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Study Examines Cross-Species Sex-Biased Expression at Gene, Organ Levels

NEW YORK – New research suggests sex-biased gene expression varies across genes and organs in different animal species, despite relatively consistent gene activity within specific cell types and developmental stages.

"[F]or this work, we studied sex differences in gene expression throughout the entire development of individuals: from very early on, when only the beginnings of the organs are present, to adults," Margarida Cardoso-Moreira, an evolutionary developmental biology researcher at the Francis Crick Institute, said in an email. "We wanted to know when (and how) the sex differences we see in adults are established during development."

As they reported in Science on Thursday, Cardoso-Moreira, Center for Molecular Biology of Heidelberg University researchers Henrik Kaessmann and Leticia Rodríguez-Montes, and their colleagues relied on bulk time-series RNA sequencing, single-cell RNA-seq, and chromatin immunoprecipitation sequencing (ChIP-seq) to focus in on sex-biased genes and gene expression profiles across cell types and developmental stages in heart, kidney, liver, brain, and cerebellum samples from humans, mice, rats, rabbits, opossums, and chickens.

From these data, the team found a relatively small subset of genes whose expression was sex-biased at early developmental stages. In contrast, most genes with sex-related differences showed a burst of sex-biased activity at or after sexual maturity, particularly within the mammalian species.

"To our great surprise, we found few differences between the sexes during organ development," Cardoso-Moreira explained. "For the most part, adult sex differences are only defined upon sexual maturity."

Consistent with prior studies of adults, the latest results pointed to rapid evolution of sex-biased gene expression from one species to the next, she noted, leading to differences in the genes and organ types affected by sex-related expression patterns.

While rabbit heart tissue appeared particularly prone to sex-biased gene activity, the investigators saw male- and female-related transcriptomic differences in brain tissue from chickens and liver tissue in opossums. In both mice and rats, on the other hand, kidney samples showed the strongest levels of gene expression-based sexual dimorphism.

The team also described a relatively small set of genes that showed consistent sex-biased expression was conserved across species, including the so-called gametolog genes KDM6A/UTY and KDM5C/KDM5D. These genes appear to code for demethylase enzymes that act on sex-biased epigenetic regulators of genes that are differentially expression in male and female humans or mice.

Based on these patterns, the authors argued that "genes that consistently show differences between the sexes during development could be involved in triggering and/or maintaining sex-specific developmental programs in each sex similarly across [placental] species."

In addition, the team's single-cell data suggested that the species-specific sex-biased gene activity identified at the gene or organ levels may be less apt to affect the activity of genes within a given cell type.

"We found that sex differences evolve slowly at the cell level," Cardoso-Moreira explained. "What this means is that even though different sets of genes are sex-biased across species, these genes operate in the same types of cells in different species."

The investigators argued that the relatively slow evolution of sex-biased expression at the cell level suggests animal models can provide a window into human biology in a biomedical research setting, despite species differences detected at the gene or organ level.

On the other hand, INSERM and Claude Bernard Lyon University researcher Marie Sémon, who was not involved in the study, suggested that "it will be difficult to apply knowledge on sex biases found in preclinical animal studies to predict sex biases in clinical trials," due to the gene-level differences in sex bias detected in the analyses.

"[M]ost sex-biased genes were species specific, even in closely related species such as the mouse and rat, and the trajectories of expression during development of thousands of genes (including disease-related genes) differ between human and other mammalian species," Sémon wrote in a corresponding commentary in Science.