Retroelement distributions in the human genome: variations associated with age and proximity to genes

Abstract

Remnants of more than 3 million transposable elements, primarily retroelements, comprise nearly half of the human genome and have generated much speculation concerning their evolutionary significance. We have exploited the draft human genome sequence to examine the distributions of retroelements on a genome-wide scale. Here we show that genomic densities of 10 major classes of human retroelements are distributed differently with respect to surrounding GC content and also show that the oldest elements are preferentially found in regions of lower GC compared with their younger relatives. In addition, we determined whether retroelement densities with respect to genes could be accurately predicted based on surrounding GC content or if genes exert independent effects on the density distributions. This analysis revealed that all classes of long terminal repeat (LTR) retroelements and L1 elements, particularly those in the same orientation as the nearest gene, are significantly underrepresented within genes and older LTR elements are also underrepresented in regions within 5 kb of genes. Thus, LTR elements have been excluded from gene regions, likely because of their potential to affect gene transcription. In contrast, the density of Alu sequences in the proximity of genes is significantly greater than that predicted based on the surrounding GC content. Furthermore, we show that the previously described density shift of Alu repeats with age to domains of higher GC was markedly delayed on the Y chromosome, suggesting that recombination between chromosome pairs greatly facilitates genomic redistributions of retroelements. These findings suggest that retroelements can be removed from the genome, possibly through recombination resulting in re-creation of insert-free alleles. Such a process may provide an explanation for the shifting distributions of retroelements with time.

Figure 1

Density of retroelements in different GC fractions in the human genome, calculated over 20-kb windows across the genome sequence. (A–C) The density of various retroelement classes. Those represented in each panel are indicated in the box below the graphs. The bins from left to right correspond to an increasing 2% GC fraction.

Figure 2

Density of retroelements as a function of average GC content of each human chromosome. The line connecting solid diamonds indicates the general correlation trend between retroelement and GC content of individual chromosomes. The level of significance (P values) of the correlation for each data set is indicated. Open diamonds were excluded from the correlation analysis and indicate over- or underrepresentation of retroelement density on a particular chromosome. Chromosomes 20, 21, and 22 were excluded from the Class II graph (J) because they had <100 supporting elements.

Figure 3

Ratios of observed to predicted retroelement densities with respect to genes in the human genome. The points above “gene” and “<5” of each graph indicate the density in gene regions, and in the first 5 kb either 5′ or 3′ of genes. The other bins are 5–10, 10–20, 20–30, and >30 kb either upstream or downstream of genes. Open symbols and broken lines indicate elements in the same or sense orientation with respect to the nearest gene and solid symbols and lines indicate elements in the reverse direction. Standard deviation error bars, which are too small to see in some cases, were determined as described in Methods. Solid boxes below the graphs represent gene regions and the lines indicate the distance bins of the intergenic regions. It should be noted that the vast majority of retroelements within genes are located in introns.

Figure 4

Retroelement densities of different divergence classes in various GC fractions of the human genome. The density distribution of each retroelement divergence cohort was plotted in GC bins as indicated in the legend to Figure 1. The divergence classes are indicated in % divergence from the consensus sequence below the graphs. Data points missing in traces are due to GC bins containing <100 elements. Standard deviations were calculated (see Methods) but are not shown in the interest of clarity.

Figure 5

Length distribution of retroelements with respect to surrounding GC content. Retroelements of each group were classified as belonging to divergence cohorts as described in the text. The average length in base pairs (bp) of each retroelement divergence cohort contained within each GC bin (see legend to Fig. 1) is shown for L1 (A) and Alu (B) elements. GC bins containing <100 elements were excluded from the graphs.

Figure 6

Density of Alu divergence cohorts in different GC fractions on chromosome Y compared with the whole genome. Solid lines indicate Alu elements on chromosome Y; broken lines represent the Alu density in the whole genome. (A–F) The density of specific divergence classes, which are indicated on the top of each panel. There were insufficient numbers of Alu elements on the Y chromosome in the first two divergence cohorts to be plotted in A and B. The density distribution of each Alu divergence class is plotted against the local 20-kb genome GC content. Standard deviations were calculated as described in Methods.