Conservation of gene co-expression networks and neuropsychiatric-neurological disease gene programs between mouse and human frontal cortex at single-cell resolution

Mouse models are widely used in translational neuroscience, but whether a gene has the same partners in mouse and human prefrontal cortex (PFC) is unknown. The genes whose expression rises and falls with a given gene across samples (its co-expression partners) indicate the molecular program to which it belongs. We compared the co-expression of 13,214 genes between mouse medial PFC and human dorsolateral PFC in 246,211 single-nucleus RNA-sequencing profiles. These two regions are not homologous, so part of any measured difference may reflect region and not species. The study has five main findings. First, the similarity of partners for single genes was modest (median 0.169; 0, unrelated; 1, identical). This median was below that of every comparison among human datasets but within the range of comparisons among mouse datasets, and correction for measurement noise raised it to 0.349 at most. Second, groups of co-expressed genes (modules) were strongly preserved. Third, neuropsychiatric disease genes were modestly more conserved than other genes, but no more than control genes matched for mutational constraint and expression, consistent with general gene properties and with how these genes are discovered. Fourth, no disease gene was shown to have different partners in the two species. Fifth, four of five human modules recurred in an independent human dataset. We also identified two sources of error: analyzing only the most variable genes excludes most disease genes, and networks built from few samples, as for glial cells, underestimate the similarity between species. Scores and code are released for cross-species studies.