Men and women are alike in many ways. However, there are significant biological and behavioral differences between the two genders. They affect the manifestation, epidemiology, and pathophysiology of many widespread diseases and the approach to health care.
For example, Lupus and Alzheimer’s diseases commonly affect females. On the other hand, COVID-19 infections are frequently more severe in males.
Sex differences are based on biological factors- mainly attributable to the sex chromosomes (X and Y). The X chromosome is known to play an essential role in human development and disease.
A new study by the Penn State College of Medicine reveals for the first time that sex-biased diseases can be attributable to genes that escape X chromosome inactivation (XCI). Because of XCI, most genes are only expressed from one allele.
By using a newly developed genetic tool, scientists identified XCI escape genes. The tool could also predict whether a female will produce a sex-biased disease and if the disease will become progressively worse over time.
The tool may even be useful in understanding the sex differences in immune responses to COVID-19, as the disease is thought to produce more severe symptoms and higher mortality in men than in women.
Laura Carrel, associate professor of biochemistry and molecular biology, Penn State College of Medicine, said, “The X chromosome plays an important role in human development and disease, yet the X chromosome is frequently ignored in human genetic studies because of bioinformatics challenges in the analysis of the data.”
“Our new method gets around these challenges and allows us to identify XCI escape genes and assess their role in sex-biased diseases. With further research and fine-tuning, we think it could serve as a predictive tool in these disorders and could lead to the identification of new disease treatments and interventions.”
The human genome is organized into 23 pairs of chromosomes, one pair of which is the sex chromosomes. This pair comprises two X chromosomes for females and one X and one Y chromosome for males. Early in embryonic development in females, one of the two X chromosomes is randomly inactivated to ensure that, like in males, only one functional copy of the X chromosome — either inherited from the female’s mother or inherited from her father — occurs in each cell.
Carrel said, “In females, about 30% of the genes on the X chromosome escape this inactivation — or XCI — leaving them with two functional copies of those genes. The question is, does having two copies of those genes make a female more susceptible to traits, such as lupus, that show a sex bias?”
Answering this question requires identifying the XCI escape genes. However, conducting a chromosome-wide analysis is difficult due to the random nature of XCI in early development, as XCI affects the X chromosome that a female inherits from one parent in some cells but the other X in other cells.
Using a newly developed model called XCIR (X-Chromosome Inactivation for RNA-seq), scientists were able to identify XCI escape genes using bulk RNA-sequencing data. The method independently assesses how much a gene is expressed from each X chromosome.
A gene is considered to escape from XCI if the ratio of its expression from the two X chromosomes contrasts fundamentally from genes that are known to be X-inactivated. The technique beats different methodologies since it can adequately handle the errors emerging from next-generation sequencing techniques and the complex biology of XCI.
Dajiang Liu, associate professor of public health sciences and biochemistry and molecular biology, Penn State College of Medicine, said, “Our method — available in an intuitive, well-documented and freely available software — is more powerful than alternative approaches and is computationally efficient to handle large population-scale datasets.”
By applying the method to a dataset, scientists identified hundreds of traits, including male- or female-biased diseases such as lupus, that may be influenced by these genes that escape XCI. As shown by others, the escape genes also contribute to Alzheimer’s disease and response to COVID-19 infections as well.
Liu said, “We have developed the methodology needed to establish XCI status for population-sized datasets. This work highlights the increased importance of XCI escape genes to female-biased diseases and may one day be used to predict disease accurately. Importantly, a better understanding of the sex chromosomes will be an important step in resolving health disparities between the sexes.”
- Renan Sauteraud et al. Inferring genes that escape X-chromosome inactivation reveal variable escape genes’ important contribution to sex-biased diseases. DOI: 10.1101/gr.275677.121