Genetic architecture of skewed X inactivation in the laboratory mouse.
Genetic architecture of skewed X inactivation in the laboratory mouse.
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DOI：
10.1371/journal.pgen.1003853
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Pardo-Manuel de Villena F
中科院分区：
文献类型：
--
作者：
Calaway JD;Lenarcic AB;Didion JP;Wang JR;Searle JB;McMillan L;Valdar W;Pardo-Manuel de Villena F
X染色体失活（XCI）是哺乳动物平衡两性间X连锁基因表达的剂量补偿机制。在女性发育的早期，胚胎的每个细胞都独立地使其亲本x染色体中的一条失活。在小鼠中，哪条X染色体失活的选择受到顺式作用位点（X染色体控制元件）的基因型的影响。Xce定位于x -失活中心（Xic）内1.9 Mb的间隔，但其分子身份和作用机制尚不清楚。我们将小鼠种群的基因型和序列数据与10个自交系的详细表型相结合，并建立了一个统计模型，该模型结合了来自多个来源的表型数据，以阐明X失活时自然雌性群体XCI表型变异的来源。我们将Xce候选区域缩小了10倍，仅为距离Xist近500 kb的176 kb区域。我们认为，这一区间的结构变异解释了小家鼠属中存在多个功能性Xce等位基因。我们在小家鼠中发现了一个新的等位基因Xcee，并在小家鼠中发现了可能的第六个功能等位基因。我们还证实了双亲对X失活选择的影响，并提供证据表明母亲遗传放大了与强Xce等位基因相关的偏态。基于155个实验室菌株和野生小鼠的系统发育分析，我们得出结论：Xcea是一个衍生等位基因，与花式小鼠驯化同时出现，但在大多数经典近交系的衍生之前，或者是一个罕见的野生等位基因。此外，我们发现尽管在野生家鼠中存在多个单倍型，但家鼠只有一个功能性的Xce等位基因Xceb。最后，我们得出结论，每个小鼠分类群具有不同的功能Xce等位基因。尽管雌性哺乳动物在每个细胞中都有两条X染色体，但只有一条是功能性的，而另一条的基因表达通过X染色体失活的过程被沉默。人们对这一过程的早期阶段知之甚少，包括亲本X染色体是如何一个细胞一个细胞地失活的。然而，已有研究表明，某些近交系小鼠在控制这种选择的位点上功能不同，这为鉴定位点并确定其分子机制提供了机会。在过去的40年里，这一直是许多研究人员的目标，并取得了越来越大的成功。在这里，我们利用新的小鼠基因型和全基因组测序数据来确定基因座控制选择。我们的结果在X染色体上发现了一个包含大量重复序列的较小区域。我们提出了对小鼠多重功能等位基因的解释，并提供了X染色体失活选择的可能分子机制。我们的进化分析揭示了为什么这个位点的功能多样性在实验室小鼠中很常见，并解释了为什么我们在人类中没有看到这种水平的多样性。
X chromosome inactivation (XCI) is the mammalian mechanism of dosage compensation that balances X-linked gene expression between the sexes. Early during female development, each cell of the embryo proper independently inactivates one of its two parental X-chromosomes. In mice, the choice of which X chromosome is inactivated is affected by the genotype of a cis-acting locus, the X-chromosome controlling element (Xce). Xce has been localized to a 1.9 Mb interval within the X-inactivation center (Xic), yet its molecular identity and mechanism of action remain unknown. We combined genotype and sequence data for mouse stocks with detailed phenotyping of ten inbred strains and with the development of a statistical model that incorporates phenotyping data from multiple sources to disentangle sources of XCI phenotypic variance in natural female populations on X inactivation. We have reduced the Xce candidate 10-fold to a 176 kb region located approximately 500 kb proximal to Xist. We propose that structural variation in this interval explains the presence of multiple functional Xce alleles in the genus Mus. We have identified a new allele, Xcee present in Mus musculus and a possible sixth functional allele in Mus spicilegus. We have also confirmed a parent-of-origin effect on X inactivation choice and provide evidence that maternal inheritance magnifies the skewing associated with strong Xce alleles. Based on the phylogenetic analysis of 155 laboratory strains and wild mice we conclude that Xcea is either a derived allele that arose concurrently with the domestication of fancy mice but prior the derivation of most classical inbred strains or a rare allele in the wild. Furthermore, we have found that despite the presence of multiple haplotypes in the wild Mus musculus domesticus has only one functional Xce allele, Xceb. Lastly, we conclude that each mouse taxa examined has a different functional Xce allele. Although mammalian females have two X chromosomes in each cell, only one is functional, while gene expression from the other is silenced through a process called X chromosome inactivation. Little is known about the early stages of this process including how one parental X chromosome is inactivated over the other on a cell-by-cell basis. It has been shown, however, that certain inbred mouse strains are functionally different at a locus that controls this choice that provides an opportunity to identify the locus and determine its molecular mechanism. This has been the goal of many researchers over the past 40 years with incremental success. Here we took advantage of new mouse genotype and whole genome sequencing data to pinpoint the locus controlling choice. Our results identified a smaller region on the X chromosome that contains large duplicated sequences. We propose an explanation for multiple functional alleles in mouse and provide insight into the possible molecular mechanism of X chromosome inactivation choice. Our evolutionary analysis reveals why functional diversity at this locus appears to be common in laboratory mice and offers an explanation as to why we do not see this level of diversity in humans.
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影响因子：
9.8
作者：
Church DM;Goodstadt L;Hillier LW;Zody MC;Goldstein S;She X;Bult CJ;Agarwala R;Cherry JL;DiCuccio M;Hlavina W;Kapustin Y;Meric P;Maglott D;Birtle Z;Marques AC;Graves T;Zhou S;Teague B;Potamousis K;Churas C;Place M;Herschleb J;Runnheim R;Forrest D;Amos-Landgraf J;Schwartz DC;Cheng Z;Lindblad-Toh K;Eichler EE;Ponting CP;Mouse Genome Sequencing Consortium
通讯作者：
Mouse Genome Sequencing Consortium
影响因子：
1.5
作者：
CATTANACH, BM;PAPWORTH, D
通讯作者：
PAPWORTH, D
影响因子：
1.5
作者：
CATTANACH, BM;POLLARD, CE;PEREZ, JN
通讯作者：
PEREZ, JN
影响因子：
9.8
作者：
Assie, Guillaume;LaFramboise, Thomas;Eng, Charis
通讯作者：
Eng, Charis
DOI：
10.1073/pnas.96.24.13825
发表时间：
1999-11-23
影响因子：
11.1
作者：
Gilbert, SL;Sharp, PA
通讯作者：
Sharp, PA