The importance of having two X chromosomes
Open accessAbstract
Historically, it was thought that the number of X chromosomes plays little role in causing sex differences in traits. Recently, selected mouse models have been used increasingly to compare mice with the same type of gonad but with one versus two copies of the X chromosome. Study of these models demonstrates that mice with one X chromosome can be strikingly different from those with two X chromosomes, when the differences are not attributable to confounding group differences in gonadal hormones. The number of X chromosomes affects adiposity and metabolic disease, cardiovascular ischaemia/reperfusion injury and behaviour. The effects of X chromosome number are likely the result of inherent differences in expression of X genes that escape inactivation, and are therefore expressed from both X chromosomes in XX mice, resulting in a higher level of expression when two X chromosomes are present. The effects of X chromosome number contribute to sex differences in disease phenotypes, and may explain some features of X chromosome aneuploidies such as in Turner and Klinefelter syndromes.
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X and Y gene dose discrepancies account for several sex-biased phenotypes in the brain and periphery.
“Questions regarding the effects of X and Y gene imbalance have been explored over the past decade, and the data suggests that X and Y gene dose discrepancies account for several sex-biased phenotypes in the brain and periphery (Arnold, 2004; Arnold et al., 2016; Burgoyne et al., 1995).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Arnold et al., 2016
The Conclusion and prospectus reports that differences in X and Y chromosome effects cause sex differences in non-gonadal tissues, and section 4 gives an example involving body weight. But the Conclusion says the responsible X genes have not yet been identified and nongenic effects cannot be ruled out. The paper therefore supports sex-chromosome effects on phenotypes, not the stronger claim that X and Y gene-dose discrepancies have been established as their cause. (LLM, conf=0.85)
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Holásková, I., Franko, J., Goodman, R. L., Arnold, A. P., & Schafer, R. (2015) · American Journal of Reproductive Immunology · doi:10.1111/aji.12378 · Cited by 18 · see citing works
Self-citationQuinnies, K. M., Bonthuis, P. J., Harris, E. P., Shetty, S. R. J., & Rissman, E. F. (2015) · Biology of Sex Differences · doi:10.1186/s13293-015-0026-x · Cited by 17 · see citing works
X Chromosome and Autosome Dosage Responses in Drosophila melanogaster Heads
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Lue, Y., Wang, C., Liu, P. Y., Erkkilä, K., & Swerdloff, R. S. (2010) · PubMed · Cited by 12 · see citing works
Flagged first, then by citations
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Cited by
Sorted by citations
Iorga, A., Cunningham, C. M., Moazeni, S., Ruffenach, G., Umar, S., & Eghbali, M. (2017) · Biology of Sex Differences · doi:10.1186/s13293-017-0152-8 · Cited by 914 · see citing works
Self-citationOyola, M. G., & Handa, R. J. (2017) · Stress · doi:10.1080/10253890.2017.1369523 · Cited by 710 · see citing works
“Questions regarding the effects of X and Y gene imbalance have been explored over the past decade, and the data suggests that X and Y gene dose discrepancies account for several sex-biased phenotypes in the brain and periphery (Arnold, 2004; Arnold et al., 2016; Burgoyne et al., 1995).”
BackgroundBurgoyne, P. S., & Arnold, A. P. (2016) · Biology of Sex Differences · doi:10.1186/s13293-016-0115-5 · Cited by 154 · see citing works
Self-citationBhargava, A., Arnold, A. P., Bangasser, D. A., Denton, K. M., Gupta, A., Hilliard Krause, L. M., Mayer, E. A., McCarthy, M., Miller, W. L., Raznahan, A., et al. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnaa034 · Cited by 130 · see citing works
Self-citationSex differences in neuroinflammation and neuroprotection in ischemic stroke
Spychala, M. S., Honarpisheh, P., & McCullough, L. D. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.23962 · Cited by 127 · see citing works
“The development of the immune system occurs in the setting of the XX versus XY chromosomal background, with an additional contribution from gonadal hormones (Arnold et al., 2016; Fischer et al., 2015; Trigunaite et al., 2015).”
BackgroundFast, furious and enduring: Sensitive versus critical periods in sexual differentiation of the brain
McCarthy, M. M., Herold, K., & Stockman, S. L. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.10.030 · Cited by 97 · see citing works
A new view of sexual differentiation of mammalian brain
McCarthy, M. M. (2020) · Journal of Comparative Physiology A · doi:10.1007/s00359-019-01376-8 · Cited by 85 · see citing works
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- Authors
- Arnold, A. P., Reue, K., Eghbali, M., Vilain, E., Chen, X., Ghahramani, N., Itoh, Y., Li, J., Link, J. C., Ngun, T., & Williams-Burris, S. M.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Arnold, Arthur P.
- ORCID
- Venue
- Philosophical Transactions of the Royal Society B: Biological Sciences
- Publisher
- The Royal Society
- Published
- 2016-02-19
- Volume
- 371
- Issue
- 1688
- Pages
- 20150113
- ISSN
- 0962-8436 (ISSN-L)
- 1471-2970
- PMC
- PMC4785899
- OpenAlex
- W2338995534
- Cited by
- 114
- References
- 98
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 10 · 2023: 5 · 2022: 9 · 2021: 11 · 2020: 11 · 2019: 13 · 2018: 15 · 2017: 13 · 2016: 17
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Philosophical Transactions of the Royal Society B Biological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (DK083561, HD076125, HL119886, HL90553, NS043196, T32GM007185, T32HD007228)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Keywords
- X chromosome number, sex differences, X chromosome inactivation, X chromosome aneuploidy, Turner syndrome, Klinefelter syndrome, adiposity, metabolic disorders, behavior, mouse model
- MeSH terms
- Animals, Female, Gene Expression Regulation, Genotype, Male, Sex Factors, Gonadal Steroid Hormones, X Chromosome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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