DNA usually forms the classic double helix shape — two strands wound around each other. But approximately 1% of the human genome has the ability to fold into four-stranded ‘quadruple helix’ DNA structures called G-quadruplexes (G4s). G4s regulate several key cellular processes (e.g., transcription) and have been hypothesized to participate in others. In new research, a team of scientists at Penn State University conducted the first genome-wide analysis of G4 distribution, thermostability, and selection. Their results, published in the journal Genome Research, suggest that G4s should be added to the list of functional elements of the genome along with genes, regulatory sequences, and non-protein coding RNAs, among others.
“There have been only a handful of studies that provided experimental evidence for individual G4 elements playing functional roles,” said Dr. Wilfried Guiblet, a graduate student at Penn State University at the time of research and now a postdoctoral researcher at the National Cancer Institute.
“Our study is the first to look at G4s across the genome to see if they show the characteristics of functional elements as a general rule.”
To better understand the function of G4s, Dr. Guiblet and colleagues looked at their distribution across the genome, their thermostability, and whether or not they showed signs of being under the influence of natural selection, all in relation to other functional elements of the genome.
The researchers confirmed that, as a rule, G4s are more common in regions of the genome known to have important cellular functions and that the G4s in these regions are more stable than elsewhere in the genome.
“The 3D structure of G4s can form transiently and how stable their structure is depends on their underlying DNA sequence and other factors,” Dr. Guilbet said.
“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.”
Functional regions of the genome are generally maintained by a type of natural selection called purifying selection.
Mutations in these regions could disrupt their function and be harmful to the organism. The mutations therefore are usually eliminated by purifying selection, which keeps the DNA sequence relatively unchanged over time.
In nonfunctional regions of the genome, a mutation may have no impact and can persist in the genome without any consequences. These regions of the genome are said to evolve neutrally.
Where G4s fall in this spectrum depends on their location in the genome.
“We can look at the patterns of change in a DNA sequence among human individuals and between humans and our close primate relatives as a test of natural selection and then use selection as an indicator of function,” said Dr. Yi-Fei Huang, a researcher in the Department of Biology and the Center for Medical Genomics at Penn State University.
“Our tests show that G4s located within functional regions of the genome appear to be under purifying selections, which is further evidence that G4s should be considered as functional elements.”
“The only exception from this pattern were protein-coding regions of genes, where G4s are relatively uncommon, rather unstable, and do not evolve under purifying selection. G4s in protein-coding regions of genes might be nonfunctional and costly to maintain.”
“We think that we are seeing evidence for a paradigm shift for how scientists define function in the genome,” said Dr. Kateryna Makova, a researcher in the Department of Biology and the Center for Medical Genomics at Penn State University.
“First, geneticists focused almost exclusively on protein-coding genes, then we became aware of many functional non-coding elements, and now we have G4s and possibly other non-B DNA elements.”
“3D structure may be just as important for defining function as the underlying DNA sequence.”
“Defining the full complement of functional genome elements is crucial for interpreting the potential disease consequences not only of inherited genetic variants but also of mutations arising within tissues over the lifetime of individuals,” said Professor Kristin Eckert, a researcher in the Center for Medical Genomics and the Department of Pathology at Penn State University.
“The identification of G4s as novel functional elements within the human genome is key to advancing the use of genetics in precision medicine.”
Wilfried M. Guiblet et al. 2021. Selection and thermostability suggest G-quadruplexes are novel functional elements of the human genome. Genome Res 31: 1136-1149; doi: 10.1101/gr.269589.120
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