New tool reveals genetic influence of certain sexist diseases, including lupus

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HERSHEY, Pa .– Many human diseases can differ between men and women in terms of prevalence, manifestation, severity, or age of onset. Examples include lupus, where over 80% of patients are women; Alzheimer’s disease, where women have a higher incidence and tend to suffer from faster cognitive decline; and COVID-19 infections which are often more serious in men.

These sex differences may have a genetic basis attributable to sex chromosomes. The X chromosome – one of two sex chromosomes – is known to play an important role in human development and disease. New research from Penn State College of Medicine reveals for the first time that gender-based illnesses may be attributable to genes that escape X chromosome inactivation (XCI), a process that ensures women do not overexpress them. genes on their X chromosomes.

The team has developed a genetic tool that can identify these XCI escape genes, and it can also help determine if a woman will develop a sexual disease and if the disease will gradually worsen over time. The tool may even be useful in understanding gender differences in immune responses to COVID-19, as the disease is believed to produce more severe symptoms and higher mortality in men than in women.

“The X chromosome plays an important role in human development and disease, but the X chromosome is frequently ignored in human genetic studies due to bioinformatic challenges in data analysis,” said Laura Carrel, associate professor of biochemistry and molecular biology, Penn State College of Medicine. “Our new method circumvents these challenges and allows us to identify XCI escape genes and assess their role in sexist diseases. With further research and adjustment, we believe this could serve as a predictive tool in these disorders and could lead to the identification of new treatments and interventions for the disease. “

IMAGE: Laura Carrel, State of Pennsylvania

The human genome is organized into 23 pairs of chromosomes, one pair of which is made up of sex chromosomes. This pair includes two X chromosomes for females and one X and one Y chromosome for males. At the start of embryonic development in females, one of the two X chromosomes is randomly inactivated to ensure that, as in males, only one functional copy of the X chromosome – either the one inherited from the female’s mother or the one inherited. from his father – occurs in every cell.

“In women, about 30% of the genes on the X chromosome escape this inactivation – or XCI – leaving them with two functional copies of these genes,” Carrel said. “The question is, does having two copies of these genes make a woman more susceptible to traits, such as lupus, that show sexual bias?”

To answer this question, a critical first step is to identify the XCI escape genes. Yet performing a chromosome-wide analysis is difficult due to the random nature of XCI early in development, as XCI affects the X chromosome that a woman inherits from one parent in some cells, but the other. X in other cells.

In their study, published Aug. 23 in the journal Genome Research, the researchers developed a new statistical model, called XCIR (X-Chromosome Inactivation for RNA-seq), which can identify XCI escape genes using Bulk RNA sequencing data, a type of genetic data. The method separately assesses the amount of expression of a gene from each X chromosome. A gene is deemed to escape XCI if the ratio of its expression from the two X chromosomes significantly differs from genes known to be inactivated X. . The method outperforms other approaches as it can more effectively handle errors resulting from next-generation sequencing technologies and complex XCI biology.

“Our method – available in intuitive, well-documented, and freely available software – is more powerful than alternative approaches and is computationally efficient at handling large data sets at the population level,” said Dajiang Liu. , associate professor of public health sciences and biochemistry and molecular. biology, Penn State College of Medicine.

The team applied their method to a dataset comprising nearly half a million people and identified hundreds of traits, including male or female diseases such as lupus, that can be influenced by these genes that escape the XCI. As others have shown, escape genes also contribute to Alzheimer’s disease and the response to COVID-19 infections.

“We have developed the methodology necessary to establish the XCI status for population size datasets,” Liu said. “This work highlights the increased importance of XCI escape genes for predominantly female diseases and could one day be used to accurately predict disease. Importantly, a better understanding of sex chromosomes will be an important step in resolving health disparities between the sexes. “

Other Penn State authors on the paper include Renan Sauteraud, a recent doctoral graduate in biostatistics; Jill M. Stahl and Jesica James, former graduate students in genetics and biomedical sciences; Marisa Englebright, research technologist; and Fang Chen, postdoctoral researcher in biostatistics. Xiaowei Zhan, assistant professor of population and data sciences at Southwestern Medical Center at the University of Texas, is also an author.

This research was supported by the National Institutes of Health, the Lupus Research Alliance, and the Pennsylvania Department of Health.


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