Why Do Women Have a Silent X Chromosome?
Major new discovery:
The female inactivated
X-chromosome can be
reactivated
by Jerry Bergman, PhD
Introduction
Females have two X chromosomes and, to prevent overdosing, one X must be silenced. It was assumed for over a century that the silencing cannot be reversed. New research indicates that if a gene on the remaining X chromosome is damaged, or a part is mutated, a section of the inactivated chromosome can be activated to allow the undamaged gene to be used. This illustrates a clear advantage of the female double-X chromosome, and partly explains women’s longer lifespan compared to males. It also explains why women are, on average, more resilient to cognitive decline than men as they age.
Discussion
Normal males have XY chromosomes and females have XX chromosomes. Males have only one X chromosome. In order to ensure that females also have only one functional X chromosome, the second X is “silenced” by a process called X-chromosome inactivation. The end result is one activated (Xa) chromosome and one inactivated (Xi) chromosome exist in females. This X-chromosome inactivation is called “Lyonization” after Mary F. Lyon (1925-2014), the British geneticist who discovered it. The biological process of Lyonization causes one of the two X chromosomes in female mammals to be randomly silenced in each cell during early embryonic development.
The inactive X chromosome is silenced by being packaged into a transcriptionally dormant structure called heterochromatin. Consequently, most of the genes on the Xi chromosome are not expressed, effectively turning them off. The complex X-inactivation process causes compaction of the Xi chromosome, producing a small, dense structure called a Barr body named after its discoverer, Canadian physician and medical researcher, Murray Barr (1908-1995). The main purpose of the X-chromosome inactivation, as discussed below, is to prevent females from having a double dosage of X-linked genes compared to the male XY.
Most, but not all, of the genes on the Barr body are inactive and are, therefore, unable to be transcribed. Which ones are not inactivated and why are still being researched. A critically important research area is the fact that the few select genes from the Xi chromosome escape inactivation in a tissue-specific manner.[1]
Reasons for the X-inactivation
It is important that the correct dosage, not more or less of X-carried genetic material, is maintained. Lyonization ensures that females do not express twice the amount of X-linked gene products. Too high a dosage of certain genes can cause serious health problems, as illustrated by the set of trisomy diseases. Trisomy 13 (Patau syndrome) adversely affects the development of the face, brain, heart, and several other internal organs. The trisomy 13 condition is life-threatening and most cases result in a miscarriage, or death before one year of age. The same concern exists for two Xa chromosomes in a female embryo, which can also cause major health problems.
Consequently, females have an inactive X (Xi) and an active X (Xa) chromosome, in contrast to males which have only one Xa. Sometimes Triple X syndrome occurs, producing Xa, Xa and Xi.
Until recently, it was universally believed that “one of the X chromosomes is randomly and permanently inactivated.”[2] Margaret Gadek of the Department of Neurology at the University of California in San Francisco, with her research colleagues, have shown experimentally a revolutionary finding: namely, that the inactivation of certain chromosomal genes can be reversed in certain circumstances.[3]
Genetic Differences Between Males and Females
Backup genes on Xi may contribute to greater average longevity in women, but the full reasons are unknown.
X-inactivation plays a role in balancing gene expression in female cells, but the Gadek et al. research indicates that multiple factors, including hormonal differences, contribute to the observed sex differences in life expectancy. The result is that women, on average, live longer than men.[4] The reason Gadek et al. postulate is that reactivation of certain genes on the Xi chromosome can compensate for possible gene mutations and defects on the other Xa chromosome.
The finding supports the conclusion that an important factor in aging is that the Xa chromosome in both males and females contains gene segments that positively influence the body’s immune system. For females, the Xi serves as a backup if certain genes are mutated.
Because this fact is true worldwide, despite socioeconomic status and regardless of famines and epidemics, this suggests that X-chromosome differential expression is a common biological contribution to female longevity.[8] Furthermore, with some exceptions, this is also often true in the animal kingdom. This is an area that needs to be explored in more depth to understand why.
The Research Procedure
The Gadek et al. research team, using mice and human cadavers, uncovered a genetic source for the health advantage in females: the reactivation of the second X chromosome in certain female cells that was previously considered ‘silent.’[9] The researchers specifically studied hippocampus cells because this brain region is crucial for learning and memory functions. Analysis of several different hippocampal cell types located about 20 genes on the normally silenced area of the X chromosome.
They also found that aging itself activates the expression of genes on what is usually the ‘silent,’ or inactivated, X chromosome in hippocampus cells. When the Gadek et al., researchers gave mature mice of both sexes gene therapy designed to boost the expression of specific hippocampus genes, the therapy improved their cognition as measured by how well they performed in maze evaluations. They concluded that women’s brains are protected by their reactivated second X chromosome as they age — a finding that could translate into future therapies boosting the cognition abilities of both males and females.
The steps proposed that lead up to the reactivation include the function of p53 protein, encoded by the TP53 gene, known as the “guardian of the genome” which plays a vital role in maintaining genomic stability. Before cell division can proceed, p53 evaluates genome integrity.[10] If, from the evaluation, no potential problems are found that would require repair to the genes regulating the cell cycle, the cell divides. If repairs are needed, they are directed by the p53 system. If the repair is successful, cell division results. If the damage is too extensive, however, programmed cell death called apoptosis is activated, leading to the cell’s demise.[11] This process ensures that damaged or mutated cells are removed.
