Blame Mom? Maternal X Chromosome Worsens Memory

The cells of female mammals randomly inactivate one X chromosome to keep gene dosage the same as in males. Does it matter which X becomes inactive? Surprisingly, it does, according to new research from scientists led by Dena Dubal at the University of California, San Francisco. On January 22 in Nature online, they reported that female mice engineered to keep only their maternal X chromosome active had worse memories than did mice with X chromosome mosaicism, i.e., about 50/50 maternal and paternal X inactivation. The memory problems began at 4 months, and worsened with age. The authors traced this to the silencing of specific genes on the maternal, but not paternal, X chromosome. Activating those genes via CRISPR maintained memory.

  • Female mice that expressed genes on their maternal but not paternal X chromosomes did worse on memory tests.
  • The mice silenced specific maternal X genes.
  • Expressing three of those genes in aging females boosted their memory.

The X contains more genes related to brain function than does any other chromosome. “The X chromosome may be a treasure trove of genes that influence cognition, and these could be therapeutic targets,” Dubal told Alzforum.

Other scientists were enthusiastic. “This is an amazing paper. It goes to the heart of trying to understand how the X chromosome, parental history, and epigenetics all combine to influence rates of cognitive decline,” Rachel Buckley at Massachusetts General Hospital, Boston, wrote to Alzforum. Michael Belloy at Washington University in St. Louis agreed that the genes identified in this study could be important. “We will certainly take a close look at these genes in ongoing X chromosome genetic studies of Alzheimer’s disease to understand how they may tie into female risk biases,” he wrote (comments below).

Mosaic or All Mom’s. Scientists generated female mice that had an active maternal X chromosome in every cell (right), unlike the cellular mosaicism of wild-type mice (left). [Courtesy of Abdulai-Saiku, Nature.]

Because cells randomly silence X chromosomes, females typically express an unequal mix of maternal and paternal X genes in their bodies. Occasionally, cells skew toward mostly maternal or mostly paternal ones; this shift can be associated with X-linked diseases (Amos-Landgraf et al., 2006; Eble et al., 2009). However, no one had examined what effects X-chromosome skew might have in healthy females.

To do this, first author Samira Abdulai-Saiku generated mice that lacked the inactivation gene XIST on their maternal X chromosomes. That forced the maternal X to stay active and the paternal X to be silenced in every cell (image above). This had no apparent effect on most systems, including bone, heart, and metabolism. However, it did affect the brain. Compared to females with balanced mosaicism, 4-month-old maternal X females took twice as long to remember the location of a hidden platform in the Morris water maze. By 9 months, or middle age for a mouse, maternal X females had trouble recognizing familiar environments, a less-demanding task.

To find out why their cognition faltered with age, Abdulai-Saiku looked to methylation, an epigenetic alteration that condenses DNA and silences genes. Methylation increases with age, serving as a type of biological clock (Horvath 2013). She found that mouse neurons with active maternal X chromosomes were biologically older, having more methylated DNA than did neurons with active paternal X chromosomes. To the authors, this suggested that maternal X chromosomes might have more silenced genes.

Cognition Genes? In mice, 11 genes, shown here by location, were differently silenced on maternal versus paternal X chromosomes. [Courtesy of Abdulai-Saiku, Nature.]

They then compared the gene expression of maternal X and paternal X mice for about half of the 1,500 mouse X genes. Nine were silenced on maternal but active on paternal X mice, while two had the opposite pattern. The three maternal X genes silenced by the most cells were SASH3, toll-like receptor 7, and cysteinyl leukotriene receptor 1. SASH3 promotes the survival of T cells, TLR7 controls neuron shape and synapses, and CYSLTR1 is a microglial receptor (Kubo et al., 2012; Hung et al., 2018). 

“All the silenced genes are involved in the neuroimmune axis, which has a newly understood role in synaptic pruning,” Dubal said.

To test if the silenced genes were responsible for the cognitive deficits, the authors activated SASH3, TLR7, and CYSLTR1 in the hippocampi of 18-month-old maternal X mice using CRISPR editing machinery delivered on a lentiviral vector. About 10 percent of neurons took up the vector. Lo and behold, transfected mice remembered the hidden platform and recognized familiar places better than did their untransfected peers. Dubal was surprised by the size of this effect. “It points to a direct role for these genes in cognition,” she told Alzforum.

Dubal said the three X genes have human homologues, hinting something similar might be going on in people. Indeed, girls with Turner’s syndrome, who inherit only one X chromosome, have fewer intellectual deficits when that chromosome comes from the father (Skuse et al., 1997). 

Carmel Armon at Loma Linda University, California, noted that having two X chromosomes may sometimes be better than one, given women’s lower risk of amyotrophic lateral sclerosis, Parkinson’s disease, and other neurodegenerative diseases. “That balanced expression of both X chromosomes [in mice] is better than reliance on one is consistent with these clinical observations,” he wrote (comment below). Dubal has found evidence in mice for the protective benefits of two X chromosomes (Aug 2020 news).

