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Developmental biology - DNA

3D Structure of DNA Affects Disease and Evolution

Whether DNA is twisted 'right' or not, impacts the rate and accuracy of how DNA functions...


The speed and error rate of of how DNA functions (DNA synthesis) is influenced by its 3D shape. A team of researchers from Penn State and the Czech Academy of Sciences finds that DNA sequences frequently associated with cancer and neurologic diseases, can in fact slow down or speed up based on the structure of the DNA molecule, causing errors. Their work appears online in the journal Genome Research.
"We want to understand factors affecting mutation rates across the human genome. Sequences that can form non-B DNA, form structures other than the common right-handed double-helix with ten bases per turn (B-DNA), These structures make up about 13 percent of our genome and play an important role in cell function, gene regulation and protection of telomeres that cap and stabilize the ends of chromosomes."

Kateryna Makova PhD, Pentz Professor of Biology, Eberly College, Penn State University, Pennsylvania, USA.


Non-B DNA includes DNA sequences that have:
"G" nucleotide, guanine, which form G-quadruplex structures
"A" rich regions, which can cause helix bending
Tandem repeats of one-to-six nucleotides, form slip strands and hairpins

"There are hundreds of thousands of sequence motifs that are predicted to form non-B DNA across the genome," explains Wilfried Guiblet, a graduate student in the bioinformatics and genomics program at Penn State and co-first author of the paper. "We used data from the SMRT sequencer from Pacific Biosciences to compare nucleotide incorporation times along non-B DNA regions with those along regions of more common B-DNA."

SMRT (Single-Molecule-Real-Time sequencing) tracks the time between incorporation of each nucleotide while DNA processes that order along a chromosome.
The comparison revealed that some forms of non-B DNA, G-quadruplexes for example, cause the polymerase enzyme to slow down by as much as 70 percent, while other non-B DNA caused the same enzyme to speed up.

To analyze the data, the team developed a statistical tool called the Functional Data Analysis (FDA) to contrast DNA nucleotide incorporation times in non-B and B-DNA. Each region was treated as a curve or mathematical function. A software package implementing the testing procedure is now publicly available.

In addition to capturing time changes in nucleotide incorporation, researchers noted error rates increased in some non-B DNA regions. For example: in G-quadruplex motifs, increased error rates lined up with increased DNA sequence variation when using data from the "1000 Genomes Project." Researchers also saw increased divergence between human and orangutan.
"It seems likely that the same phenomenon causing the increased error rate in the sequencer is also causing the increase we see in human variation and divergence from the orangutan.

"Understanding how the structure of non-B DNA impacts mutation rates is extremely interesting from the standpoint of genome evolution, as these regions are also implicated in human disease."


Kateryna D Makova PhD

Abstract
DNA conformation may deviate from the classical B-form in ~13% of the human genome. Non-B DNA regulates many cellular processes, including transcription and telomere maintenance; however, its effects on DNA polymerization speed and accuracy have not been investigated genome-wide. Such an inquiry is critical for informing neurological diseases and cancer genome instability, which are frequently associated with mutations at non-B DNA. Here we present the first genome-wide, simultaneous examination of DNA polymerization kinetics and accuracy in the human genome sequenced with Single-Molecule-Real-Time (SMRT) technology. We show that polymerization speed differs markedly between non-B and B-DNA: for instance, it decelerates at G-quadruplexes and fluctuates periodically at disease-causing tandem repeats. Applying Functional Data Analysis statistical techniques to polymerization kinetics profiles, we predict non-B DNA formation for a novel motif, which we validate experimentally with circular dichroism. We demonstrate that several non-B DNA motifs affect polymerization accuracy (e.g., G-quadruplexes increase sequencing error rates). Moreover, sequencing errors are positively associated with polymerization slowdown, and this relationship is amplified at non-B DNA. Finally, we show that G4 motifs highly divergent between human and orangutan (or having high diversity in the 1,000 Genomes Project data set) have pronounced polymerization slowdown and high sequencing error rates, suggesting similar mechanisms for sequencing errors and germline mutations. Our results demonstrate how SMRT sequencing data can be used to study polymerization kinetics and accuracy and contribute to our understanding of mutagenesis at non-B DNA.

Authors
Wilfried Guiblet, Marzia Cremona, Monika Cechova, Robert Harris, Iva Kejnovska, Eduard Kejnovsky, Kristin A. Eckert, Francesca Chiaromonte and Kateryna D Makova.


Acknowledgements
The research was funded by the Eberly College of Sciences, the Huck Institutes of the Life Sciences, and the Institute for CyberScience, at Penn State; by grants from the Pennsylvania Department of Health; and by the Czech Science Foundation.


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Nov 16, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




The speed and error rate of DNA Synthesis differs between regions of the genome that form the usual DNA structure (B DNA) and those regions that can form other structures (non-B DNA). Regions that can form G-quadruplexes (illustrated) slow down DNA synthesis and increase error rates. Other non-B DNA structures can have the opposite effect. This phenomenon could help explain increased human genetic variation and increased divergence between human and orangutan at these sites and has implications for understanding cancer and neurological diseases associated with non-B DNA.
Credit: Wilfried Guiblet, Penn State


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