Earlier in the summer, I pointed to a study that shows evidence of genome reformatting during human evolution:
In new research the Leeds team reports that a protein known as REST plays a central role in switching specific genes on and off, thereby determining how specific traits develop in offspring.
The study shows that REST controls the process by which proteins are made, following the instructions encoded in genes. It also reveals that while REST regulates a core set of genes in all vertebrates, it has also evolved to work with a greater number of genes specific to mammals, in particular in the brain – potentially playing a leading role in the evolution of our intelligence.
Says lead researcher Dr Ian Wood of the University’s Faculty of Biological Sciences: “This is the first study of the human genome to look at REST in such detail and compare the specific genes it regulates in different species. We’ve found that it works by binding to specific genetic sequences and repressing or enhancing the expression of genes associated with these sequences.
“Scientists have believed for many years that differences in the way genes are expressed into functional proteins is what differentiates one species from another and drives evolutionary change – but no-one has been able to prove it until now.”
Consider the abstract of this study:
Specific wiring of gene-regulatory networks is likely to underlie much of the phenotypic difference between species, but the extent of lineage-specific regulatory architecture remains poorly understood. The essential vertebrate transcriptional repressor REST (RE1-Silencing Transcription Factor) targets many neural genes during development of the preimplantation embryo and the central nervous system, through its cognate DNA motif, the RE1 (Repressor Element1). Here we present a comparative genomic analysis of REST recruitment in multiple species by integrating both sequence and experimental data. We use an accurate, experimentally validated Position-Specific Scoring Matrix method to identify REST binding sites in multiply aligned vertebrate genomes, allowing us to infer the evolutionary origin of each of 1,298 human RE1 elements. We validate these findings using experimental data of REST binding across the whole genomes of human and mouse. We show that one-third of human RE1s are unique to primates: These sites recruit REST in vivo, target neural genes, and are under purifying evolutionary selection. We observe a consistent and significant trend for more ancient RE1s to have higher affinity for REST than lineage-specific sites and to be more proximal to target genes. Our results lead us to propose a model where new transcription factor binding sites are constantly generated throughout the genome; thereafter, refinement of their sequence and location consolidates this remodeling of networks governing neural gene regulation.
In other words, RE1 is a piece of DNA that is spread about the genome, where it can bind the protein REST and alter the level of expression in near-by genes. And during human evolution, RE1 may have been tweaking the expression of genes involved in brain evolution. So why is this so interesting?
The authors note:
Emerging evidence, including that presented in this manuscript, points to highly divergent transcription factor recruitment between mammalian species. What is the basis for this divergence? Many transcription factors bind short degenerate sequences that can be readily created by single base pair mutations of a similar sequence. However, this is unlikely to be the case for transcription factors with long recognition elements, such as REST, p53 or CTCF: For simple probabilistic reasons, long periods of time must pass before long regulatory motifs can arise through DNA mutation in a given stretch of random sequence. What processes can explain the genomic remodeling of transcriptional regulatory networks observed in vertebrates?
The process of simple point mutation, ticking away over time like a clock, is insufficient for distributing these RE1 sites around the genome. So how did they spread all over the genome?
A couple of years ago, the same researchers published a paper entitled, “Identification of the REST regulon reveals extensive transposable element-mediated binding site duplication.” Here are some excerpts:
We reasoned that duplication and insertion by TEs [transposable elements – MG ]might be a potential mechanism of RE1 duplication. We therefore tested the duplicated RE1s for repetitive or transposon characteristics. We submitted the flanking sequences of duplicated RE1s to the online tool RepeatMasker, which indicated that the majority of duplicated RE1s are located in TEs of most major classes, including long interspersed repeats (LINEs, principally LINE2s), short interspersed repeats (SINEs, principally Alus) and hERV sequences.
Most of those sequences tested, including those associated with Alu, LINE1 and LINE2 sequences, as well as two pairs residing in non-repetitive DNA, were capable of interacting with REST.
TEs have gone through bursts of active transposition during distinct periods of evolutionary history: although LINE2 elements were thought to be active ∼200 million years ago and before human–mouse divergence, LINE1 and Alu elements continue to retrotranspose in humans. This is reflected in the phylogenetic conservation of human TE-associated RE1s: those associated with Alu and LINE1 elements have no aligned sequences other than in chimp, while a number of ancient LINE2 elements are conserved amongst multiple species.
Whoa. The Alu elements, derived from the SRP, seemed to have been involved in spreading the RE1 elements around the genome and thus influencing brain evolution.
But it just won’t stop getting better……
[Don’t forget some related context].