Mary Frances Lyon (1925–2014)

Mary Frances Lyon studied gene expression and developed the theory of X-chromosome inactivation, also called Lyonization, during the twentieth century in the United Kingdom. The Lyonization hypothesis proposes that, even though females have two X-chromosomes and males have only one, one X-chromosome in females is always randomly inactivated, which causes males and females to have the same level of X-chromosome gene expression. Prior to Lyon’s hypothesis, scientists understood that there must be a biological way to compensate for the difference in X-chromosomes in males and females, but they did not know the exact mechanism. To investigate the topic, Lyon studied coat color in mice, a trait influenced by genes on the X-chromosome. Her resulting hypothesis highlighted X-chromosome inactivation as a mechanism for controlling gene expression in females without altering their DNA sequence. Through her research, Lyon aided scientists in understanding X-linked disorders, which laid the foundation for the development of gene therapies designed to treat X-linked disorders that affect hundreds of thousands of people globally.

1. Early Life and Education
2. Early Research at the Medical Research Council
3. X-Inactivation Theory
4. Research from the 1960s to 1980s
5. Awards and Legacy

Early Life and Education

Lyon was born on 15 May 1925 in Norwich, England. She was the oldest child, born to Louise Frances Lyon, née Kirby, and Clifford James Lyon, and had a younger brother and sister. Lyon’s mother worked as a schoolteacher, and her father was a civil servant. The Lyon family moved to Yorkshire, England, when Lyon was four years old, then to Birmingham, England, in 1935, when she was ten years old. In Birmingham, Lyon briefly attended King Edward VI High School. According to a 2010 interview with Jane Gitschier, a professor emeritus at the University of California, San Francisco, California, it was there that Lyon developed her interests in physics, chemistry, and biology. In 1939, when she was fourteen years old, Lyon’s family moved to Woking, England, where she lived throughout the remainder of her childhood.

Lyon received a titular undergraduate degree in zoology from the all-women’s Girton College in Girton, England, in 1946. At the time, the University of Cambridge system, of which Girton College was part, provided women with only titular degrees. A titular degree means that, for the same coursework and exams as men, women would only receive a certificate, not an official degree from the university.

After graduating with her titular degree, Lyon started her doctoral research in 1946. Lyon initially began her doctoral research with Ronald Aylmer Fisher, a researcher who studied math and genetics at the University of Cambridge in Cambridge, England. During her time with Fisher, she started researching the pallid mutation, which causes platelets, a particle in the blood that helps in clotting, to not function properly, in mice. Lyon observed that mice with the mutation tended to tip their heads to one side and were missing part of their inner ear. Due to her observations, she began to investigate the effects and correlation between those traits. However, to continue her research project, Lyon required larger resources than the ones available at her institution, so she transferred to the Institute of Animal Genetics at the University of Edinburgh in Edinburgh, Scotland, to finish her work under the supervision of Douglas Falconer, a researcher who discovered one of the first sex-linked mouse mutations. Conrad Hal Waddington, a researcher who studied embryology and helped describe the paths cells can take as they differentiate and specialize, also worked at the same university. Lyon worked with both Falconer and Waddington to successfully finish her doctoral degree in genetics in 1950, with a thesis focusing on the pallid gene mutation in mice.

Early Research at the Medical Research Council

In 1950, Lyon began working as a postdoctoral researcher at the University of Edinburgh, where she continued studying pallid mutations and started studying the genetic effects of radiation on mice through funding from the Medical Research Council, or MRC. The MRC is an agency in the United Kingdom that funds medical research, with a focus on improving public health. The MRC was an organization that provided equal pay for women, a rare circumstance during the 1950s. Waddington aided Lyon in gaining postdoctoral funding from the MRC so that she could continue her work on the pallid mutation. After World War II ended, concerns regarding the potential radiation effects from the atomic bombings on Japan arose, so Lyon also received MRC funding to join Toby Carter, a researcher who studied embryology and genetics at the University of Edinburgh, to study the genetic mutation effects of radiation. Lyon and Carter’s team studied mutant mice in an attempt to better understand the inherited genetic risks associated with exposure to radiation from the atomic bombs. Although the team obtained results with some mutants, they required additional resources to breed the mice than what were available in Edinburgh and so moved to the MRC Radiobiological Research Unit in Harwell, England, in 1955 for access to larger facilities. Concurrently, starting in 1956, Lyon also worked as the editor of the Mouse News Letter, or MNL, until 1970. The MNL was an informal publication that spread information about mutants and linkage maps, which show the order and relative distance of genes on a chromosome, among mouse geneticists, mostly in the United States and United Kingdom.

