Modeling the amplification dynamics of human Alu retrotransposons

Abstract

Retrotransposons have had a considerable impact on the overall architecture of the human genome. Currently, there are three lineages of retrotransposons (Alu, L1, and SVA) that are believed to be actively replicating in humans. While estimates of their copy number, sequence diversity, and levels of insertion polymorphism can readily be obtained from existing genomic sequence data and population sampling, a detailed understanding of the temporal pattern of retrotransposon amplification remains elusive. Here we pose the question of whether, using genomic sequence and population frequency data from extant taxa, one can adequately reconstruct historical amplification patterns. To this end, we developed a computer simulation that incorporates several known aspects of primate Alu retrotransposon biology and accommodates sampling effects resulting from the methods by which mobile elements are typically discovered and characterized. By modeling a number of amplification scenarios and comparing simulation-generated expectations to empirical data gathered from existing Alu subfamilies, we were able to statistically reject a number of amplification scenarios for individual subfamilies, including that of a rapid expansion or explosion of Alu amplification at the time of human-chimpanzee divergence.

Figure 1. Temporal Variation of Subfamily Sequence Variation π and IPL

Results for three expansion models are shown, in which retrotransposition activity was instantaneous (M0) or lasted for 3 (M3) or 6 (M6) myrs. Variation in π (A) is slowed during retrotransposition, but increases immediately upon the cessation of retrotransposition. Rate of IPL decay (B) is attenuated during retrotransposition activity but increases once retrotransposition ends.

Figure 2. Distribution of Subfamily Sequence Variation π (x-Axis) versus IPL (y-Axis)

Expectations based on 1,000 replicates of expansion models M0–M6. Shaded area in each plot indicates 95% of resulting values for each model. Observed (π and IPL) values for ten recent human Alu subfamilies are shown as black diamonds. These results are based on a generation time of 25 y and an effective population size of 10,000 individuals.

Figure 3. Estimation of the Age of the Ya5a2 Alu Subfamily under Simulation M4

In M4, N _e is 10,000 and generation time is 25 y. Data are based on observed subfamily sequence variation π and IPL parameters. Time estimates consistent with π and IPL values are indicated in boxes. The bold double arrow indicates age estimates concordant with both parameters.

Figure 4. Impact of Subfamily Copy Number (n) on the Sequence Variation π Parameter

Increasing subfamily size beyond 100 copies had little effect on between-replicate variation.