Dubal plans to test whether male mice, which inherit only a maternal X chromosome, have worse memories than mosaic females. The authors have been unable to generate female mice with only paternal X chromosomes, because mouse embryos transiently silence the paternal X chromosome to allow implantation in the womb. When the paternal X is forced to stay active by deleting the XIST gene, embryos do not develop.

Besides effects on cognition, research on X chromosome genetics has recently taken off, with several X-chromosome-wide association studies for Alzheimer’s, autism, macular degeneration, and other disorders (Sep 2024 news; Mendes et al., 2025; Grunin et al., 2024). In the latest, published January 24 in Science Advances, scientists led by Hongtu Zhu at the University of North Carolina, Chapel Hill, looked at how X genes affect brain structure and function. First author Zhiwen Jiang used data from 38,529 participants in the U.K. Biobank to link SNPs on X to variations in structural and diffusion MRIs, as well as resting-state and task-evoked functional MRIs. This yielded 29 SNPs that associated with 72 brain-imaging traits, mostly differences in brain surface area and white-matter tracts.

Linking these associations to disease, the authors saw that an SNP associated with having a smaller hypothalamus also has been correlated with a greater risk of schizophrenia. The authors searched for potential causal genes as well, linking 38 genes to the 72 traits. Finally, they examined brain structure differences between males and females, finding that these were likely driven by the sex-specific expression of certain X-linked genes. The data could offer insights into the X chromosome’s effects on the brain, the authors noted.—Madolyn Bowman Rogers

Comments

    • User Profile Image Carmel Armon
      Loma Linda University School of Medicine
    • Posted:

    This very interesting paper addresses questions about which I have been thinking for a while. It deals with elucidating the elusive role of the X chromosome in contributing to the development of late-onset cognitive decline. It showed that, in female mice, the unbalanced expression of maternally derived X chromosomes may convey a greater risk than does the equal expression of maternally and paternally derived chromosomes. The authors attributed the difference to the operation of epigenetic mechanisms, causing shutdown of some gene expression in maternally derived X chromosomes that are expressed in an unbalanced manner. They restored expression by CRISPR activation of these genes.

    These are fascinating and important observations, because they show how the X chromosome might contribute to the impaired development of neural function, and greater susceptibility to late-onset decline in function, without appearing to be genetically different from X chromosomes that were associated with normal development and normally sustained function.

    Any explanation that assumes greater robustness to a paternally derived X chromosome needs to consider that all paternally derived X chromosomes came from the father's mother (that is, started out as maternally derived), and that paternally derived X chromosomes in a female become maternally derived when passed on to her offspring. It would be necessary to postulate that something happens to modify a maternally derived X-chromosome due to its passage in a male that would make it more robust to withstand harmful epigenetic influences, and that this effect would wane after passage in a female.

    Further—having two copies of the X chromosome is better than one, in terms of reduced risk to develop ALS, Parkinson's disease, and amnestic mild cognitive impairment. The latter condition is frequently the forerunner of Alzheimer's disease (as determined before biomarkers became available), and its incidence is greater in men when using population-based, age-adjusted data. The greater prevalence of Alzheimer's disease in women is due to their greater longevity. The observation that balanced expression of both X chromosomes is better than reliance on one is consistent with these clinical observations.

    The authors did not check what would happen in female mice if there were an unbalanced expression of paternally derived X chromosomes, compared with equal expression of maternally and paternally derived chromosomes. The authors also point out that comparison of their results to what might be seen in males (who only have a maternally derived X chromosome) was not done. We are therefore lacking two comparison groups that would be needed to fully understand the implications of the current observations. It may be best to withhold further speculation until these data are available.

    View all comments by Carmel Armon
    • User Profile Image Rachel Buckley
      Massachusetts General Hospital/Harvard Medical School
    • Posted:

    This is an amazing paper. It goes to the heart of trying to understand how the X chromosome, paternal history, and epigenetics all combine to influence rates of cognitive decline. We have seen increasing evidence over the years of maternal family history having an influence on Alzheimer’s disease risk. Dr. Mabel Seto from our group had a recent paper showing that maternal family history is associated with higher levels of amyloid in offspring of either sex, regardless of the maternal age of onset (Seto et al., 2024).

    This work fits with the growing literature on the importance of X-linked genes and their impact on AD. While this focuses on epigenetics on the maternal X, there are a broad range of questions being asked by many groups (citations below) that are trying to get to the bottom of whether, why, and how X-linked genes are associated with amyloid, tau and cognitive decline, in postmortem tissue and whole blood (RNA-Seq) as well as in DNA (GWAS). I think the exciting thing about the X is that we’re seeing more and more evidence of protection on this chromosome and not just risk.

    We can’t yet draw conclusions from Abdulai-Saiku et al. to human cohorts because we haven’t directly tested these questions, but the paper certainly gives us food for thought about the impact of sex-specific biological pathways that might echo through the generations. We should work on understanding how much these animal model findings can be replicated and how much they tell us about what is happening in the human condition.

    References:

    Seto M, Hohman TJ, Mormino EC, Papp KV, Amariglio RE, Rentz DM, Johnson KA, Schultz AP, Sperling RA, Buckley RF, Yang HS. Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults. JAMA Neurol. 2024 Aug 1;81(8):798-804. PubMed.

