Contributions to Science

Lyon's Major Scientific Contributions

Lyon's Law

"It is here suggested that this mosaic phenotype is due to the inactivation of one or other X chromosome early in embryonic development."

"Thus, the general picture concerning heterozygotes for sex-linked genes in man is one of variable expression, which accords with the predicted result of random inactivation of one or the other X chromosome".

From Disteche (2015)

Figure 1. Artist rendition on an X-chromosome.

X-Chromosome Inactivation (Lyonization)

Lyon established her X-chromosome inactivation theory when she was working with mice that had variations in coat colours. She determined that female mice with multicoloured coats were heterozygous for sex-linked genes related to coat colour. She went on to study this phenomenon in more depth and discovered that only one X-chromosome is required for full development. Somatic cells only have one active X-chromosome, thus providing a dosage of the present genes. Additionally, the inactivation is irreversible and produces an all or none effect on the chromosome involved (Lyon 1974). The process is different in germ cells, in which both X-chromosomes are active. Lyon goes into more depth about each factor involved with X-chromosome inactivation and postulates various activation, or inactivation methods that may be present. One possibility is that X-chromosomes carry genes that regulate their own development and inactivation. She also hypothesized that there may be an inactivation center present on the chromosome. This latter theory held more promising results and can be read in more detail in a paper from (Disteche 2015).

Genetic Mosaicism

Genetic mosaicism is the presence of two or more cell lineages with different genotypes. This was observed in the mice heterozygous for a sex-linked “mutant” from Lyon's original studies and relates back to X-chromosome inactivation and dosage dependence (Lyon 1961). Similar to tortishell cats, the gene for coat colour is found on the X-chromosome. Each X-chromosome may have a different gene for coat colour, for example one chromosome may contain a gene that codes for black fur and the other for orange fur. The mosaic pattern only occurs in females because if they are heterozygous they have two colour options depending on which gene remains active, whereas males only have one X-chromosome and thus one colour gene. X-chromosome inactivation is random, therefore producing the variegated coat colour, and the slight differences of genotypes, and phenotypes, between patches.

Figure 2. Example of genetic mosaicism in tortishell cats. (Good Horse [accessed 2023 Nov])

Impact on Human Genetics

The X-chromosome encodes Innumerable genes In both women and men. Issues in its inactivation/regulation have profound pathological Implications.

Figure 3: X-linked variegation (Krebs).

The Problem

Does X-chromosome dosage compensation occur via "up-regulation of X-linked genes in males... [or] the inactivation of one of the two X-chromosomes in females?" (Loda et al. 2022)

The Solution

"[Lyon's] X-chromosome inactivation (XCI) is now accepted as the strategy that equalizes gene dosage between the sexes, through the transcriptional silencing of almost the entire X chromosome during female development" (Loda et al. 2022).

XCI and Intellectual Disability

"Extreme skewing of X-chromosome inactivation (XCI) can be associated with ID (intellectual disability) phenotypes caused by pathogenic variants in the X chromosome" (Luiza Dias Chaves et al. 2023).

XCI and Substance Abuse Disorder

"The role of XCI and XCI escape on the epigenetic regulation of X linked genes are of crucial importance in clarifying sex associated differences associated with substance use disorders" (Krueger et al. 2023).

XCI and Recurrent Pregnancy Loss (RPL)

"Patients with RPL exhibited a significantly more skewed XCI distribution pattern" (Sui et al. 2022).

Click here to view references for this page

Disteche CM. 2015. X-chromosome Inactivation and Escape. Journal of Genetics. [accessed 2023 Nov 6]. 94; 591–599. https://doi-org.login.ezproxy.library.ualberta.ca/10.1007/s12041-015-0574-1

Loda A, Collombet S, Heard E. 2022. Gene regulation in time and space during X-chromosome inactivation. Nature Reviews Molecular Cell Biology. 23. doi:https://doi.org/10.1038/s41580-021-00438-7

Krueger K, Lamenza F, Gu HH, El‐Hodiri HM, Wester JC, Oberdick J, Fischer AJ, Oghumu S. 2023. Sex differences in susceptibility to substance use disorder: Role for X chromosome inactivation and escape? Molecular and Cellular Neuroscience. 125:103859–103859. doi: https://doi.org/10.1016/j.mcn.2023.103859.

Luiza Dias Chaves, Machado L, Giovanna Cantini Tolezano, Sara Ferreira Pires, Souza S, Scliar MO, Liane, Débora Romeo Bertola, Cíntia Barros Santos-Rebouças, Go Hun Seo, et al. 2023. Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants. Molecular Neurobiology. 60(7):3758–3769. doi:https://doi.org/10.1007/s12035-023-03311-0.

Lyon MF. 1961. Gene Action in the X-chromosome of the Mouse (Mus musculus L.). Nature. [accessed 2023 Oct 30];90:372-373. https://doi.org/10.1038/190372a0

Lyon MF. 1974. Review Lecture: Mechanisms and evolutionary origins of variable X-chromosome activity in mammals. The Royal Society. [accessed 2023 Nov 6]; 187(1088):243–268. http://doi.org.login.ezproxy.library.ualberta.ca/10.1098/rspb.1974.0073

Lyon MF. 1962. Sex chromatin and gene action in the mammalian X-chromosome. American Journal of Human Genetics. [accessed 2023 Nov];14(2):135–148. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1932279/

Sui Y, Fu J, Zhang S, Li L, Sun X. 2022. Investigation of the role of X chromosome inactivation and androgen receptor CAG repeat polymorphisms in patients with recurrent pregnancy loss: a prospective case–control study. BMC Pregnancy and Childbirth. 22(1). doi:https://doi.org/10.1186/s12884-022-05113-z.

Photo references

Header image courtesy of: Giersch ABS. 2014. Introduction to Cytogenetics. Pathobiology of Human Disease. [accessed 2023 Nov 6]; 2014: 3304-3310. https://doi.org/10.1016/B978-0-12-386456-7.06401-7

Figure 1. X Chromosome Reactivation Provides a Potential Strategy for Treating X-Linked Disorders. 2018. Massachusetts General Hospital. Sci Tech Daily; [accessed 2023 Nov] https://scitechdaily.com/x-chromosome-reactivation-provides-a-potential-strategy-for-treating-x-linked-disorders/

Figure 2. Introduction to Genetics, Case Study 1: Tortoiseshell cat colour. 2019. Good Horse. Introduction to Genetics, Case Study 1: Tortoiseshell cat colour; [accessed 2023 Nov]. https://good-horse.com/genetics-evolution/introduction-genetics-case-study-1-tortoiseshell-cat-colour/

Figure 3. Krebs J. X Chromosomes Undergo Global Changes. المرجع الالكتروني للمعلوماتية. [accessed 2023 Dec 3]. https://almerja.net/reading.php?idm=153151&PageSpeed=noscript.

Page updated

Report abuse