Lyons, tigers and pussycats
Nettie Stevens had always loved biology. Born in Vermont in 1861, her research career got off to a slow start due to a lack of opportunities for women to study science in the late 19th century and having to wait to do a degree and PhD until she’d saved enough money through long stints of teaching.
But by the age of 39 she was able to pursue a research career, choosing to focus on the exciting new science of genetics and the fascinating chromosomes that had recently been discovered. And in 1905, she made an important discovery of her own.
While studying the chromosomes in the eggs and sperm of beetles, she realized that while most of the pairs were all the same, there were two that were a mismatched pair of little and large. She called the bigger of the two the X chromosome, and the smaller one Y.
Sperm appeared to contain either an X or a Y chromosome, while eggs only ever had Xs. The same thing was true in the eggs and sperm of fruit flies. Therefore, Nettie concluded, being genetically male or female depended on the combination of these unusual chromosomes - XY making males and XX making females – and that the sex of the offspring was dependent on whether an X or Y chromosome had come along in the sperm.
For a long time the credit for this discovery went to Edmund Wilson, who had made similar observations around the same time but come to slightly wrong conclusions about them. He was working on a species of insect where the male sex chromosome is missing and also thought that genetic sex determination had more to do with the environment, unlike Nettie’s theory that it was entirely down to chromosomes. Sadly she died of breast cancer in 1912, and because Wilson published his paper first, he got much of the glory.
But Nettie’s theory of sex chromosomes turned out to hold true across a huge range of species, although not all use the same version of the X and Y system – for example, birds have W and Z chromosomes, with males being ZZ and females ZW.
We also now know that the same kind of XY sex determination system that Nettie Stevens discovered in beetles is at work in mammals, including humans. But this raises an interesting question.
If females have two X chromosomes, then that means they have a double dose of all the genes on that chromosome compared with males. So how does that work? The answer came from a woman named Mary Lyon, working at the MRC’s genetics unit in Oxfordshire, and some strangely patterned mice.
While carrying out experiments looking at the impact of radiation on mice, Mary noticed an unusual male mouse with a splotchy, mottled coat. When she started breeding him with normal females in the hope of getting some blotchy babies, she noticed something odd – around half of the males carrying the mutation died during development in the womb, while the survivors were all born with pure white coats. But female offspring all had blotchy coats, just like their dad.
She figured out that the mutation must be carried on one of the X chromosomes in the female pups, eventually realising that one copy of the X must be randomly switched off in small groups of stem cells very early on in development in the womb, giving them the mottled pattern. In males, inheriting a normal X chromosome from mum was fine, but inheriting the faulty X meant that all their cells would be faulty too, causing a fatal developmental error. Despite the mutation, the normal, non-mutated X chromosome in females was functioning in enough the cells in which is was active to act as a back-up, so all the females survived.
In 1961, Mary published her discovery. Despite resistance from sceptics who didn’t understand how X inactivation early on in development could give rise to the kind of blotchy patterns – and didn’t believe that Mary was an established or important enough scientist to have made such a discovery – her idea was subsequently shown to be correct. In fact, the process of X-inactivation is sometimes known as Lyonisation in her honour.
Since then, the molecular mechanisms behind X inactivation have been mapped out in exquisite detail. The main player is a gene called XIST, which is found on the X chromosome. Very early on in development, when an embryo is nothing more than a ball of cells, each cell somehow ‘counts’ how many copies of the X chromosome are present – if there are two, then one gets randomly switched off.
The inactive X gets coated in long RNA molecules made from the XIST gene and is tightly packed down and shoved into a corner of the nucleus, leaving just one active chromosome. Because this process is happening independently in all the cells in the early embryo, a female fetus ends up being a mosaic of cells in which one or other of her X chromosomes is inactive.
Because females have two X chromosomes, which are randomly inactivated throughout the body, they effectively have a back-up copy of all the genes on the X, while males don’t. This leads to a number of what’s known as X-linked diseases and traits, where only males in a family are affected, while females can carry the faulty X chromosome but not be seriously affected thanks to their back-up copy. X-linked conditions include the blood clotting disorder haemophilia – which affected the male descendants of Queen Victoria for three generations – the muscle wasting disease Duchenne muscular dystrophy, and colour blindness.
Unusual conditions can still arise in females due to X chromosome mosaicism. In 1901, German dermatologist Alfred Blaschko noticed that certain skin conditions all seemed to follow the same sweeping lines running across the chest and along the arms and legs, similar to the stripes on a striped tiger or brindled dog.
These stripes correspond to the paths taken by skin cells as a fetus grows in the womb and are completely invisible in most people. But in females with faults in pigmentation genes on one of their two X chromosomes, random X inactivation means that some cells have the functioning gene while others don’t, creating tiger stripes of genetically different skin cells across the body.
But if you really want to see X-inactivation in action, look no further than a tortoiseshell cat, which – unsurprisingly – Mary Lyon owned.
Blotchy tortoiseshells, also known as calico cats are good-luck charms in many parts of the world. Their multicolour coats are due to a gene found on the X chromosome that exists in two different versions or variants, making either black or orange fur.
A female kitten randomly switches off one or other of her two X chromosomes in different cells as she grows in the womb – so if she inherits one orange and one black fur variant on each of her two Xs, they’ll create characteristic blotches as her fur grows.
Because male cats have just one X chromosome which is always active, they only have one of the coat-colour variants – orange or black – painting a ginger or jet black tom. Male calico cats do exist but are extremely rare and usually turn out to have two X chromosomes, one orange and the other with the black, giving them the characteristic tortoiseshell coat.
References and further reading: