Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance.
Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance.
复制标题
DOI：
10.1101/gr.130740.111
复制
发表时间：
2012-05
期刊：
影响因子：
7
通讯作者：
Symer DE
中科院分区：
文献类型：
--
作者：
Li J;Akagi K;Hu Y;Trivett AL;Hlynialuk CJ;Swing DA;Volfovsky N;Morgan TC;Golubeva Y;Stephens RM;Smith DE;Symer DE
内源性反转录转座子在哺乳动物物种中引起了广泛的基因组变异，但这种动员的功能意义大多是未知的。我们绘制了数千个内源性逆转录病毒（ERV）种系整合体在高度分歧，以前未测序的小鼠谱系，促进比较基因表达的存在或不存在的本地插入。多态性ERV在基因内含子中相对较少出现，并且特别是从涉及胚胎发生或在胚胎干细胞中高度表达的基因中耗尽。它们的基因组分布意味着由于对基因表达和功能的有害影响而进行的负选择。一个多态性，内含子ERV在Slc15a2触发高达49倍的提前转录终止增加和高达39倍的减少在成年小鼠组织中的全长转录本，从而破坏蛋白质表达和功能活性。当内含子ERV多态性存在时，也会在Polr1a、Spon1和高达105%的其他基因上发生前体截短的转录物。在重组BxD小鼠品系中的表达数量性状位点（eQTL）的分析表明，在顺式和破坏转录水平的多态性ERV之间存在非常强的遗传关联。在顺式和等位基因之间，在ERV上游的基因组距离>12.5 kb处触发过早的多聚腺苷酸化。ERV的起源亲本与非终止转录本的可变表达和其5′长末端重复序列的差异DNA甲基化相关。这项研究定义了一个意想不到的强大的功能影响ERVs在破坏基因转录的距离，并表明，正在进行的逆转录转座可以显着地促进自然表型多样性。
Endogenous retrotransposons have caused extensive genomic variation within mammalian species, but the functional implications of such mobilization are mostly unknown. We mapped thousands of endogenous retrovirus (ERV) germline integrants in highly divergent, previously unsequenced mouse lineages, facilitating a comparison of gene expression in the presence or absence of local insertions. Polymorphic ERVs occur relatively infrequently in gene introns and are particularly depleted from genes involved in embryogenesis or that are highly expressed in embryonic stem cells. Their genomic distribution implies ongoing negative selection due to deleterious effects on gene expression and function. A polymorphic, intronic ERV at Slc15a2 triggers up to 49-fold increases in premature transcriptional termination and up to 39-fold reductions in full-length transcripts in adult mouse tissues, thereby disrupting protein expression and functional activity. Prematurely truncated transcripts also occur at Polr1a, Spon1, and up to ∼5% of other genes when intronic ERV polymorphisms are present. Analysis of expression quantitative trait loci (eQTLs) in recombinant BxD mouse strains demonstrated very strong genetic associations between the polymorphic ERV in cis and disrupted transcript levels. Premature polyadenylation is triggered at genomic distances up to >12.5 kb upstream of the ERV, both in cis and between alleles. The parent of origin of the ERV is associated with variable expression of nonterminated transcripts and differential DNA methylation at its 5′-long terminal repeat. This study defines an unexpectedly strong functional impact of ERVs in disrupting gene transcription at a distance and demonstrates that ongoing retrotransposition can contribute significantly to natural phenotypic diversity.
登录
查看更多内容
影响因子：
30.8
作者：
Cahan, Patrick;Li, Yedda;Izumi, Masayo;Graubert, Timothy A.
通讯作者：
Graubert, Timothy A.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.7
作者：
Hu, Yongjun;Shen, Hong;Smith, David E.
通讯作者：
Smith, David E.
影响因子：
5.4
作者：
Barr, SD;Leipzig, J;Bushman, FD
通讯作者：
Bushman, FD
影响因子：
3.3
作者：
Horie, Kyoji;Saito, Ei-suke;Takeda, Junji
通讯作者：
Takeda, Junji