Understanding the sexome: measuring and reporting sex differences in gene systems

Abstract

The current male bias in biomedical research should be eliminated. The large sex differences in incidence and progression of diseases mean that sex-biased factors are an untapped source of factors that protect from disease. Greater understanding will come from intensified study of the "sexome," which is the sum of sex-biased effects on gene networks and cell systems. The global search for sites and mechanisms of sex-specific regulation in diverse tissues will provide unanticipated insights into physiological regulation and targets for novel therapies.

Fig. 1.

The sexome. Green circles are gene products connected in a network, with green arrows indicating interactions between network nodes. The female (F) and male (M) boxes show the origins of sex-biasing actions in the network. Female-biasing factors include two X chromosomes, ovarian secretions, etc. Male-biasing factors include a single X chromosome, the Y chromosome, testicular secretions, etc. The sex-biasing influence of these factors on the network is illustrated by the pink or blue shading of gene product nodes. Gene products influenced both by female-biasing and male-biasing factors show pink and blue shading. The sex-biasing factors can increase or decrease activity at specific sites in the network, and their effects can propagate through the network to sex-bias various gene modules (data not shown). The sexome is defined as the total of all sex-biasing actions within the network.

Fig. 2.

A, Global sex differences in the mouse transcriptome of tissues not directly involved in reproduction. Histograms show male (M):female (F) ratios of expression of all mRNA measured by microarray profiling in mice (i.e. genes with 2-fold higher expression in males are +1 and those with 2-fold higher in females are −1). Sex differences were found in 72% of liver genes and 68% of adipose. Over 70% of genes showing sex bias have less than 20% greater expression in one sex relative to the other, and sex differences of 2-fold are rare. X-inactivation prevents strong female bias in expression of X genes (red curve), and results in sex bias in X genes that roughly matches, tissue for tissue, the global sex bias of autosomal genes (black curve) with which they interact in each tissue. Republished from Ref. based on data of Ref. . B, Sex differences in the human plasma metabolome; 131 metabolites are graphed by the first two principal components (PC) in a partial least square analysis of levels of metabolites in human plasma; 78% of metabolites showed statistically significant sex differences. Reprinted with permission from Ref. .