mice. We identified ten loci that displayed complex and diverse patterns of effect, including four loci with effects similar to the unusual callipyge mutation found in sheep and three that displayed a new phenotypic pattern that we refer to as bipolar dominance. Surprisingly, most imprinting effects were strongest during the post-weaning period, and many showed shifts in the pattern of imprinting over ontogenetic time.
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