A yeast's eye view of mammalian reproduction: cross-species gene co-expression in meiotic prophase

Yunfei Li,Ka-Sum Lam,Ping Ye,Nairanjana Dasgupta

doi:10.1186/1752-0509-4-125

Abstract

BackgroundMeiotic 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.ResultsOrthologous 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.ConclusionsWe 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.

Highlights

Meiotic prophase is a critical stage in sexual reproduction
Conserved gene co-expression recovers known meiotic genes We evaluated conserved co-expression networks using known meiotic genes annotated by gene ontology (GO:0007126) [20]
When using yeast genes to search for GO terms, we found that the meiosis term was significantly enriched in all four networks (P-values = 0.001 for Y-Mm, 0.019 for Y-Mf, 0.009 for Y-human fetal ovary (Hf), 0.033 for Y-Mm-Mf-Hf) (Table 2)

Summary

Introduction

Meiotic prophase is a critical stage in sexual reproduction. We aim to identify novel meiotic genes important in human reproduction through computational mining of crossspecies and cross-sex time-series expression data from budding yeast, mouse postnatal testis, mouse embryonic ovary, and human fetal ovary. Meiosis is essential for sexual reproduction in eukaryotes. It is a conserved process in which diploid cells undergo one round of DNA replication followed by two rounds of chromosome segregation to produce haploid cells. General chromosome behavior during meiosis is conserved in a range of organisms from unicellular budding yeast to multi-cellular mammals [1,2]. The time frame required for each meiotic stage varies greatly by sex and species (Figure 1).

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