G-quadruplexes as functional elements of the human genome

Avani Dave, Jai Hind College

Natural selection has evidently preserved several specific sites in the human genome that allow an atypical 3-D conformation of the DNA which are referred to as G-quadruplexes (G4s). A new study demonstrates an increased occurrence and high stability of these not-so-usual G-quadruplexes if they are situated either in the sequences that control the gene expression or in the functional, but non-protein-coding, sequences of the genome. On the contrary, the stability and the occurrence of these structures are reduced when present anywhere outside the above-mentioned sites, this can be attributed to a lack of support from natural selection in preserving them, leading to evolution. Considering prior studies, it is suggested that these G-quadruplexes should be regarded as functional elements together with the predetermined  elements like the genes, sequences involved in regulation, and non-protein-coding RNAs, etc. 

The study

A paper by a group of researchers guided by Penn State scientists demonstrating the study was published in the journal – Genome Research on June 29, 2021. Wilfried Guiblet, first author of the paper (Penn State &  National Cancer Institute), stated that there are only a few research studies that have successfully demonstrated functional roles of G4s. He also mentioned that their study is one of its kind, as they focused on viewing the G-quadruplexes as functional elements in the human genome; as ruled by the standard notions. 

G4s are amongst the several non-canonical structures that the DNA can assume, a rough average of 1% of the genome can fold into G4s in contrast to the usual double helix structure, this proportion of the genome is called ‘Non-B DNA’. The G4 conformation is usually visualized in a DNA sequence that is rich in Guanine residues. These G4s have also been associated with essential cellular functions and are assumed to perform a vital role in human diseases like neurological disorders and cancer.

For a better understanding of the functions of G4s at a large scale, the researchers analyzed the distribution of these structures throughout the genome. They also examined several other characteristics traits like their thermo-stability, the influence of natural selection, and related the outcomes to the pre-discovered functional elements of the genome. This warranted the trend that G4s are more frequently present in regions associated with several cellular functions, and it is in such regions that G4 elements show elevated stability. Hence, the folding of DNA into a G4 can be accounted to be functionally essential. According to Guiblet, these structures form transiently, and the DNA sequence involved in this conformation along with a few other factors account for the stability conferred by G4s. 

Significance of the study

Any mutations that occur in the functional regions alter their function leading to an ill-functioning system causing harm to the host. Hence, the functional regions of the genome are usually under the influence of purifying selection- a type of natural selection that eliminates such harmful mutations and conserves the DNA sequence. This selection is not crucial in the case of non-functional regions as any mutation here may not have a detrimental effect. Hence such regions are under the influence of neutral evolution. As per Yi-Fei Huang (Lead of the research & Professor, Penn State), the function of a particular region can be identified by comparing the changes in its DNA sequence in humans and our close primate relatives as a test of natural selection.  When G4s are not governed by natural selection, they might be considered to not play any functional role in the genome and hence, maintenance of such non-functional G4s is not beneficial. 

The key that will lead to the advanced use of genetics in precision medicine lies in the recognition of G-quadruplexes as functional elements within the human genome. 

Also read: Polyphenol metabolism in anoxic soil decoded

References: 

1. Guiblet, W. M., DeGiorgio, M., et al. (2021). Selection and thermostability suggest G-quadruplexes are novel functional elements of the human genome. Genome research, 10.1101/gr.269589.120. Advance online publication. https://doi.org/10.1101/gr.269589.120
2. Penn State. (2021, June 29). A new class of functional elements in the human genome? Study provides first genome-wide evidence for functional importance of unusual DNA structures. ScienceDaily. Retrieved June 30, 2021 from www.sciencedaily.com/releases/2021/06/210629134330.htm

About author:

Avani Dave is currently in the final year of her Bachelor’s degree, majoring in Life Sciences. Holding a good academic and extra-curricular record, she is on a constant journey of acquiring exposure in her field of interest while simultaneously not limiting herself to just that. Avani likes studying Diseases and Syndromes and everything under this umbrella! That being said, she is adept at working across departments and promises to deliver.

LinkedIn – https://www.linkedin.com/avani-dave/

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