DNA mutation motifs in the genes associated with inherited diseases

Abstract

Mutations in human genes can be responsible for inherited genetic disorders and cancer. Mutations can arise due to environmental factors or spontaneously. It has been shown that certain DNA sequences are more prone to mutate. These sites are termed hotspots and exhibit a higher mutation frequency than expected by chance. In contrast, DNA sequences with lower mutation frequencies than expected by chance are termed coldspots. Mutation hotspots are usually derived from a mutation spectrum, which reflects particular population where an effect of a common ancestor plays a role. To detect coldspots/hotspots unaffected by population bias, we analysed the presence of germline mutations obtained from HGMD database in the 5-nucleotide segments repeatedly occurring in genes associated with common inherited disorders, in particular, the PAH, LDLR, CFTR, F8, and F9 genes. Statistically significant sequences (mutational motifs) rarely associated with mutations (coldspots) and frequently associated with mutations (hotspots) exhibited characteristic sequence patterns, e.g. coldspots contained purine tract while hotspots showed alternating purine-pyrimidine bases, often with the presence of dinucleotide. Using molecular dynamics simulations and free energy calculations, we analysed the global bending properties of two selected coldspots and two hotspots with a mismatch. We observed that the coldspots were inherently more flexible than the hotspots. We assume that this property might be critical for effective mismatch repair as DNA with a mutation recognized by MutSα protein is noticeably bent.

Strategies for the Development of Metallic‐Nanoparticle‐Based Label‐Free Biosensors and Their Biomedical Applications

“…Single base pair disparity in DNA can lead to diseases,s uch as cancer, cardiovascular,o rn eurodegenerative-related disease, due to am odification in the activity of the protein. [45] Although many methods exist for the detection of SNPs, these techniques suffer from al ow discriminationr atio, [46] which requires highly sensitive SNP detection. Sanromµn-Iglesiasa nd co-workers proposed the effect of particle size on the precise and specific detection of the BRCA1 mutant gene; [47] this is ab iomarker for the identification of breast and ovarian cancer.…”

Importance of base-pair opening for mismatch recognition

“…Proteins responsible for mismatch recognition are very effective despite structural similarities between some mismatches and canonical base pairs. Understanding how such delicate discrimination is achieved on the molecular level can be beneficial for biomedical applications providing early diagnosis of inherited diseases ( 3 , 4 ). Further, the molecular origin of the recognition can be helpful in the development of more efficient anti-cancer drugs ( 5–8 ) targeting damaged DNA.…”

“…Upon mismatch recognition, two main motions within DNA can be detected in experimental structures of MutS/DNA complexes: sharp DNA bending at a site of mismatch (blue arrows) and mismatch opening into the minor groove (red arrow). Models describing the DNA bending in the absence of MutS are: ( B ) DNA bending in the presence of PHE intercalator; ( C ) DNA bending induced by a simple bending angle α ( 28 ), which results in a smooth DNA bending; ( D ) DNA bending induced by a root-mean-square distance δ ( 3 ) from the DNA in the MutS/DNA complex (orange), which recovers correct DNA shape. Models C and D are deficient due to the absence of the PHE intercalator.…”

“…Despite the limitation of the employed model, their results revealed the relation between the mutability of DNA sequences and their bending properties. Mainly, coldspots were found to be more flexible than hotspots suggesting that altered flexibility can influence the effectivity of MMR ( 3 , 4 ).…”

Role of Inosine–Uracil Base Pairs in the Canonical RNA Duplexes

“…In this study, we employed molecular dynamics (MD) simulations to investigate the role of single and tandem I–U base pairs in dsRNA duplexes at positions that were found to be deaminated by ADAR1 [ 22 ]. This computational technique provides insight into structural dynamics of molecules on a nanosecond (ns) to microsecond (μs) time scale, and was instrumental in previous studies focused on RNA and DNA duplex flexibility [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. We performed a detailed structural analysis of 500 ns long standard simulations.…”