The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.
The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.
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DOI：
10.1371/journal.pbio.1002315
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发表时间：
2015-12
期刊：
影响因子：
9.8
通讯作者：
Huminiecki L
中科院分区：
文献类型：
--
作者：
Hurst LD;Ghanbarian AT;Forrest AR;FANTOM consortium;Huminiecki L
X染色体在许多方面都是不寻常的，尤其是它们的非随机基因内容。这种偏见的原因通常在性对抗和避免男性生殖细胞活动的背景下讨论。在这里，我们研究的概念，至少在某些类群，功能偏向的基因内容可能会更深刻地塑造由于X染色体的单倍体表达的基因表达的限制。值得注意的是，如果在灵长类动物中，在X染色体形成之前，X的转录速率与祖先的转录速率（每个启动子）相当，那么由于转录交通堵塞，对于具有非常高的最大净表达水平的基因来说，X不是一个可容忍的环境。我们使用DNA元件百科全书（ENCODE）和哺乳动物基因组功能注释（FANTOM 5）项目的数据来验证这一假设。正如预测的那样，人类X连锁基因的最大表达比常染色体上的基因低得多：平均而言，X染色体上的最大表达比常染色体上的低三倍。类似地，常染色体到X的逆转录事件与X上的逆转录基因的最大表达低于常染色体上的X到常染色体逆转录基因的最大表达相关。也正如预期的那样，如果X连锁基因高表达，则其基因表达的增加程度低于常染色体基因（与人类/黑猩猩共同祖先相比），但如果低表达则不然。交通堵塞模型还解释了已知的X（和鸟类的Z）上基因的较低表达宽度，因为平均而言，具有广泛表达的基因具有较高的最大表达。正如随后进一步预测的那样，在X染色体上高度表达的组织特异性基因也是罕见的，而在X染色体上广泛表达的基因往往是低表达的，这两者都表明这种趋势是由最大表达水平而不是表达宽度本身形成的。重要的是，最大表达水平的限制解释了X连锁基因表达谱的偏倚组织。组织特异性基因高度表达的组织（例如，分泌组织、富含结构蛋白的组织）也是其中基因表达在X染色体上相对罕见的组织。这些趋势不能完全用其他有偏见的表达模式来解释。总之，由于转录交通堵塞，Therian X上的基因很难高度表达的概念，为X的基因内容，基因表达和进化的许多独特特征提供了一个简单而有力的支持。Laurence Hurst、Lukasz Huminiecki和FANTOM 5联盟提出了一种新的解释，解释了人类X染色体上基因的特殊表达特性，其前提是在单倍体表达的染色体上不能实现非常高的表达水平。位于人类X染色体上的基因不是基因的随机混合：它们倾向于在相对较少的组织中表达，或者对特定的一组组织具有特异性，例如，大脑区域。先前试图解释这种倾斜的基因内容的假设是，X染色体可能是特殊的，因为它必须平衡对一种性别有利但对另一种性别有害的突变，或者因为它必须在男性精子制造过程中关闭。在这里，我们提出并验证了第三种可能的解释：X染色体上的基因在转录水平上受到限制，因此往往是低表达或特异表达的基因。我们认为，由于这些基因只能从一条染色体上表达，因为男性只有一个X，由于潜在的转录交通堵塞，以非常高的速率表达基因的能力是有限的。正如预测的那样，我们发现人类X定位基因的最大表达率远低于常染色体上的基因。当我们观察在最近的进化过程中转移到X染色体上或离开X染色体的基因时，我们发现当不在X染色体上时，最大表达更高。我们还发现，相对高表达的X定位基因不能进一步增加其表达水平。我们的模型解释了组织特异性的富集和X定位基因的某些组织的缺乏。在X上表达不足的基因要么在许多组织中表达-这样的基因往往具有高的最大表达-要么来自需要大量转录的组织（例如，快速分泌组织如肝脏）。正如许多发现不能用两个早期的模型来解释一样，交通堵塞模型也不能解释X染色体上发现的基因的所有特殊特征。事实上，我们在X定位基因中发现了与生殖相关的偏见的证据，即使考虑到交通堵塞问题。
X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X’s gene content, gene expression, and evolution. Laurence Hurst, Lukasz Huminiecki, and the FANTOM5 consortium propose a new explanation for the peculiar expression properties of genes on the human X chromosome, based on the premise that very high expression levels cannot be achieved on a haploid-expressed chromosome. Genes located on the human X chromosome are not a random mix of genes: they tend to be expressed in relatively few tissues or are specific for a particular set of tissues, e.g., brain regions. Prior attempts to explain this skewed gene content have hypothesized that the X chromosome might be peculiar because it has to balance mutations that are advantageous to one sex but deleterious to the other, or because it has to shut down during the process of sperm manufacture in males. Here we suggest and test a third possible explanation: that genes on the X chromosome are limited in their transcription levels and thus tend to be genes that are lowly or specifically expressed. We consider the suggestion that since these genes can only be expressed from one chromosome, as males only have one X, the ability to express a gene at very high rates is limited owing to potential transcriptional traffic jams. As predicted, we find that human X-located genes have maximal expression rates far below that of genes residing on autosomes. When we look at genes that have moved onto or off the X chromosome during recent evolution, we find the maximal expression is higher when not on the X chromosome. We also find that X-located genes that are relatively highly expressed are not able to increase their expression level further. Our model explains both the enrichment for tissue specificity and the paucity of certain tissues with X-located genes. Genes underrepresented on the X are either expressed in many tissues—such genes tend to have high maximal expression—or are from tissues that require a lot of transcription (e.g., fast secreting tissues like the liver). Just as many of the findings cannot be explained by the two earlier models, neither can the traffic jam model explain all the peculiar features of the genes found on the X chromosome. Indeed, we find evidence of a reproduction-related bias in X-located genes, even after allowing for the traffic jam problem.