Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity

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.

Nature and mRNA effect of 282 differentNF1point mutations: focus on splicing alterations

“…Small deletions (95/135, 70%) were 2.3 times more common than small insertions (40/135, 27%). These proportions are comparable with those given in a comprehensive review of microdeletions and microinsertions deposited in the Human Gene Mutation Database (Ball et al, 2005), where deletions are reported to be approximately 2.5 times more frequent than insertions. The authors suggest that a biased mechanism in the mutational process generating these alterations accounts for the greater probability of small deletions than small insertions.…”

“…Although most deletions/insertions cause a frameshift, amino acid deletions are found in 4.3% (16/374) of the studied patients (9/282 mutations). Ball et al detected a significantly lower frequency of in-frame 3-bp and 6-bp events (Ball et al, 2005), which would cause the deletion of one or two amino acids. The authors hypothesize that some of these in-frame lesions would probably produce a milder or null phenotype that would not be identified by clinicians.…”

Five Novel Mutations in Cystinuria Genes SLC3A1 and SLC7A9

“…A deletion of four nucleotides (ACTC) at position 1048-1051 in exon 10 in the SLC7A9 gene ( Figure 2C) was detected in the homozygous state, in a Turkish patient (CY-36). This mutation was most probably generated by a mechanism of "slipped misspairing" between the two direct repeats (TC), followed by a deletion of one of the direct repeats and the intervening AC sequence [14]. Because of the urinary excretion profile of the parents, the patient was classified as non type I/non type I (Table 1).…”

Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation

“…The proposed independent origins of the identical duplication in at least three different FEO pedigrees suggest that the duplication occurs at a mutation hotspot and is consistent with these models. The repetitive and G/C-rich nature of the sequences surrounding the close and partly overlapping duplications of the FEO, early-onset PDB, and ESH duplications are likely to promote mutation events [15]. The preponderance of CTG repeats may be particularly important in this regard [16].…”