Lingering Lyonization:The Genetics of Asperger's Syndrome?

Source: Wikimedia commons

As I pointed out in a previous post, female mammals deal with the problem of having two X chromosomes (left) to the male’s one by randomly inactivating one of them in each cell. The effect is sometimes called Lyonization after Mary Lyon, who discovered it. Lyonization explains why one of a pair of American identical twin sisters suffers from Duchenne Muscular Dystrophy (DMD, an X-linked genetic disease which has made her paraplegic) while the other is a successful athlete. Identical twins result when the fertilized egg has only divided a few times but then splits into two individuals, and X-inactivation occurs at the same stage. Cell lineages inherit their pattern of Lyonization from their predecessors, and so in this case it looks as if only one twin was unfortunate enough to inherit the cell lineages which expressed the DMD gene from one parental X chromosome, while the other inherited those expressed from the other parent’s unaffected X.

As I also pointed out in the previous post, a recent study found that compared to male, female identical twins vary more on measures of pro-social behaviour, peer problems, and verbal ability thanks to differential Lyonization. Deficits and deviations in precisely these traits are symptomatic of Asperger’s syndrome (AS), and one possible explanation of the strange genetics of the disorder (which demonstrably runs in families, but does not obey the rules of classical genetic inheritance like DMD does) might be found in lingering Lyonization.

What I mean by this is the known possibility that X-inactivation imprints placed on specific X genes in a woman’s body might be accidentally retained on the X chromosome she passed on to her children. If these inactivating imprints affected the very same genes implicated in AS, the striking sex ratio of the disorder’s incidence would be explained. AS affects approximately 10 to 20 times more males than females (depending on the exact diagnostic criteria). Because males have only a single X, they could be predicted to be much more vulnerable to lingering Lyonization than a woman’s daughters, who would always have a second, paternal X chromosome lacking such imprints to compensate and dilute the effect. However, the fact that 35% of women have a greater than 70:30 skew in their pattern of Lyonization and that 7% have more than a 90:10 skew in favour of one parent’s X, a much smaller number of females might also be predicted to be vulnerable. In other words, highly skewed Lyonization in a minority of females would inevitably resemble the single X situation found in males, and if the lingering Lyonization imprints were inactivating the critical genes in those cases, AS would result, but at a far lower incidence than in males—just as we find.

The same reasoning would explain the often-remarked variability of the symptoms in AS. Classically-heritable single-gene disorders like DMD usually have strikingly consistent symptoms because only one gene is affected, usually in the same way (in the case of DMD, this is Dystrophin, the longest gene in the human genome). But if imperfectly-erased Lyonization imprints on several genes were at issue in AS, the outcome in each case might be surprisingly different, and the combined effects highly variable—again, just as we find.

At present this is only speculation: we do not know the genetic causes of AS. But the model proposed here fits the general theory outlined in The Imprinted Brain. This is that increased paternal and/or reduced maternal and/or X-chromosome gene expression causes autistic disorders like AS. Given the fact that so many cognitive capacities seem to be inherited from the mother as my previous post pointed out, the likelihood must be that the latter alternative—reduced maternal and perhaps especially X-chromosome gene expression—is the likely culprit. Time will tell.