Obituary: Mary Frances Lyon, geneticist

Heavyweight geneticist whose work led to greater understanding of haemophilia. Picture: Contributed

Mary Lyon was born into a post-Great War era, when women who had served their country with distinction were being subsequently returned to the home, and those who endeavoured to carve out a career encountered the prejudices and inequalities in the workplace that would plague them over the ensuing decades.

Lyon, however, successfully entered the male-dominated world of academia and, with unrelenting determination, overcame this prejudice to become one of the foremost geneticists of the 20th century. Her ground-breaking research culminated in the theory of X-chromosome inactivation, an important cytogenetic phenomenon.

The process of X-chromosome inactivation, later known as “Lyonisation” in her honour, led to huge advances in science’s understanding of diseases such as haemophilia and Duchenne Muscular Dystrophy and her research in mouse genetics contributed to a better understanding of human genetic inheritance – how traits and diseases are passed on.

In 1961, while working on the effects of radiation, Lyon’s Nature Paper proposed the random but permanent inactivation in early embryonic life of one of the two X-chromosomes in the cells of mammalian females, so the genes were effectively switched off; this explained the mottled or dappled phenotype of female mice heterozygous for coat colour genes.

The Lyon hypothesis also accounted for the findings that one copy of the X-chromosome in female cells was highly condensed, and that mice with only one copy of the X-chromosome developed as infertile females, but which X-chromosome is inactivated is purely random and varies from cell to cell.

This is how female cats, but not males, can have tortoiseshell coats – there was the existence of two or more genetically distinct types of cells, with some cells responsible for black fur and others determining orange fur.

This theory was later extended to all mammals and led to an explanation for why women who are carriers of X-linked diseases can still show symptoms, such as bruising and excessive bleeding if carrying the recessive haemophilia gene, and was one of the first examples of epigenetics, now a scientific field in its own right, whereby changes in the expression of genes are caused not by alterations in the DNA itself but by non-genetic factors.

Further notoriety came with Lyon’s work on the T-complex, a genetic peculiarity found in wild-type mice, which also came out of work on radiation, as well as her mouse genetics advocacy, and made many other contributions to mammalian genetics.

The European Cytogeneticists Association said: “Mary was among the first to recognise the importance of mouse mutants both as potential models of human disease and for investigating biological processes.”

Born in Norwich in 1925, Mary Lyon was the oldest of three children to Clifford, a civil servant with the Inland Revenue, and Louise, a schoolteacher. Her father’s work took the family around the country, living in Yorkshire and Birmingham before settling in Woking, Surrey at the outbreak of the Second World War. While in Birmingham at King Edward VI Grammar School, Mary’s interest in biology was first triggered after she entered an essay-writing competition and won a set of nature books.

In 1943, she went to Girton College, Cambridge to read Zoology, Physiology and Biochemistry, becoming the Turle Scholar (1944) and receiving the Crewdson Prize (1945). As women did not receive full membership of the university until 1948, she graduated in 1946, with a “titular” degree, one of only 500 women out of over 5,500 students.

During this period, Lyon was influenced by Conrad Hal Waddington’s work and became interested in genetics, not yet a degree subject, and believing that genes must underlie all embryological development.

Remaining in Cambridge, she began a PhD in genetics with the eccentric but eminent geneticist and statistician Sir Ronald Fisher, but completed her research under the supervision of acclaimed Scottish geneticist Douglas Falconer at Edinburgh University, where she had access to better facilities.

Upon completion of her doctorate in 1950, she was offered a position working with Toby Carter at Edinburgh’s Institute of Animal Genetics, headed by Waddington, to conduct research on mice into the genetic hazards of radiation in the aftermath of the Japan nuclear bombings; there was mounting fear about the harmful effects of fallout in the atmosphere. Some suffered from ataxia, restricting movement; others had inner ear problems and ran in circles with no sense of balance.

Headed by Carter, in 1954, the team moved to the Medical Research Council Radiobiological Research Unit at Harwell, Oxfordshire, where a genetics division was established in order to understand the mechanisms of radiation damage in the atomic era.

Lyon also made significant contributions to understanding environmental mutagenesis. Her work on the effects of low-dose radiation on female germ-cells mutation in mammals indicated that only a fraction of mutation is due to low-dose environmental radiation.

In 1962, Lyon became head of the Genetics section of the Radiobiology unit where she remained until retirement in 1990, although she continued academic research until 2012.

She expanded the expertise of the unit by introducing Cytogenetics, work on biochemical genetic markers and early pre- and post-implantation mouse embryo manipulation. In 2004 the Mary Lyon Centre, which is a national facility for mouse functional genomics, was opened on the site where she worked in order to generate mouse models of human diseases.

Elected a fellow of the Royal Society in 1973, Lyon was also recognised with international honours and prizes, including becoming a Foreign Associate of the US National Academy of Sciences, receiving the Society’s Royal Medal (1984), the Wolf Prize for Medicine (1997) and the Pearl Meister Greengard Prize (2006), an international award to recognise the accomplishments of outstanding women scientists. In 2014, the UK Genetics Society created the Mary Lyon medal in her honour.

She is survived by her two siblings, Francis and Julia.