For the first time, researchers have found that G-quadruplex structures (G4s) in DNA could be added to the list of functional elements of the human genome.
Functional regions of the genome are usually maintained by purifying selection. This is a type of natural selection that eliminates harmful mutations and keeps a DNA sequence relatively unchanged over time. The human genome is also dominated by large tracts of DNA with no known function. In these non-functional regions of the genome, a mutation may have no impact and persist without any consequences. Therefore, these regions are said to evolve neutrally.
About 1% of the human genome has the ability to fold into G-quadruplexes (G4s). These structures are mainly formed in guanine-rich DNA sequences and were initially considered a structural curiosity. However, recently evidence has suggested that G4s are involved in key genomic functions, such as transcription, replication, genome stability and epigenetic regulation. They have also been implicated in cancer growth and the progression of neurological disorders.
G4s differ in their thermostability, and depending on their genomic location, this could affect their function. Evolution of G4s under these different selection pressures, and the consequences on the whole genome, have not been investigated – until now.
A guanine quartet (left) and a G-rich single strand (middle) that folds into a G-quadruplex structure (right). Orange ribbons represent the phosphate sugar backbone. Image credit: Institut Curie
G4s are functional elements in the genome
Recently, scientists from Penn State conducted the first genome-wide analysis of G4 distribution, thermostability and selection in relation to other functional elements of the genome.
The team found an overrepresentation, high thermostability and purifying selection for G4s within functional genetic components, such as promoters. Similar patterns were also observed within replication origins, enhancers and expression quantitative trait locis (eQTLs). On the other hand, G4s on the non-transcribed strand of genic components were underrepresented, unstable and evolved neutrally. Across the genome, purifying selection was stronger at stable G4s.
Essentially, the G4 regions of human DNA showed signs that they were preserved by natural selection. G4s that were in regulatory or other functional regions of the genome, which have important cellular functions, were more common and stable than G4s outside these regions.
Prospect of G4 elements
For the first time, scientists had provided evidence to suggest that G4 structures are, in fact, fundamental and should be added to the list of functional elements of the genome. Wilfried Guiblet, a researcher from Penn State, explained: “There have been only a handful of studies that provide experimental evidence for individual G4 elements playing functional roles. Our study is the first to look at G4s across the genome to see if they show the characteristics of functional elements. We found that, usually, G4s located within functional regions of the genome tend to be more stable. In other words, it’s more likely that the DNA is folded into a G4 at any given time and thus, more likely that the G4 is there for a functional reason.”
Defining the complete list of functional genome elements is crucial for the interpretation of inherited genetic variants and mutations that arise within tissues to predict potential disease consequences. The identification of G4s and additional novel functional elements within the human genome will be key to driving the use of genetics in precision medicine.
Kateryna Makova, also a scientist from Penn State, said: “We think that we are seeing evidence for a paradigm shift for how scientists define function in the genome. First, geneticists focused almost exclusively on protein-coding genes, then we became aware of many functional non-coding elements, and now we have G4s. Maybe three-dimensional structures are just as important for defining function as the underlying DNA sequence.”
Image credit: FreePik iuriimotov