Diverse cis factors controlling AIu retrotransposition: What causes AIu elements to die?

Abstract

The human genome contains nearly 1.1 million AIu elements comprising roughly 11% of its total DNA content. AIu elements use a copy and paste retrotransposition mechanism that can result in de novo disease insertion alleles. There are nearly 900,000 old AIu elements from subfamilies S and J that appear to be almost completely inactive, and about 200,000 from subfamily Y or younger, which include a few thousand copies of the Ya5 subfamily which makes up the majority of current activity. Given the much higher copy number of the older AIu subfamilies, it is not known why all of the active AIu elements belong to the younger subfamilies. We present a systematic analysis evaluating the observed sequence variation in the different sections of an AIu element on retrotransposition. The length of the longest number of uninterrupted adenines in the A-tail, the degree of A-tail heterogeneity, the length of the 3' unique end after the A-tail and before the RNA polymerase III terminator, and random mutations found in the right monomer all modulate the retrotransposition efficiency. These changes occur over different evolutionary time frames. The combined impact of sequence changes in all of these regions explains why young AIus are currently causing disease through retrotransposition, and the old AIus have lost their ability to retrotranspose. We present a predictive model to evaluate the retrotransposition capability of individual AIu elements and successfully applied it to identify the first putative source element for a disease-causing AIu insertion in a patient with cystic fibrosis. © 2009 by Cold Spring Harbor Laboratory Press.