Li Yunfei, Lam Ka-sum, Dasgupta Nairanjana, Ye Ping
School of Molecular Biosciences, Washington State University, PO Box 647520, Pullman, WA 99164, USA.
BMC Syst Biol. 2010 Sep 6;4:125. doi: 10.1186/1752-0509-4-125.
Meiotic prophase is a critical stage in sexual reproduction. Aberrant chromosome recombination during this stage is a leading cause of human miscarriages and birth defects. However, due to the experimental intractability of mammalian gonads, only a very limited number of meiotic genes have been characterized. Here we aim to identify novel meiotic genes important in human reproduction through computational mining of cross-species and cross-sex time-series expression data from budding yeast, mouse postnatal testis, mouse embryonic ovary, and human fetal ovary.
Orthologous gene pairs were ranked by order statistics according to their co-expression profiles across species, allowing us to infer conserved meiotic genes despite obvious differences in cellular synchronicity and composition in organisms. We demonstrated that conserved co-expression networks could successfully recover known meiotic genes, including homologous recombination genes, chromatin cohesion genes, and genes regulating meiotic entry. We also showed that conserved co-expression pairs exhibit functional connections, as evidenced by the annotation similarity in Gene Ontology and overlap with physical interactions. More importantly, we predicted six new meiotic genes through their co-expression linkages with known meiotic genes, and subsequently used the genetically more amenable yeast system for experimental validation. The deletion mutants of all six genes showed sporulation defects, equivalent to a 100% validation rate.
We identified evolutionarily conserved gene modules in meiotic prophase by integrating cross-species and cross-sex expression profiles from budding yeast, mouse, and human. Our co-expression linkage analyses confirmed known meiotic genes and identified several novel genes that might be critical players in meiosis in multiple species. These results demonstrate that our approach is highly efficient to discover evolutionarily conserved novel meiotic genes, and yeast can serve as a valuable model system for investigating mammalian meiotic prophase.
减数分裂前期是有性生殖中的关键阶段。此阶段染色体异常重组是人类流产和出生缺陷的主要原因。然而，由于哺乳动物性腺在实验上难以处理，仅有非常有限数量的减数分裂基因得到了表征。在此，我们旨在通过对来自芽殖酵母、小鼠出生后睾丸、小鼠胚胎卵巢和人类胎儿卵巢的跨物种和跨性别时间序列表达数据进行计算挖掘，来鉴定对人类生殖重要的新型减数分裂基因。
直系同源基因对根据其跨物种的共表达谱通过顺序统计进行排序，这使我们能够推断出保守的减数分裂基因，尽管生物体在细胞同步性和组成上存在明显差异。我们证明保守的共表达网络能够成功找回已知的减数分裂基因，包括同源重组基因、染色质凝聚基因以及调节减数分裂起始的基因。我们还表明保守的共表达对呈现出功能联系，这在基因本体论中的注释相似性以及与物理相互作用的重叠中得到了证明。更重要的是，我们通过与已知减数分裂基因的共表达联系预测了六个新的减数分裂基因，随后使用遗传上更易操作的酵母系统进行实验验证。所有六个基因的缺失突变体均表现出孢子形成缺陷，验证率达100%。
我们通过整合来自芽殖酵母、小鼠和人类的跨物种和跨性别表达谱，鉴定了减数分裂前期进化上保守的基因模块。我们的共表达连锁分析证实了已知的减数分裂基因，并鉴定了几个可能在多个物种减数分裂中起关键作用的新基因。这些结果表明我们的方法在发现进化上保守的新型减数分裂基因方面非常高效，并且酵母可作为研究哺乳动物减数分裂前期的有价值的模型系统。
