Deletion of ultraconserved elements yields viable mice.
Deletion of ultraconserved elements yields viable mice.
复制标题
DOI：
10.1371/journal.pbio.0050234
复制
发表时间：
2007-09
期刊：
影响因子：
9.8
通讯作者：
Rubin EM
中科院分区：
文献类型：
--
作者：
Ahituv N;Zhu Y;Visel A;Holt A;Afzal V;Pennacchio LA;Rubin EM
由于基本的功能特性，超冷冻元件被认为可以在人类、小鼠和大鼠基因组之间保持扩展的完美序列同一性。为了研究这些元件在体内的必要性，我们从小鼠基因组中移除了四个非编码的超服务元件(长度从222到731个碱基对)。为了最大限度地增加观察表型的可能性，我们选择删除在小鼠转基因试验中作为增强剂的元件，以及当在小鼠中完全失活时以及当它们的表达因其他基因组修改而改变时，靠近表现出明显表型的基因的元件。值得注意的是，所有四个缺乏这些超冷冻元素的小鼠的结果系都是活的和可育的，当分析包括生长、寿命、病理和新陈代谢在内的各种表型时，都没有发现任何关键的异常。此外，在老鼠身上观察到的异常情况下，更有针对性的筛查也未能揭示显著的异常情况。在这些异常情况下，与被调查元素接近的基因发生了变化。这些结果虽然不包括缺失序列的所有可能的表型影响，但表明极端序列限制并不一定反映生存所需的关键功能。人们普遍认为，人类基因组中进化上最保守的DNA序列之所以被保存下来，是因为它们具有重要的功能，因此它们的移除将对生物体产生毁灭性的影响。为了确定这一点，我们从小鼠基因组中删除了四个超冷冻元件-人类、小鼠和大鼠之间100%相同的200个碱基对或更长的序列。令我们惊讶的是，我们发现缺乏这些元素的小鼠是存活的、有生育能力的，并且没有表现出明显的异常。这一完全出人意料的发现表明，DNA序列保守的极端水平并不一定表明一种不可或缺的功能性质。超低温处理的基因组元件可能是保守的，因为它们具有功能。在这里，许多这样的元件在小鼠体内被删除了，动物是活的，这表明这些序列是可有可无的。
Ultraconserved elements have been suggested to retain extended perfect sequence identity between the human, mouse, and rat genomes due to essential functional properties. To investigate the necessities of these elements in vivo, we removed four noncoding ultraconserved elements (ranging in length from 222 to 731 base pairs) from the mouse genome. To maximize the likelihood of observing a phenotype, we chose to delete elements that function as enhancers in a mouse transgenic assay and that are near genes that exhibit marked phenotypes both when completely inactivated in the mouse and when their expression is altered due to other genomic modifications. Remarkably, all four resulting lines of mice lacking these ultraconserved elements were viable and fertile, and failed to reveal any critical abnormalities when assayed for a variety of phenotypes including growth, longevity, pathology, and metabolism. In addition, more targeted screens, informed by the abnormalities observed in mice in which genes in proximity to the investigated elements had been altered, also failed to reveal notable abnormalities. These results, while not inclusive of all the possible phenotypic impact of the deleted sequences, indicate that extreme sequence constraint does not necessarily reflect crucial functions required for viability. It is widely believed that the most evolutionarily conserved DNA sequences in the human genome have been preserved because of their functional importance and that their removal would thus have a devastating effect on the organism. To ascertain this we removed from the mouse genome four ultraconserved elements—sequences of 200 base pairs or longer that are 100% identical among human, mouse, and rat. To our surprise, we found that the mice lacking these elements are viable, fertile, and show no apparent abnormalities. This completely unexpected finding indicates that extreme levels of DNA sequence conservation are not necessarily indicative of an indispensable functional nature. Ultraconserved genomic elements may be conserved because they are functional. Here, a number of these elements have been deleted in the mouse, and animals are viable, suggesting that these sequences are dispensable.
登录
查看更多内容
影响因子：
10.5
作者：
Raymond, CS;Murphy, MW;Zarkower, D
通讯作者：
Zarkower, D
影响因子：
64.5
作者：
Lee, TI;Jenner, RG;Young, RA
通讯作者：
Young, RA
影响因子：
3
作者：
ARGUESO, LR;RITCHEY, ML;KRAMER, SA
通讯作者：
KRAMER, SA
影响因子：
5.8
作者：
Muroya, K;Okuyama, T;Ogata, T
通讯作者：
Ogata, T
影响因子：
30.8
作者：
Drake, JA;Bird, C;Hirschhorn, JN
通讯作者：
Hirschhorn, JN