The loss of a single chromosome in a diploid organism halves the dosage of many genes and is usually accompanied by a substantial decrease in fitness. We asked whether this decrease simply reflects the joint damage caused by individual gene dosage deficiencies. We measured the fitness effects of single heterozygous gene deletions in yeast and combined them for each chromosome. This predicted a negative growth rate, that is, lethality, for multiple monosomies. However, monosomic strains remained alive and grew as if much (often most) of the damage caused by single mutations had disappeared, revealing an exceptionally large and positive epistatic component of fitness. We looked for functional explanations by analyzing the transcriptomes. There was no evidence of increased (compensatory) gene expression on the monosomic chromosomes. Nor were there signs of the cellular stress response that would be expected if monosomy led to protein destabilization and thus cytotoxicity. Instead, all monosomic strains showed extensive upregulation of genes encoding ribosomal proteins, but in an indiscriminate manner that did not correspond to their altered dosage. This response did not restore the stoichiometry required for efficient biosynthesis, which probably became growth limiting, making all other mutation-induced metabolic defects much less important. In general, the modular structure of the cell leads to an effective fragmentation of the total mutational load. Defects outside the module(s) currently defining fitness lose at least some of their relevance, producing the epiphenomenon of positive interactions between individually negative effects.

Male germ cells share a common origin across animal species, therefore they likely retain a conserved genetic program that defines their cellular identity. However, the unique evolutionary dynamics of male germ cells coupled with their widespread leaky transcription pose significant obstacles to the identification of the core spermatogenic program. Through network analysis of the spermatocyte transcriptome of vertebrate and invertebrate species, we describe the conserved evolutionary origin of metazoan male germ cells at the molecular level. We estimate the average functional requirement of a metazoan male germ cell to correspond to the expression of approximately 10,000 protein-coding genes, a third of which defines a genetic scaffold of deeply conserved genes that has been retained throughout evolution. Such scaffold contains a set of 79 functional associations between 104 gene expression regulators that represent a core component of the conserved genetic program of metazoan spermatogenesis. By genetically interfering with the acquisition and maintenance of male germ cell identity, we uncover 161 previously unknown spermatogenesis genes and three new potential genetic causes of human infertility. These findings emphasize the importance of evolutionary history on human reproductive disease and establish a cross-species analytical pipeline that can be repurposed to other cell types and pathologies.