A high-resolution map of segmental DNA copy number variation in the mouse genome.
A high-resolution map of segmental DNA copy number variation in the mouse genome.
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DOI：
10.1371/journal.pgen.0030003
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发表时间：
2007-01-05
期刊：
影响因子：
4.5
通讯作者：
Ley TJ
中科院分区：
文献类型：
--
作者：
Graubert TA;Cahan P;Edwin D;Selzer RR;Richmond TA;Eis PS;Shannon WD;Li X;McLeod HL;Cheverud JM;Ley TJ
亚微观（小于2mb）片段DNA拷贝数变化是最近认识到的个体之间遗传变异的来源。拷贝数变异（CNVs）的生物学后果在很大程度上是不确定的。在某些情况下，引起基因剂量效应的CNVs与表型变异有关。在包括小鼠和人类在内的多种物种中都发现了CNVs。已发表的小鼠研究受到分辨率和品系选择的限制。我们选择研究21个特征良好的近交小鼠品系，这些品系是国际上测量、编目和传播表型数据的重点。我们使用长寡聚体阵列进行比较基因组杂交来表征这些菌株的CNVs。该技术比以前的方法提高了CNV检测的分辨率超过一个数量级。cnv的大小范围从21到2,002 kb。通过CNV谱聚类菌株概括了这些菌株已知祖先的各个方面。大多数cnv（77.5%）包含注释基因，许多（47.5%）与先前在小鼠基因组中定位的片段重复共定位。我们证明这种技术可以识别与已知多态性性状相关的拷贝数差异。以前未表征的菌株的表型可以根据它们在这些位点的拷贝数来预测。小鼠基因组中CNVs的注释结合基于序列的分析提供了一个重要的资源，将有助于定义复杂性状的遗传基础。遗传学和基因组学的一个主要目标是了解个体之间的遗传差异（基因型）如何转化为疾病易感性、行为和许多其他生物体水平特征（表型）的差异。虽然遗传变异的大小范围从单个碱基到整个染色体，但历史上，只有这个光谱的极端末端被探索过。DNA拷贝数变异（CNVs）介于这两个极端之间，大小从数百个碱基到数百万个碱基不等。最近微阵列技术在人类遗传变异检测中的应用使人们认识到CNVs是普遍存在的。事实上，粗略的估计表明，CNVs和小规模变异可能构成总基因组DNA的相似比例。在这篇报告中，作者描述了21个近交系小鼠基因组中的80个CNVs。小鼠CNVs的鉴定和表征非常重要，因为小鼠近交系是探索生物医学遗传学最广泛使用的模型系统。这些CNVs位于另一类基因组特征，片段复制附近，比偶然预期的更频繁，这支持了CNVs和片段复制之间存在因果关系的假设。重要的是，许多CNVs包含已知基因，因此可能是菌株之间基因表达和表型变异的基础。
Submicroscopic (less than 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined. In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation. CNVs have been detected in diverse species, including mice and humans. Published studies in mice have been limited by resolution and strain selection. We chose to study 21 well-characterized inbred mouse strains that are the focus of an international effort to measure, catalog, and disseminate phenotype data. We performed comparative genomic hybridization using long oligomer arrays to characterize CNVs in these strains. This technique increased the resolution of CNV detection by more than an order of magnitude over previous methodologies. The CNVs range in size from 21 to 2,002 kb. Clustering strains by CNV profile recapitulates aspects of the known ancestry of these strains. Most of the CNVs (77.5%) contain annotated genes, and many (47.5%) colocalize with previously mapped segmental duplications in the mouse genome. We demonstrate that this technique can identify copy number differences associated with known polymorphic traits. The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci. Annotation of CNVs in the mouse genome combined with sequence-based analysis provides an important resource that will help define the genetic basis of complex traits. A major goal of genetics and genomics is to understand how genetic differences between individuals (genotypes) translate into variation in disease susceptibility, behavior, and many other organism-level characteristics (phenotypes). While the sizes of genetic variants range from a single base to whole chromosomes, historically, only the extreme ends of this spectrum have been explored. DNA copy number variants (CNVs) lie between these two extremes, ranging in size from hundreds to millions of bases. The recent application of microarray technology to detect genetic variation in humans has led to the realization that CNVs are common. In fact, rough estimates indicate that CNVs and small-scale variants may constitute similar proportions of total genomic DNA. In this report, the authors characterize 80 CNVs across the genomes of 21 inbred strains of mice. The identification and characterization of mouse CNVs are important because inbred strains of mice are the most widely used model system to explore biomedical genetics. These CNVs are located near another class of genomic features, segmental duplications, more often than would be expected by chance, which supports the hypothesis that CNVs and segmental duplications are causally linked. Importantly, many of the CNVs contain known genes and thus may underlie both gene expression and phenotypic variation between strains.
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