Gene function and expression level influence the insertion/fixation dynamics of distinct transposon families in mammalian introns

Abstract

Background: Transposable elements (TEs) represent more than 45% of the human and mouse genomes. Both parasitic and mutualistic features have been shown to apply to the host-TE relationship but a comprehensive scenario of the forces driving TE fixation within mammalian genes is still missing.

Results: We show that intronic multispecies conserved sequences (MCSs) have been affecting TE integration frequency over time. We verify that a selective economizing pressure has been acting on TEs to decrease their frequency in highly expressed genes. After correcting for GC content, MCS density and intron size, we identified TE-enriched and TE-depleted gene categories. In addition to developmental regulators and transcription factors, TE-depleted regions encompass loci that might require subtle regulation of transcript levels or precise activation timing, such as growth factors, cytokines, hormones, and genes involved in the immune response. The latter, despite having reduced frequencies of most TE types, are significantly enriched in mammalian-wide interspersed repeats (MIRs). Analysis of orthologous genes indicated that MIR over-representation also occurs in dog and opossum immune response genes, suggesting, given the partially independent origin of MIR sequences in eutheria and metatheria, the evolutionary conservation of a specific function for MIRs located in these loci. Consistently, the core MIR sequence is over-represented in defense response genes compared to the background intronic frequency.

Conclusion: Our data indicate that gene function, expression level, and sequence conservation influence TE insertion/fixation in mammalian introns. Moreover, we provide the first report showing that a specific TE family is evolutionarily associated with a gene function category.

Figure 1

Analysis of MIR frequency in dog and opossum immune defense genes. MIR sequences were divided into mammalian-wide and metatherian/monotremata-specific. Immune response genes displayed significantly higher frequencies of both MIR types compared to the remaining genes. Box height represents sample interquartile range and the bold line depicts the median position. The whiskers extend to the most extreme data point, which is no more than 1.5 times the interquartile range from the box.

Figure 2

Analysis of human MIR sequences associated with immune response genes. (a) Relative frequency at each position of MIR (n = 277), MIRb (n = 382) and MIR3 (n = 104) consensus sequences in immune response gene introns (red lines). Mean profiles and intervals corresponding to the 1st and 99th percentiles in 100 random sample frequency distributions are represented by black lines and grey areas, respectively. (b) The same as in (a) for MIRs located in intergenic regions. MIR, n = 239; MIRb, n = 345; MIR3, n = 97. Hatched lines delimit the MIR CORE region.

Figure 3

Co-conservation profile of MIR sequences. Co-conservation frequency at each position of (a) MIR (n = 277), (b) MIRb (n = 382) and (c) MIR3 (n = 104) consensus sequences in immune response gene introns (red lines). Frequency intervals corresponding to the 1st and 99th percentiles in 100 random sample frequency distributions are represented by the black lines. (d) Co-conservation profiles of MIR sequences located in human introns; in this case, positions correspond to the alignment of the three MIR subtypes: MIR (black), MIRb (red) and MIR3 (blue).

Figure 4

Gene-expression dependent variation in TE intronic abundance. Gene expression levels were derived from microarray data. (a) Lowess fit (solid line) and probability intervals (hatched lines) of TE_na versus gene expression level (log transformed values) for the six TE families. (b) Lowess fit (solid line) and probability intervals (hatched lines) of intronic to intergenic relative TE frequency difference (see text) versus gene expression level (log transformed values).