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X chromosome inactivation

Mary Lyon was a geneticist who worked at MRC Harwell Institute for a period spanning more than 50 years. One of the most important discoveries she made was the process of X inactivation in 1961 while studying a mutant strain of mice with mottled fur, also known as ‘Lyonisation’.

Whether we are male or female depends on the genes we inherit from our parents. Our genes are carried on chromosomes and the two sex chromosomes X and Y determine whether we are chromosomally male or female. If we inherit XX chromosomes we are female, and if we inherit XY we are male.

The X chromosome carries over 1,000 important genes whereas the Y chromosome carries relatively few. This means that a female carries twice the amount of X chromosome genes as a male – a potentially toxic double dose. Mary hypothesised that one of the two X chromosomes in the cells of female mammals is randomly inactivated during early development so that females do not have twice the number of X chromosome gene products as males.

‘I got stuck and I thought; let’s change the subject. Perhaps a change will give me some new ideas’

A prime example of this is the genetics of tortoiseshell cats – nearly all tortoiseshell cats are female. The genes encoding coat colour are carried on the X chromosome. As males have one X chromosome they have one version of the gene and therefore have an entirely ginger or non-ginger coat. For females, one of the X chromosomes in each cell is randomly inactivated early in development. This means the active gene is different in different groups of cells. These cells then divide giving rise to large clumps of cells with the same active X chromosome. This eventually gives rise to patches of ginger and non-ginger fur – the characteristic mosaic pattern seen in tortoiseshell cats.

In recognition of her work, Mary Lyon was made a Fellow of the Royal Society and in 1984 received their Royal Medal, and has been awarded the Pearl Meister Greengard Prize, the March of Dimes Prize and the Wolf Prize in Medicine. Her discovery has led to great advances in our understanding of X-linked inherited diseases such as haemophilia, Duchenne muscular dystrophy, fragile X syndrome and certain cancers.

‘One exciting moment in my scientific career was the glow of excitement when I was developing the inactive X-chromosome idea and it began to seem as if my idea was right. That was a very big glow’

In 2016, MRC Harwell opened a brand new exhibition dedicated to Mary’s life and achievements, including a timeline of her life and a world map showing all the places she visited during her life as a scientist.

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