Certain regions of the human genome seem to be prone towards copy number variations (CNV), which are large rearrangements of DNA that often occur in the form of deletions and duplications of genetic material. This is so much the case that there are many recognized chromosomal deletion and duplication disorders that present with characteristic syndromes or constellations of symptoms, such as 15q Duplication Syndrome.

But if CNVs often occur with an identifiable pattern, that would suggest certain regions of the genome are inherently vulnerable, perhaps even unstable. What types of sequences could have such an effect?

Bose et al. (2014) suggest that at least for CNVs contained within a chromosomes (i.e., “interstitial”), transposable elements and in particular Alu elements frequently reside at CNV breakpoints. Given their highly repetitive content, transposable elements are comparatively unstable, sometimes accidentally pairing with one another and disrupting DNA replication (as shown in the image below).

Above Bose et al. (2014) show the points in the DNA using black X’s where Alu elements have mismatched with one another, likely leading to double stranded breakage.

As we’ve reported in the past and continue to extend on that work (hopefully to be published this fall), autism risk genes tend to be particularly enriched in transposable element content. This means that these genes may increase the likelihood that chromosomal breakage occurs. Interestingly, the breakpoints can often be thousands of base pairs away from the points at which the DNA attempts to repair itself (known as the area of DNA resection), so it can sometimes be challenging to identify the original breakage point.

It will be interesting to see in future to what extent transposable element content plays in the development of CNVs linked to neurodevelopmental conditions. In particular, to what extent Alu elements, which are primate-specific and arose within the last 75 million years, increase the likelihood of CNV occurrence. It’s quite possible that many of the genetic changes that have made us most human have also increased the likelihood of rare mutations in our species.