Adaptive evolution in non-coding DNA and the evolution of gene expression.

82% of the Drosophila genome (and 98% of the human genome) is non-coding DNA - what fraction of the non-coding genome is functional? What fraction of non-coding divergence accumulating between closely related species is functional? Is there a correlation between adaptive non-coding DNA sequence divergence and gene expression divergence?

        A growing body of evidence supports the view that regulatory evolution – the evolution of where and when a gene is expressed – is the primary genetic mechanism behind the modular organization, functional diversification and origin of novel traits in higher organisms. Most elements regulating gene expression in eukaryotic genomes reside in noncoding DNA (i.e. DNA that does not encode protein). Recent studies suggest that much of the non-coding portion of the Drosophila melanogaster genome is evolutionarily constrained, implying that these regions are important for an organism’s fitness and may be the target of substantial adaptive evolution.  In a pair of recent papers (Andolfatto Nature 2005; Haddrill et al. MBE 2008), we have shown that this signature of adaptive evolution is concentrated in untranslated transcribed regions (UTRs).  This past year, we began a NIH-funded project that combines novel computational and experimental approaches to i) identify UTRs and cis-regulatory modules (CRMs) that may have been targets of recurrent adaptive evolution and ii) experimentally test the effects of putatively functional substitutions on levels of gene expression divergence between species.  This research will identify new cis-regulatory elements, develop novel methodologies for mapping such elements and provide important insights into how gene regulatory changes have led to the evolution of new species and diversity in animal forms. We hope the computational methods and biological intuitions developed will become widely applicable to other model systems, including humans.

A transgenic reporter gene system to measure in vivo effects of nucleotide divergence between species in UTRs on gene expression divergence. 

Results of trangenic assays showing a significant effect of Dmel-Dsim divergence in the UTR of the Hybrid male rescue gene on expression (right).  The chimeric constructs reveal possible compensatory interactions among divergent mutations.