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Transposable elements: insertion pattern and impact on gene expression evolution in hominids Maria Warnefors, Vini Pereira, Adam Eyre-Walker University of Sussex, Brighton, United Kingdom SMBE, Lyon, 2010 Species-specific transposable elements (TEs) 7786 insertions 2933 insertions ~95% of these TEs are Alu, L1 or SVA elements (Mills et al, Am J Hum Genet, 2006) Images: Wikimedia Commons TEs can influence gene expression via several mechanisms Me Me Me Me TEs provide transcription start sites (TSSs) for 30% of human transcripts (Faulkner et al, Nature Genetics, 2009) Intronic L1 insertion reduces reporter gene expression in HeLa cells (Han et al, Nature, 2004) TE silencing downregulates neighbouring genes in Arabidopsis (Hollister and Gaut, Genome Research, 2009) Have TEs increased expression divergence (ED) between humans and chimpanzees? Low ED Have TEs increased expression divergence (ED) between humans and chimpanzees? Low ED High ED Previous studies of TEs and expression divergence 20% of mouse/rat ED is due to TEs (Pereira et al, PLoS ONE, 2009) Alu elements correlate with mouse/human ED, but the direction depends on the definition of ED (Urrutia et al, Genome Biology, 2008) Materials and methods Expression divergence was calculated for ~9000 genes based on expression in five tissues (data from Khaitovich et al, Science, 2005) Expression divergence is the Euclidean distance between expression levels in one or more tissues Species-specific TEs (Mills et al, Am J Hum Genet, 2006) were grouped according to insertion site: UPSTREAM 20 kb 10 kb INTRONIC 2 kb DOWNSTREAM 2 kb 10 kb 20 kb Species-specific TEs are associated with an increase in expression divergence ED TE No TE Combined p = 0.024 Z transformation method (Whitlock, J Evol Biol, 2005) Do TEs cause the change in expression? H. sapiens P. troglodytes M. mulatta SPECIFIC Contribute to ED SHARED Do not contribute to ED Images: Wikimedia Commons Shared TEs are also associated with an increase in expression divergence SPECIFIC (p = 0.024) ED TE No TE ED SHARED (p = 0.00003) Recent TE insertions did not cause an increase in expression divergence Relative effect = EDSPECIFIC / EDNO SPECIFIC EDSHARED / EDNO SHARED Second approach: Human-macaque versus chimpmacaque expression divergence H. sapiens Expression data: ~3700 genes in the prefrontal cortex (Somel et al, PNAS, 2009) P. troglodytes M. mulatta Images: Wikimedia Commons Species-specific TEs have not caused increased ED p = 0.32 H/M C/M p = 0.13 Do TEs act to increase transcript diversity? New TE No new TE p value (M-W) Human 2.7 2.3 2 x 10-16 Chimp 2.0 1.8 5 x 10-10 Do TEs act to increase transcript diversity? New TE No new TE p value (M-W) Human 2.7 2.3 2 x 10-16 Chimp 2.0 1.8 5 x 10-10 Expected transcript div. Transcripts per gene Transcripts per gene No evidence that recently inserted TEs have contributed to hominid transcript diversity TE insertions are more common upstream than downstream of genes 496 TEs 561 TEs Summary of ~9000 genes (from the Khaitovich dataset) The upstream bias is just significant (p = 0.049). TE insertions are more common upstream than downstream of genes 496 TEs 561 TEs Summary of ~9000 genes (from the Khaitovich dataset) The upstream bias is just significant (p = 0.049). TEs may accumulate upstream because they have a role in chromatin regulation. (Huda et al, Gene, 2009) TEs may preferentially insert upstream (as known for Drosophila P elements) Hominid TEs are subject to insertion bias TE upstream TE downstream Active in germ line 255 181 Inactive in germ line 306 315 Expression state from eGenetics data (Kelso et al, Genome Research, 2003) Only germ line expressed genes exhibit upstream bias (p = 0.003, c2 test) The enrichment of TEs in upstream sequences can be explained in terms of insertion bias and does not indicate a role for TEs in gene regulation Summary New TEs are correlated with, but not causal to, an increase in expression divergence between human and chimpanzee. (However, TEs may still contribute substantially to within-species variation). We do not find evidence for a TE-induced increase in transcript diversity. Excess of upstream insertions can be explained by neutral insertion bias. To what extent do regulatory regions evolve within TEs, simply because TEs are so abundant? Acknowledgements Adam Eyre-Walker Vini Pereira John Brookfield