Fitness cost of LINE-1 (L1) activity in humans

Abstract

The self-replicating LINE-1 (L1) retrotransposon family is the dominant retrotransposon family in mammals and has generated 30-40% of their genomes. Active L1 families are present in modern mammals but the important question of whether these currently active families affect the genetic fitness of their hosts has not been addressed. This issue is of particular relevance to humans as Homo sapiens contains the active L1 Ta1 subfamily of the human specific Ta (L1Pa1) L1 family. Although DNA insertions generated by the Ta1 subfamily can cause genetic defects in current humans, these are relatively rare, and it is not known whether Ta1-generated inserts or any other property of Ta1 elements have been sufficiently deleterious to reduce the fitness of humans. Here we show that full-length (FL) Ta1 elements, but not the truncated Ta1 elements or SINE (Alu) insertions generated by Ta1 activity, were subject to negative selection. Thus, one or more properties unique to FL L1 elements constitute a genetic burden for modern humans. We also found that the FL Ta1 elements became more deleterious as the expansion of Ta1 has proceeded. Because this expansion is ongoing, the Ta1 subfamily almost certainly continues to decrease the fitness of modern humans.

Fig. 1.

The frequency distribution of polymorphic Ta1 elements. The fractions of FL (filled bars) and TR (open bars) Ta1 inserts are plotted as a function of different polymorphic frequencies. The distribution of FL insertions is significantly skewed toward lower frequencies. Thus, whereas ≈59% of the FL element-containing loci are present in 30% of the population sampled (i.e., 0.25 + 0.25 + 0.09 in the 0–10%, 10–20%, and 20–30% frequency bins respectively), only ≈30.5% (0.08 + 0.025 + 0.21) of the TR elements are present at these low frequencies. In contrast, whereas ≈23% of the TR element-containing loci are present in 70% or more of the population sampled, only ≈6% of the FL element-containing loci are.