The Page Lab’s long-term goal is to understand, at the molecular level, the differences and similarities between males and females throughout the body, in health and disease. This understanding of where male and female cells, tissues, and organs are essentially the same and where they are fundamentally different is a critical and overlooked facet of the teaching and practice of medicine and the conduct of biomedical research.
Many debilitating diseases, including heart failure, systemic lupus, autism spectrum disorder, and many cancers, show striking yet unexplained sex biases in prevalence and severity. Such biases have historically been attributed entirely to cell-extrinsic factors, such as sex hormones or environment. For a number of reasons, the medical and biomedical research community have long ignored the multifaceted function and impact of the X and Y chromosomes (the sex chromosomes). The resulting blind spot means that biomedicine has little knowledge of the regulatory capacities and specific effects of sex chromosomes, or of the potentially widespread molecular differences—and health implications—that result from being male (XY) or female (XX).
Recent advances by the Page Lab provide an intellectual framework for studying these fundamental questions. Through comprehensively sequencing sex chromosomes across multiple mammalian species, the Page Lab discovered that a group of genes on the sex chromosomes encode master transcriptional and epigenetic regulators, which control how cells turn genes on and off throughout the genome. The fact that the X version is expressed in females and both the X and Y versions are expressed in males implies that gene activity across the genome is controlled differently in XX and XY cells. The resulting female- and male-specific regulation of the genome likely affects all dimensions of human biology, including how disease susceptibility varies between males and females in both severity and incidence.
The Page Lab has embarked on a long-term, integrated program of scientific research, with the goal of understanding, at the genomic, epigenetic, molecular, and cellular levels, the contributions of the sex chromosomes to sex differences in health and disease. This program involves a network of collaborators, with the Page Lab serving as the hub, which expands their basic science investigations and pursues translational research and development. The lab is currently pursuing multiple parallel and interactive investigative tracks:
The Page lab assessed and compared sex bias in mammalian gene expression across an unprecedented number of tissues and species. They employed a combination of publicly available human RNA sequencing data from the GTEx Consortium, and data newly generated in the Page Lab from four non-human mammals (macaque, mouse, rat, and dog). Sex-biased gene expression represents a key intermediate in the pathway from genetic to phenotypic sex differences. This study is unique in that it jointly analyzes sex differences across a broad range of non-reproductive tissues and mammalian species. The Page Lab found that evolutionarily conserved sex-biased gene expression exists across the body, and that it is largely tissue-specific. Turning to species-specific sex biases, they discovered that most sex bias in gene expression has been recently acquired during mammalian evolution, sounding a cautionary note about the use of other species as models of human sex bias in pharmaceutical and basic research. Furthermore, this study sheds light on the mechanisms by which such lineage-specific changes have occurred, through gains or losses of DNA sequence motifs for sex-biased transcriptional regulators.
The Page Lab used the results of the above-described survey to examine how sex-biased gene expression contributes to a phenotypic sex difference found in most mammalian species – an upward shift in the distribution of height or body size in males relative to females. In human, males are ~13 cm or 5 inches taller than females, on average. By incorporating a wealth of publicly available data on the genetics of height with the Page Lab’s new data, this study found that autosomal genes with conserved male or female bias show opposing effects on height: Male-biased genes show largely height-increasing effects, while female-biased genes show largely height-decreasing effects. These results explain a significant proportion (~1.6 cm or 12%) of the sex difference in height. In addition to demonstrating a proof-of-concept for how sex-biased gene expression can contribute to complex trait distributions shifted between the sexes, these findings provide a molecular basis to support suggestions that the sex difference in mammalian height and body size resulted from opposing selective pressures – for increased height in males and decreased height in females.
A living histogram from the Connecticut State Agricultural College (Genetics, 1997). Mean height of males (in black) is 70.1 inches; mean height of females (in white) is 64.8 inches.