Dosage Compensation of an Aneuploid Genome in Mouse Spermatogenic Cells

Autosomal trisomies and monosomies bring serious threats to embryonic development through transcriptional disarray primarily caused by the dosage effect of the aneuploid part of the genome. The present study compared the effect of a mouse viable 30 Mb segmental trisomy on the genome-wide transcriptional profile of somatic (liver) cells and male germ cells. While the 1.6-fold change in expression of triplicated genes reflected the gene dosage in liver cells, the extra copy was almost fully compensated in early pachytene spermatocytes, showing 1.18-fold increase. Allele-specific semi-quantitative evaluation of steady-state mRNA levels of the triplicated Amdhd2 gene revealed silencing evenly distributed among all three copies in these meiotic cells. Although more pronounced, the dosage compensation of trisomic genes was concordant with the incidence of HORMAD2 and gammaH2AX markers of unsynapsed chromatin. The possible explanations include insufficient sensitivity to detect both MSUC markers in the 30 Mb region of the chromosome, or an early silencing effect of another epigenetic factor. Taken together, our results indicate that the meiotic silencing of unsynapsed chromatin is the major but not the only factor driving the dosage compensation of triplicated genes in primary spermatocytes. We compared the global expression profiles in isolated popoulations of meiotic cells and liver cells of Ts43H trisomic males and their t121/D17 euploid siblings.常染色体三体与染色体单体可通过基因组非整倍体区段的剂量效应引发转录紊乱，进而对胚胎发育构成严重威胁。本研究针对小鼠可存活的30 Mb节段三体，比较了其对体细胞（肝脏细胞）与雄性生殖细胞的全基因组转录谱的影响。尽管三倍拷贝基因的表达量呈1.6倍变化，契合肝脏细胞中的基因剂量效应，但在早期粗线期精母细胞中，额外的基因拷贝几乎得到完全补偿，仅表现出1.18倍的表达上调。针对三倍拷贝的Amdhd2基因的稳态mRNA水平开展等位基因特异性半定量分析后发现，此类减数分裂细胞中，该基因的全部三个拷贝均出现了均匀分布的沉默现象。尽管补偿效应更为显著，但三体基因的剂量补偿与未联会染色质的HORMAD2及gammaH2AX标记的出现率相一致。可能的解释包括：现有检测手段灵敏度不足，无法检出染色体30 Mb区段内的两类未联会染色质减数分裂沉默（meiotic silencing of unsynapsed chromatin, MSUC）标记，或是另一表观遗传因子介导的早期沉默效应。综上，本研究结果表明，未联会染色质的减数分裂沉默是驱动初级精母细胞中三倍拷贝基因剂量补偿的主要而非唯一因素。本研究对Ts43H三体雄性小鼠及其t121/D17整倍体同胞的分离减数分裂细胞群与肝脏细胞的全局表达谱进行了比较。