Bayesian modeling of skewed X inactivation in genetically diverse mice identifies a novel Xce allele associated with copy number changes.
Bayesian modeling of skewed X inactivation in genetically diverse mice identifies a novel Xce allele associated with copy number changes.
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遗传多样性小鼠中偏态 X 失活的贝叶斯模型识别出与拷贝数变化相关的新型 Xce 等位基因。
DOI：
10.1093/genetics/iyab034
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发表时间：
2021
期刊：
影响因子：
3.3
通讯作者：
Valdar,William
中科院分区：
文献类型：
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作者：
Sun,KathieY;Oreper,Daniel;Schoenrock,SarahA;McMullan,Rachel;Giusti-Rodríguez,Paola;Zhabotynsky,Vasyl;Miller,DarlaR;Tarantino,LisaM;Pardo-ManueldeVillena,Fernando;Valdar,William
由于X染色体失活（XCI），雌性哺乳动物是亲本X连锁基因表达的功能性嵌合体。在胚胎发生过程中，这个过程使每个细胞中的X染色体的一个拷贝失活，这种状态通过有丝分裂被维持。在小鼠中，亲本X染色体保持活性的选择是由X染色体控制元件（Xce）决定的，该元件已被映射到一个176-kb的候选间隔。根据亲本X染色体在菌株间杂交中的偏态失活，已经对经典近交系的一系列功能性X等位基因进行了表征或推断。为了进一步探索xce的功能、结构基础和定位，我们在协作杂交（CC）菌株产生的大量F1雌性群体中测量了x连锁基因的等位基因特异性表达。利用已发表的序列数据并应用XCI偏度的贝叶斯“Pólya urn”模型，我们报告了两个主要发现。首先，XCI的个体间差异表明小鼠外表皮细胞平均含有20-30个对大脑有贡献的细胞。其次，CC始创菌株NOD/ShiLtJ具有新颖独特的功能等位基因Xceg，是Xceg等位基因系列中最弱的等位基因。尽管系统发育分析证实NOD/ShiLtJ携带的单倍型与C57BL/6J （Xceb）几乎相同，但我们在携带NOD/ShiLtJ单倍型的女性中发现了意想不到的XCI偏态。拷贝数变异在xcelocus中是常见的，我们得出结论，观察到的等位基因序列是弱xceloces之间共享的独立和重复重复的产物。
Female mammals are functional mosaics of their parental X-linked gene expression due to X chromosome inactivation (XCI). This process inactivates one copy of the X chromosome in each cell during embryogenesis and that state is maintained clonally through mitosis. In mice, the choice of which parental X chromosome remains active is determined by the X chromosome controlling element (Xce), which has been mapped to a 176-kb candidate interval. A series of functionalXcealleles has been characterized or inferred for classical inbred strains based on biased, or skewed, inactivation of the parental X chromosomes in crosses between strains. To further explore the function structure basis and location of theXce, we measured allele-specific expression of X-linked genes in a large population of F1 females generated from Collaborative Cross (CC) strains. Using published sequence data and applying a Bayesian “Pólya urn” model of XCI skew, we report two major findings. First, inter-individual variability in XCI suggests mouse epiblasts contain on average 20–30 cells contributing to brain. Second, CC founder strain NOD/ShiLtJ has a novel and unique functional allele,Xceg, that is the weakest in theXceallelic series. Despite phylogenetic analysis confirming that NOD/ShiLtJ carries a haplotype almost identical to the well-characterized C57BL/6J (Xceb), we observed unexpected patterns of XCI skewing in females carrying the NOD/ShiLtJ haplotype within theXce. Copy number variation is common at theXcelocus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weakXcealleles.