X-Inactivation Theory

By the early 1950s, researchers understood that certain traits were sex-linked but did not have a mechanism to explain that phenomenon. At that time, scientists knew that mouse coat color was sex-linked, which suggested the relevant coat color genes were carried on the X-chromosome. They also knew that mottled mice, or mice with two coat colors caused by an altered DNA sequence, existed. Researchers had already observed that male mice were either born with one coat color, white, or died as embryos. Female mice could have a single coat color or two different coat colors, and those with two different coat colors were known as mottled mutants.

Around 1960, Lyon identified one mutant mouse that was a mottled male. In the interview with Gitschier, Lyon explained that mottled mutants are possible in females because females have two X-chromosomes and, therefore, can have different alleles on each chromosome, representing two different coat colors. In contrast, males have only one X-chromosome, so they can have only one coat color depending on the allele on their X-chromosome. Lyon hypothesized that the male mottled mouse had a small gene mutation that occurred during embryonic development, causing the mouse to have some cells with the normal X-chromosome and some with a mutated X-chromosome that created his mottled pattern. In the interview with Gitschier, Lyons explained how she applied the idea that the mottled male had two types of cells, one with the normal coat color gene active and the other with the mutant color gene active, to the mottled male’s daughters to determine if females also have two types of cells. Around the same time, other researchers were studying X-chromosomes and discovered the Barr Body, which is a condensed X-chromosome. Lyon’s work, coupled with the discovery of the Barr Body and the concept that female mice only require one X-chromosome to exhibit normal development, led Lyon to form her X-inactivation hypothesis.

Lyon published her X-inactivation hypothesis, later known as Lyonization, in her 1961 paper entitled “Gene Action in the X-Chromosome of the Mouse (Mus musculus L.)” in the journal Nature. In the paper, Lyon proposes X-chromosome inactivation as the mechanism for balancing the expression of X-linked genes between males and females. According to her hypothesis, females only express one of their X-chromosomes in each cell, similar to males, and the other is the condensed and inactivated Barr Body. She also details that X-chromosome inactivation is a random process.

Although most researchers received her 1961 paper well, it encountered criticism from Hans Grüneberg, a researcher who studied genetics and was a member of the Fellow of the Royal Society, a national organization in the United Kingdom dedicated to promoting and recognizing science. Soon after Lyon’s publication, Grüneberg published various papers detailing his criticisms of her theory. According to Gitschier, Lyon mentioned that Grüneberg disagreed with Lyon’s hypothesis for two reasons: Grüneberg did not believe Lyon had enough stature as a researcher to publish such a prominent theory, and he thought that Lyon’s evidence was not sufficient to support her hypothesis. He created his own criteria to test the Lyonization hypothesis and provided evidence that the sex-linked gene tabby in heterozygous mice, mice that have two different alleles for a gene, have both alleles active, exhibit non-random X-chromosome inactivation. As a result, Grüneberg explicitly wrote in his work that his experimental results did not indicate any sort of X-chromosome inactivation and disproved Lyon’s theory. Despite the criticism, Lyon continued her research focusing on X-chromosome inactivation, and as of 2025, researchers generally accept her hypothesis.

