Selection Against Deleterious LINE-1-Containing Loci in the Human Lineage

Abstract

We compared sex chromosomal and autosomal regions of similar GC contents and found that the human Y chromosome contains nine times as many full-length (FL) ancestral LINE-1 (L1) elements per megabase as do autosomes and that the X chromosome contains three times as many. In addition, both sex chromosomes contain a ca. twofold excess of elements that are >500 bp but not long enough to be capable of autonomous replication. In contrast, the autosomes are not deficient in short (<500 bp) L1 elements or SINE elements relative to the sex chromosomes. Since neither the Y nor the X chromosome, when present in males, can be cleared of deleterious genetic loci by recombination, we conclude that most FL L1s were deleterious and thus subject to purifying selection. Comparison between nonrecombining and recombining regions of autosome 21 supported this conclusion. We were able to identify a subset of loci in the human DNA database that once contained active L1 elements, and we found by using the polymerase chain reaction that 72% of them no longer contain L1 elements in a representative of each of eight different ethnic groups. Genetic damage produced by both L1 retrotransposition and ectopic (nonallelic) recombination between L1 elements could provide the basis for their negative selection.

Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity

“…Although these observations are also consistent with several alternative hypotheses (e.g. accumulation of deleterious insertions due to decreased selection efficiency within these regions) that do not necessitate ectopic recombination, there is increasing support from the drosophila model for significant selection against TE loci due to their potential for instability [5] Recent data from humans, showing stronger selection against full-length L1 elements than their truncated counterparts, is also highly suggestive of selection against ectopic recombination instability in our own lineage [6], particularly when taken together with an earlier genomic analysis of TE accumulation on human sex chromosomes which indicated that negative selection on L1s was related to L1 insertion size [7] as opposed to the full length vs. non-full length status of insertions. In the latter work, a statistically significant accumulation of >500bp but less-thanfull-length L1 inserts on the human sex chromosomes vs. the autosomes [7].…”

Repetitive sequence environment distinguishes housekeeping genes

“…Regardless of whether Alu elements are beneficial or merely tolerated, the increased abundance of Alu elements around housekeeping genes stood in stark contrast to the scarcity of longer (>400-bp) repeats and repeat tracts (LINE-1 elements and various other repeats) in these same regions Although, the lower abundance of the TT|AAAA target sequence near housekeeping genes may very well contribute to LINE-1 scarcity (Jurka, 1997;Cost and Boeke, 1998;Lander et al, 2001;Graham and Boissinot, 2006) despite their otherwise random insertion pattern (Smit, 1999;Boissinot et al, 2001;Lander et al, 2001;Ovchinnikov et al, 2001;Gilbert et al, 2002;Myers et al, 2002;Symer et al, 2002;Szak et al, 2002;Jurka et al, 2004;Gilbert et al, 2005), at least one additional explanation is needed since long repeats in general were scarce. One reason why long repeats might be selected against near housekeeping genes is that an abundance of these repeats might reduce gene expression via heterochromatin spread.…”

“…Alu transposons differ from other SINEs in that they are not derived from tRNA genes, but rather from the 7SL RNA gene (Ullu and Tschudi, 1984;Quentin, 1994;Smit, 1996;Okada and Hamada, 1997;Terai et al, 1998;Lander et al, 2001) which encodes the RNA component of the signal recognition particle that mediates the translocation of nascent secretory and membrane proteins (Wild et al, 2004). Aside from favoring TT|AAAA target sequences (Feng et al, 1996;Jurka, 1997;Cost and Boeke, 1998), human Alu and LINE-1 elements have been reported to insert at random positions in the genome (Smit, 1999;Boissinot et al, 2001;Lander et al, 2001;Ovchinnikov et al, 2001;Gilbert et al, 2002;Myers et al, 2002;Symer et al, 2002;Szak et al, 2002;Jurka et al, 2004;Gilbert et al, 2005). However, there is some evidence for insertional hot spots (Cost and Boeke, 1998;Myers et al, 2002;Graham and Boissinot, 2006).…”

“…However, there is some evidence for insertional hot spots (Cost and Boeke, 1998;Myers et al, 2002;Graham and Boissinot, 2006). A popular idea is that the non-random distribution of these repetitive sequences arises from their loss via purifying selection (Boissinot et al, 2001;Myers et al, 2002;Graham and Boissinot, 2006).…”

L1 integration in a transgenic mouse model

“…To complete integration, the second strand of host DNA must be cleaved, RNA removed, the newly synthesized strand copied, and breaks resolved. The mechanism by which these later steps are accomplished is only beginning to be understood, with recent biochemical data from a related non-LTR retrotransposon R2 of the silkmoth, Bombyx mori, suggesting that a second R2 protein is involved in cleavage, RNA displacement, and synthesis of the second strand (Bibillo and Eickbush 2002a; Christensen and Eickbush 2005).Following essentially random integration, endogenous L1s are thought to be lost over time due to strong negative selection leading to their uneven genomic distribution (Boissinot et al 2001(Boissinot et al , 2004Ovchinnikov et al 2001;Medstrand et al 2002). This is reflected in their overrepresentation in GC-poor genomic regions (Lander et al 2001;Ovchinnikov et al 2001;Boissinot et al 2004), under-representation within 5 kb of genes (Medstrand et al 2002), and the selective loss of longer (>500 bp) L1s from recombining regions of the genome (Boissinot et al 2001).…”