Mary F. Lyon: From Mice to Tortoiseshells
Written By Sydney Kim
Mary Frances Lyon was born in the United Kingdom in 1925 as the eldest of three children. With the help and encouragement of her elementary schoolteacher, Lyon soon developed an interest in the biological sciences, choosing to study zoology at the University of Cambridge by 1943. Although Cambridge only allowed women to receive titular degrees, Lyon successfully graduated and started her PhD under geneticist R. A. Fisher, where her lifelong studies of mice began as the Second World War drew to a close.
After moving to Harwell in 1955, Lyon earnestly dove into her research connecting mice and embryonic development. In 1959, geneticist Susumu Ohno found that two mammalian X chromosomes in each somatic cell of a female differed; one looked similar to the other chromosomes— autosomes— while the other was condensed into a compact form, visible in the nuclei. Lyon soon noticed that male mice either died during embryonic development or only had a single coat color, and female mice were still viable even if they had only one X chromosome. These observations led to her official proposal of the X-inactivation phenomenon, or “Lyonization” as it came to be known, in 1961.
Lyon presented that during early development of female embryos, pre-embryonic cells randomly inactivate one copy of the X chromosome, so that as development continues, their daughter cells inherit the same inactivation. Thus, some somatic cells would express the X chromosome inherited from the mother, while others would express the one inherited from the father, but not both. This explained why female cells did not make double the amount of X-linked gene products as male cells— one of the X chromosomes simply condensed into what we know today as a Barr Body, and methylation did not allow that chromosome to be expressed. Despite public opposition from Hans Gruneberg, one of the leading scientists in the same field of mouse genetics, Lyon’s hypothesis was proven to be correct and her work received recognition: she became a Fellow of the Royal Society in 1973 and won the Royal Medal in 1984.
Outside of the laboratory, Lyon headed the Committee on Standardized Genetic Nomenclature for Mice for 15 years, in which she developed a common language for the field, and also worked as an editor for the Mouse News Letter, helping foster scientific collaboration between the U.K. and the U.S. in the postbellum period. Lyon’s research at Harwell had not finished, either. One of her other most notable projects was discovering the mechanism behind chromosome 17’s t-complex in certain mice, which codes for “t-haplotypes” (DNA rearrangements) that offspring can inherit from the father, sometimes leading to reduced viability or fertility. This was a landmark contribution to the study of non-Mendelian genetics and the effect of chromosomal abnormalities. Over the next few decades, Lyon developed tools for using mice as model organisms in molecular biology, and in the 1980s, worked out mouse and human homology maps, setting the stage for the Human Genome Project in the 1990s.
Lyon passed away on Christmas Day in 2014, but her legacy lives on. Today, Lyon’s work has proved essential to discovering the genetic basis of X-linked diseases (such as hemophilia and Duchenne muscular dystrophy), the Xist gene (non-coding RNA molecules that switches off gene expression in the X chromosome), the origin of tumors, and the development of germ cells. Additionally, X-inactivation explains the reason behind the patchwork fur of tortoiseshell cats; if the X chromosome coding for black fur is inactivated, then the other X chromosome coding for orange fur will be expressed (and vice versa), resulting in patches of differently colored fur. Perhaps unsurprisingly, Lyon had had a tortoiseshell companion herself.
Sohaila Rastan, Lyon’s second PhD student and today a leading researcher at the Action of Hearing Loss organization in London, voices pride in her mentor’s unique personality and determined spirit: “When I began my PhD with her in 1977, she gave me a handful of papers, showed me the genetic tools — mice carrying the various mutations and chromosomal rearrangements — and said, ‘do something on X-inactivation.’ That degree of academic freedom was exhilarating, coupled as it was with the safety net of robust critique” (Rastan).
Sources
Fisher, Elizabeth M. C., and Jo Peters. “Mary Frances Lyon (1925–2014).” Cell, vol. 160, no. 4, Feb. 2015, pp. 577–78, https://doi.org/10.1016/j.cell.2015.01.039.
Rastan, Sohaila. “Mary F. Lyon (1925–2014).” Nature, vol. 518, no. 7537, Feb. 2015, pp. 36–36, https://doi.org/10.1038/518036a.
Scrase, Richard. “Mary Lyon: 20th Century Geneticist.” Understanding Animal Research, 26 Feb. 2015, www.understandinganimalresearch.org.uk/news/mary-lyon-geneticist.