Research from the 1960s to 1980s

At MRC-Harwell, in the 1960s, Lyon also focused her work with mouse genetics on chromosome 17 and received a promotion to head of the genetics division in 1962, a position she held until 1987. During that time, she studied chromosome 17, which encodes the t-complex, or a genetic anomaly found in wild mice that gives rise to genetic variations known as t-haplotypes. Lyon identified that within the t-complex, certain t-haplotypes transmit more frequently to their offspring than others, and mice carrying two copies of the same t-haplotype are either not viable or sterile. According to Sohaila Rastan, Lyon’s former student and executive director of biomedical research at Action on Hearing Loss in London, England, Lyon’s findings with the t-complex explained non-Mendelian inheritance, which occurs when traits segregate abnormally, as well as chromosomal recombination, or the exchange of genetic material between chromosomes during development.

Lyon spent most of her career at MRC-Harwell apart from a short sabbatical at Cambridge from 1970 to 1971. During that brief interlude, she held a Clothworkers’ visiting research fellowship with Richard Gardner, a researcher who studies genetics and embryos. Lyon and Gardner studied the time between mouse fertilization and implantation of the embryo to determine the timing of X-inactivation. They determined that X-inactivation occurs in the blastocyst stage of the embryo, or between three and five days after fertilization.

When she returned from her sabbatical, she started mouse embryo banking at MRC-Harwell. Lyon was one of the first researchers to recognize that mouse embryo banking, or the technique of freezing mouse embryos at specific stages of development to preserve their genetic traits, was viable. As of 2025, the bank Lyon and MRC-Harwell developed, known as Frozen Embryo and Sperm Archive, or FESA, is a public center in the United Kingdom that archives and distributes strains of mouse DNA to the community. FESA allows researchers to preserve their mouse strains for future use. Archived strains at FESA are available publicly to all scientists for cooperative research.

According to researchers Elizabeth Fisher and Jo Peters, in their biographical article on Lyon, Lyon studied age-related X-chromosome reactivation in the latter part of her career. During that time, from 1982 to 1990, she was deputy director of the Radiobiology Unit at MRC-Harwell. Through her research, Lyon posited that some X-linked genes in mice that scientists thought to be permanently inactivated could actually become reactivated as the mice age. Lyon found that certain genes on the condensed Barr Body, the inactivated X-chromosome in females, exhibited expression in aged mice. She proposed that the reactivation of those genes was age-dependent and could help scientists understand age-related diseases and the role of X-chromosome inactivation in aging. Lyon and her research team published those findings in the 1987 Nature article “Age Related Reactivation of an X-Linked Gene.”

Awards and Legacy

Lyon officially retired from MRC-Harwell in 1990 but continued working and researching there until 2012, when she received a diagnosis of Parkinson’s disease. She won many awards and honors for her research. In 1973, the Royal Society inducted Lyon as a fellow. The Royal Society is a scientific society based in the United Kingdom, known for supporting scientific research and the fellowship of scientists. In 1984, the Royal Society presented Lyon with the Royal Society Gold Medal, which is one of the highest awards a scientist can receive in the United Kingdom. Lyon won the Wolf Prize in Medicine in 1996 for her Lyonization hypothesis. The Wolf Prize is an international award in the sciences and arts that recognizes scientists who have made outstanding and impactful contributions to their respective fields. In 1998, the University of Cambridge awarded Lyon a full undergraduate degree certificate to replace the titular degree she received in 1946. Then, in 2004, the MRC created the Mary Lyon Centre in Lyon’s honor. As of 2025, the Mary Lyon Centre remains open and continues to study human diseases through mouse models. Finally, in 2015, the UK Genetics Society established what they call the Mary Lyon Medal to reward notable research in genetics.

