X and Y

Next in the A-Z series, Joni, Kirstin and Rosa are combining the letters X and Y in a blog post all about the X and Y chromosomes.

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As the noted scholars Salt N Pepa once said – “let’s talk about sex [chromosomes]”. Everybody’s got them – those of us born female have two X chromosomes, while males have one X and one Y chromosome. There’s also a minority of people who are born with different numbers and combinations of sex chromosomes, and who might consider themselves female, male or intersex, although we won’t go into more depth on that here (and, of course, your biological sex does not determine your gender identity – plenty of people who identify as men have XX and as women have XY and frankly that’s no-one’s business but theirs).

From a genetic perspective, chromosome X is pretty interesting, as it is the only chromosome that differs in number between males and females (Y being found in males only). This is not a trivial amount of variation – X is the eighth longest chromosome out of the 24 in the human genome. This sex difference makes changes to the genetic sequence of the X special.

All females inherit two X-chromosomes, but it is standard for one of them to be inactivated, preventing most of the genes on that chromosome from being expressed, and so avoiding double-dosing with X-chromosome gene products. X-inactivation (and consequent dosage compensation) discordance in monozygotic (identical) female twins is common, such that one twin expresses more paternally-received genes and the other expresses more maternal ones. X-linked genes are involved in complex behavioural traits such as cognitive ability. Hence, non-identical X-chromosome expression may reduce MZ females’ correlation, compared to male MZ twins, on complex behavioural traits that are affected by any of the 1000 or so X-linked genes. Indeed, X-inactivation partly explains why MZ males are more similar than MZ females for peer problems, prosocial behaviour, and verbal ability.

Turning back to the general population, it has been observed that genetic changes on only one X-chromosome might be hidden in females (having a “recessive” effect, meaning that the female is a “carrier” for that change), but can then have an effect if passed on to their male children (because there is no longer a second X to buffer the effect of that change). This “X-linking” occurs in several traits and disorders, of which perhaps the most famous is red-green colourblindness, which occurs because the red and the green pigment genes (but not the blue pigment gene) lie together in a single region on the X chromosome.

An interesting consequence of X-inactivation in females is something called mosaicism. This is when one individual has two different genotypes. Because one copy of the X chromosome is randomly inactivated in each cell, biological females will have X-mosaicism, expressing different X-linked genes in each cell. We can turn to the feline world for a really good visual example of the possible results of X-mosaicism. In some domestic cats, there is a gene that results in white coat pigment on one of the autosomes (not impacted by X-inactivation). However, there are additional genes that code for coloured pigment in the coat on the X-chromosome. One version of this gene codes for black coat, and the other for ginger. When a cat is heterozygous for these genes (i.e. has one of each gene on their different X chromosomes) the result will be a random pattern of ginger and black amongst the otherwise white coat. This results in what is known as a calico cat (referring to the tri-coloured coat, not a particular breed of cat). Interestingly, this means that the overwhelming majority of calico cats are female (with the exception being XXY males).

Given how interesting the X chromosome is, it is unusual that it is relatively under-studied in genome-wide association studies. In part, it is the very thing that makes the X interesting that led to its exclusion: unlike the non-sex chromosomes (the autosomes), including the X chromosome in studies requires dedicated data cleaning and analysis to address the dis-balance between males and females. Furthermore, dosage compensation complicates the interpretation of results from the X. However, this is changing, as approaches aimed at analysing the X become more commonly-used. Interest in the X and its fascinating properties outweighs the complexity of including it in GWAS, so X data is increasingly being included in new GWAS.

So what then, of the Y? Is it so unimportant that no-one really cares? Well, actually, there is some evidence that is the case – one study found that, with some clever gene-editing, all the genes on the Y could be turned off in lab mice, with relatively few effects – the mice were even able to breed with some assistance. Unlike the X, the Y is a small chromosome with few genes (only two other chromosomes are shorter). There is some evidence that X chromosome genes with an equivalent on the Y are more likely to escape inactivation, so the presence of these Y chromosome genes may reflect a dosage buffering mechanism in males. Beyond this, and making males male, the Y chromosome seems largely disinteresting. However, there is a certain circularity to this – the Y is rarely included in GWAS because its fairly disinteresting, but remains disinteresting through lack of study. Furthermore, any effect of the Y that differentiates males from females (rather than creating differences among males) is impossible to detect with GWAS, because there is a perfect correlation between having a Y and having the trait. However, it’s not all bad news for the Y – it is an invaluable tool in population genetics, helping to describe human migration from Africa, and enables high-fidelity male DNA profiles to be constructed in forensic studies.

And so to end as we started, I think Fred, R.S. (1991) said it best – I’m too XY for this blog…

XYXY Gossip Girl

PS: The authors have many, many XY jokes, and will happily tell you them endlessly with little provocation