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A Standard Methodology to Examine On-site Mutagenicity As a Function of Point Mutation Repair Catalyzed by CRISPR/Cas9 and SsODN in Human Cells
Published on: August 25, 2017
Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of
Edward V Ball1, Peter D Stenson, Shaun S Abeysinghe
1Institute of Medical Genetics, Cardiff University, Cardiff, United Kingdom.
Abstract:
In the Human Gene Mutation Database (www.hgmd.org), microdeletions and microinsertions causing inherited disease (both defined as involving < or = 20 bp of DNA) account for 8,399 (17%) and 3,345 (7%) logged mutations, in 940 and 668 genes, respectively. A positive correlation was noted between the microdeletion and microinsertion frequencies for 564 genes for which both microdeletions and microinsertions are reported in HGMD, consistent with the view that the propensity of a given gene/sequence to undergo microdeletion is related to its propensity to undergo microinsertion. While microdeletions and microinsertions of 1 bp constitute respectively 48% and 66% of the corresponding totals, the relative frequency of the remaining lesions correlates negatively with the length of the DNA sequence deleted or inserted. Many of the microdeletions and microinsertions of more than 1 bp are potentially explicable in terms of slippage mutagenesis, involving the addition or removal of one copy of a mono-, di-, or trinucleotide tandem repeat. The frequency of in-frame 3-bp and 6-bp microinsertions and microdeletions was, however, found to be significantly lower than that of mutations of other lengths, suggesting that some of these in-frame lesions may not have come to clinical attention. Various sequence motifs were found to be over-represented in the vicinity of both microinsertions and microdeletions, including the heptanucleotide CCCCCTG that shares homology with the complement of the 8-bp human minisatellite conserved sequence/chi-like element (GCWGGWGG). The previously reported indel hotspot GTAAGT and its complement ACTTAC were also found to be overrepresented in the vicinity of both microinsertions and microdeletions, thereby providing a first example of a mutational hotspot that is common to different types of gene lesion. Other motifs overrepresented in the vicinity of microdeletions and microinsertions included DNA polymerase pause sites and topoisomerase cleavage sites. Several novel microdeletion/microinsertion hotspots were noted and some of these exhibited sufficient similarity to one another to justify terming them "super-hotspot" motifs. Analysis of sequence complexity also demonstrated that a combination of slipped mispairing mediated by direct repeats, and secondary structure formation promoted by symmetric elements, can account for the majority of microdeletions and microinsertions. Thus, microinsertions and microdeletions exhibit strong similarities in terms of the characteristics of their flanking DNA sequences, implying that they are generated by very similar underlying mechanisms.
Insights
Microdeletions and microinsertions are common causes of inherited diseases, often arising from similar DNA sequence mechanisms. Their frequencies correlate, with shorter lesions being more common and specific motifs acting as mutation hotspots.
Area of Science:
- Genetics
- Molecular Biology
- Genomic Instability
Background:
- Microdeletions and microinsertions (< or = 20 bp) are significant causes of inherited diseases, documented in the Human Gene Mutation Database (HGMD).
- These small DNA alterations affect numerous genes, contributing to a substantial percentage of logged mutations.
Purpose of the Study:
- To investigate the relationship between microdeletion and microinsertion frequencies in genes.
- To identify sequence characteristics and motifs associated with these mutational events.
- To understand the underlying mechanisms driving microdeletions and microinsertions.
Main Methods:
- Analysis of mutation data from the Human Gene Mutation Database (HGMD).
- Statistical correlation of microdeletion and microinsertion frequencies across genes.
- Identification and analysis of overrepresented sequence motifs near mutation sites.
- Examination of sequence complexity and potential secondary structures.
Main Results:
- A positive correlation exists between microdeletion and microinsertion frequencies in many genes.
- Shorter lesions (1 bp) are most frequent, with longer lesions occurring less often.
- Specific sequence motifs, including known indel hotspots and novel 'super-hotspots', are overrepresented near these mutations.
- Slippage mutagenesis and secondary structure formation are implicated as key mechanisms.
Conclusions:
- Microdeletions and microinsertions share common underlying mutational mechanisms and sequence features.
- The identified hotspots provide insights into gene susceptibility to these small DNA alterations.
- Understanding these mechanisms is crucial for interpreting genetic variation and inherited diseases.
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