    Belloy ME, Le Guen Y, Stewart I, Williams K, Herz J, Sherva R, Zhang R, Merritt V, Panizzon MS, Hauger RL, Gaziano JM, Logue M, Napolioni V, Greicius MD. Role of the X Chromosome in Alzheimer Disease Genetics. JAMA Neurol. 2024 Oct 1;81(10):1032-1042. PubMed.

    Davis EJ, Broestl L, Abdulai-Saiku S, Worden K, Bonham LW, Miñones-Moyano E, Moreno AJ, Wang D, Chang K, Williams G, Garay BI, Lobach I, Devidze N, Kim D, Anderson-Bergman C, Yu GQ, White CC, Harris JA, Miller BL, Bennett DA, Arnold AP, De Jager PL, Palop JJ, Panning B, Yokoyama JS, Mucke L, Dubal DB. A second X chromosome contributes to resilience in a mouse model of Alzheimer's disease. Sci Transl Med. 2020 Aug 26;12(558) PubMed.

    View all comments by Rachel Buckley

  3. This tremendous and sophisticated study highlights the complexity of how the X chromosome may be involved in brain aging and neurodegeneration.

    It is a striking observation that when the maternally inherited X chromosome is not inactivated (while the paternal one is), some of its genes are additionally silenced due to imprinting with subsequent effects on cognition. This imprinting on the maternal X chromosome, if observed in humans, would likely lead to heterogeneity in brain aging in women and may cause a subset of women to have increased risk for neurodegenerative disorders such as Alzheimer's disease.

    This mechanism is to my knowledge essentially unexplored in human studies. It is very exciting to think that future epigenetic and genetic studies may shed light on X chromosome imprinting and the imprinted genes prioritized by Abdulai-Saiku et al. We will certainly keep a close look at these genes in ongoing X chromosome genetic studies of Alzheimer's disease to understand how they may tie into female risk biases.

    View all comments by Michael Belloy

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References

News Citations

  1. Does Second X Chromosome Boost Women’s Resilience Against Alzheimer’s?
  2. X-Chromosome-Wide Association Data Spot Alzheimer’s Loci

Paper Citations

  1. Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE, Longshore J, Willard HF. X chromosome-inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet. 2006 Sep;79(3):493-9. Epub 2006 Jul 27 PubMed.
  2. Eble TN, Sutton VR, Sangi-Haghpeykar H, Wang X, Jin W, Lewis RA, Fang P, Van den Veyver IB. Non-random X chromosome inactivation in Aicardi syndrome. Hum Genet. 2009 Mar;125(2):211-6. Epub 2009 Jan 1 PubMed.
  3. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. PubMed.
  4. Kubo Y, Yanagawa Y, Matsumoto M, Hiraide S, Kobayashi M, Togashi H. Toll-like receptor 7-mediated enhancement of contextual fear memory in mice. Pharmacol Biochem Behav. 2012 Oct;102(4):495-501. Epub 2012 Jun 28 PubMed.
  5. Hung YF, Chen CY, Li WC, Wang TF, Hsueh YP. Tlr7 deletion alters expression profiles of genes related to neural function and regulates mouse behaviors and contextual memory. Brain Behav Immun. 2018 Aug;72:101-113. Epub 2018 Jun 7 PubMed.
  6. Skuse DH, James RS, Bishop DV, Coppin B, Dalton P, Aamodt-Leeper G, Bacarese-Hamilton M, Creswell C, McGurk R, Jacobs PA. Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Nature. 1997 Jun 12;387(6634):705-8. PubMed.
  7. Mendes M, Chen DZ, Engchuan W, Leal TP, Thiruvahindrapuram B, Trost B, Howe JL, Pellecchia G, Nalpathamkalam T, Alexandrova R, Salazar NB, McKee EA, Rivera-Alfaro N, Lai MC, Bandres-Ciga S, Roshandel D, Bradley CA, Anagnostou E, Sun L, Scherer SW. Chromosome X-wide common variant association study in autism spectrum disorder. Am J Hum Genet. 2025 Jan 2;112(1):135-153. Epub 2024 Dec 19 PubMed.
  8. Grunin M, Igo RP Jr, Song YE, Blanton SH, Pericak-Vance MA, Haines JL, International Age-related Macular Degeneration Genomics Consortium. Identifying X-chromosome variants associated with age-related macular degeneration. Hum Mol Genet. 2024 Dec 6;33(24):2085-2093. PubMed.

Further Reading

Primary Papers

  1. Abdulai-Saiku S, Gupta S, Wang D, Marino F, Moreno AJ, Huang Y, Srivastava D, Panning B, Dubal DB. The maternal X chromosome affects cognition and brain ageing in female mice. Nature. 2025 Jan 22; Epub 2025 Jan 22 PubMed.
  2. Jiang Z, Sullivan PF, Li T, Zhao B, Wang X, Luo T, Huang S, Guan PY, Chen J, Yang Y, Stein JL, Li Y, Liu D, Sun L, Zhu H. The X chromosome's influences on the human brain. Sci Adv. 2025 Jan 24;11(4):eadq5360. Epub 2025 Jan 24 PubMed.

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