The new option for gene repair in females discovered by the Gadek researchers includes identifying whether a backup copy can be found. If the backup gene exists on the X chromosome, it is then used to repair the cell. If the gene exists in an inactivated chromosome, the gene is used and the body is able to achieve the function determined by the p53 evaluation. Evolutionists have not even speculated how this complex multistep mechanism could have evolved.
Further Questions
Questions that remain include “Why do some female animals have X chromosome protection and not others?” It appears that, given the advantages that women have in aging and cognitive longevity, males were shortchanged, raising questions about why. The why may relate to the different biological roles of males and females. In many species, males develop traits that help them compete for mates and support their family materially and socially. In contrast, females often have designed structures and adaptations that support pregnancy and nurturing of their offspring. The genetics of the complementary roles of the sexes and other questions will not be answered until much more is known about the entire second X reactivation mechanism.
Conclusions
P53 is the most mutated gene in cancer.
The growth of scientific knowledge has consistently revealed increased levels of specified complexity in life which evolutionists have been unable to propose viable evolutionary explanations. In the case of the Gadek et al. discovery, evolutionists have only been able to propose that the p53 family of genes (p53, p63, and p73) goes back to a common ancestor gene found in early metazoans. In metazoans its primary function is to protect germline cells from DNA damage.[12] The details of the mechanisms that cause both the inactivation and reactivation of certain genes are still unknown. It is known that somehow a determination must be made that a gene has mutated, or is broken beyond repair. Then the damaged gene that is located in the Xi that was not silenced can be used to replace the damaged gene. The details of how this occurs are still unknown.
The guardian of the genome—p53—likely plays a central role in this process.[13] If the gene was silenced, it must be reactivated and used to produce the required protein. This is also the case for the details of the mechanism that activates, or reactivates, only certain genes, and not others, to become functional. If reactivation is triggered by factors such as the aging process, the how and why are still unknown.
Such is the nature of scientific research in the area of biology: each new system that is discovered leads to more unanswered questions. Consequently, the study of female-specific biology is essential to continue exploring this newly discovered mechanism because it promotes a better understanding of female biology. This understanding contributes to improved knowledge of health and disease in both women and men.
It also provides more evidence supporting the fact that, biologically, men and women—the two God-ordained genders as taught in Genesis—are in major ways very different. This fact undermines the faddish notion that the differences between males and females can be reduced (or even largely eliminated) by hormone treatment and cosmetic surgery.
References
[1] Gadek, Margaret, et al., Aging activates escape of the silent X chromosome in the female mouse hippocampus, Science Advances 11(10), 5 March 2025.
[2] X chromosome. National Library of Medicine. https://medlineplus.gov/genetics/chromosome/x/.
[3] Gadye, Levi. 2025. The ‘silent’ X chromosome gives the aging female brain a boost. https://www.ucsf.edu/news/2025/03/429571/silent-x-chromosome-gives-aging-female-brain-boost.
[4] Gadye, 2025.
[5] Banhs, Ian, No man’s land: Men, illness, and the NHS. British Medical Journal 323(7320):1058-1060, doi: 10.1136/bmj.323.7320.1058, 3 November 2001.
[6] Gadye, 2025.
[7] Gadek et al., 2025.
[8] Gadek et al., 2025.
[9] Bourzac, Katherine, Why women’s brains are more resilient: It could be their ‘silent’ X chromosome, Nature, DOI: 10.1038/d41586-025-00682-3, 5 March 2025.
[10] Toufektchan E, Toledo F (May 2018). “The Guardian of the Genome Revisited: p53 Downregulates Genes Required for Telomere Maintenance, DNA Repair, and Centromere Structure”. Cancers. 10 (5): 135. doi:10.3390/cancers10050135. PMC 5977108. PMID 29734785.
[11] Elmore, Susan, Apoptosis: A review of programmed cell death, Toxicology Pathology 35(4):495–516, doi: 10.1080/01926230701320337, June 2007.
[12] Belyi, Vladimir A., et al., The origins and evolution of the p53 family of genes, Cold Spring Harbor Perspectives in Biology 2(6):a001198, doi: 10.1101/cshperspect.a001198, June 2010.
[13] Lane, D.P., Cancer: p53, guardian of the genome, Nature 358(6381):15-16, doi: 10.1038/358015a0, 2 July 1992.
Dr. Jerry Bergman has taught biology, genetics, chemistry, biochemistry, anthropology, geology, and microbiology for over 40 years at several colleges and universities including Bowling Green State University, Medical College of Ohio where he was a research associate in experimental pathology, and The University of Toledo. He is a graduate of the Medical College of Ohio, Wayne State University in Detroit, the University of Toledo, and Bowling Green State University. He has over 1,900 publications in 14 languages and 40 books and monographs. His books and textbooks that include chapters that he authored are in over 1,800 college libraries in 27 countries. So far over 80,000 copies of the 60 books and monographs that he has authored or co-authored are in print. For more articles by Dr Bergman, see his Author Profile.