As of 2025, researchers support Lyon’s research findings. According to Google Scholar, over 4,900 publications have cited Lyon’s 1961 paper, “Gene Action in the X-Chromosome of the Mouse (Mus musculus L.),” and her work laid the basis for understanding sex-linked traits and gene expression. Lyon’s work was one of the earliest to show how chemical modifications in chromosomes, rather than changes to the DNA sequence itself, can control gene expression. That research aided scientists in understanding key concepts behind what developmental biologists call epigenetic regulations. Epigenetic regulation is when DNA activity and expression change without an actual change in the DNA sequence. Lyonization also supported researchers in comprehending X-linked diseases such as color blindness and hemophilia, an inherited bleeding disorder in which a person’s blood does not clot properly. Around thirty years after Lyon published her Lyonization hypothesis, in the early 1990s, researchers used her work to aid in the discovery of X-inactive specific transcript, or Xist, a non-coding region of RNA that initiates X-chromosome inactivation. Xist is a long non-coding RNA molecule in females that regulates X-chromosome inactivation. Discovering the mechanism helped scientists understand the basis of epigenetic mechanisms in gene regulation, and it helped them to eventually develop gene therapies targeting X-linked disorders like Duchenne muscular dystrophy, a disorder that impacts over 200,000 people in the United States. 

Lyon died on 25 December 2014 in Oxfordshire, England. 

Sources

1. Fisher, Elizabeth M. C., and Jo Peters. “Mary Frances Lyon (1925-2014).” Cell 160 (2015): 577–8. https://www.cell.com/cell/pdf/S0092-8674(15)00117-8.pdf (Accessed July 1, 2025).
2. Fisher, Elizabeth, and Sohaila Rastan. “Mary Frances Lyon. 15 May 1925 – 25 December 2014.” In Biographical Memoirs of Fellows of the Royal Society, 2024. https://royalsocietypublishing.org/doi/10.1098/rsbm.2024.0005 (Accessed July 1, 2025).
3. Gardner, R. L., and Mary F. Lyon. “Biological Sciences: X Chromosome Inactivation Studied by Injection of a Single Cell into the Mouse Blastocyst.” Nature 231 (1971): 385–6.
4. Gitschier, Jane. “The Gift of Observation: An Interview with Mary Lyon.” PLoS Genetics 6 (2010): e1000813. https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1000813 (Accessed July 1, 2025).
5. Grüneberg, Hans. “The Molars of the Tabby Mouse, and a Test of the “Single-Active X-Chromosome’ Hypothesis.” Journal of Embryology and Experimental Morphology 15 (1966): 223–44.
6. Haines, Catharine M. C. “Lyon, Mary Frances (1925-2014).” Oxford Dictionary of National Biography (2018).
7. JPND Research. “The Harwell Frozen Embryo and Sperm Archive (FESA).” JPND Research. https://neurodegenerationresearch.eu/survey/the-harwell-frozen-embryo-and-sperm-archive-fesa/ (Accessed July 1, 2025).
8. Lyon, Mary F. “A Further Mutation of the Mottled Type: In the House Mouse.” Journal of Heredity 51 (1960): 116–21.
9. Lyon, Mary F “Transmission Ratio Distortion in Mice.” Annual Review of Genetics 37 (2003): 393–408.
10. PBS. “Women and Work After World War II.” PBS. https://www.pbs.org/wgbh/americanexperience/features/tupperware-work/ (Accessed July 1, 2025).
11. Rastan, Sohaila. “Mary F. Lyon (1925-2014).” Nature 518 (2015): 36. https://www.nature.com/articles/518036a (Accessed July 1, 2025).
12. Salari, Nader, Behnaz Fatahi, Elahe Valipour, Mohsen Kazeminia, Reza Fatahian, Aliakbar Kiaei, Shamarina Shohaimi, and Masoud Mohammadi. “Global Prevalence of Duchenne and Becker Muscular Dystrophy: A Systematic Review and Meta-Analysis.” Journal of Orthopaedic Surgery and Research 17 (2022): 96. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848641/ (Accessed July 1, 2025).
13. The Genetics Society. “Mary Lyon Medal.” The Genetics Society. https://genetics.org.uk/medals-and-prizes/genetics-society-medals-and-lectures/mary-lyon-medal/ (Accessed July 1, 2025).
14. Wareham, Kathryn A., Mary F. Lyon, P. H. Glenister, and E. D. Williams. “Age Related Reactivation of an X-linked Gene.” Nature 32 (1987): 725–7.
15. Watts, Geoff. “Mary Frances Lyon.” The Lancet 385 (2015): 768. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60427-5/fulltext (Accessed July 1, 2025).