Single base-pair substitutions at the translation initiation sites of human genes as a cause of inherited disease

A total of 405 unique single base-pair substitutions, located within the ATG translation initiation codons (TICs) of 255 different genes, and reported to cause human genetic disease, were retrieved from the Human Gene Mutation Database (HGMD). Although these lesions comprised only 0.7% of coding sequence mutations in HGMD, they nevertheless were 3.4-fold overrepresented as compared to other missense mutations. The distance between a TIC and the next downstream in-frame ATG codon was significantly greater for genes harboring TIC mutations than for the remainder of genes in HGMD (control genes). This suggests that the absence of an alternative ATG codon in the vicinity of a TIC increases the likelihood that a given TIC mutation will come to clinical attention. An additional 42 single base-pair substitutions in 37 different genes were identified in the vicinity of TICs (positions -6 to +4, comprising the so-called "Kozak consensus sequence"). These substitutions were not evenly distributed, being significantly more abundant at position +4. Finally, contrary to our initial expectation, the match between the original TIC and the Kozak consensus sequence was significantly better (rather than worse) for genes harboring TIC mutations than for the HGMD control genes.     

On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease

Different types of human gene mutation may vary in size, from structural variants (SVs) to single base-pair substitutions, but what they all have in common is that their nature, size and location are often determined either by specific characteristics of the local DNA sequence environment or by higher order features of the genomic architecture. The human genome is now recognized to contain "pervasive architectural flaws" in that certain DNA sequences are inherently mutation prone by virtue of their base composition, sequence repetitivity and/or epigenetic modification. Here, we explore how the nature, location and frequency of different types of mutation causing inherited disease are shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment. The mutability of a given gene or genomic region may also be influenced indirectly by a variety of noncanonical (non-B) secondary structures whose formation is facilitated by the underlying DNA sequence. Since these non-B DNA structures can interfere with subsequent DNA replication and repair and may serve to increase mutation frequencies in generalized fashion (i.e., both in the context of subtle mutations and SVs), they have the potential to serve as a unifying concept in studies of mutational mechanisms underlying human inherited disease.     

Triangulation of the human, chimpanzee, and Neanderthal genome sequences identifies potentially compensated mutations

Triangulation of the human, chimpanzee, and Neanderthal genome sequences with respect to 44,348 disease‐causing or disease‐associated missense mutations and 1,712 putative regulatory mutations listed in the Human Gene Mutation Database was employed to identify genetic variants that are apparently pathogenic in humans but which may represent a “compensated” wild‐type state in at least one of the other two species. Of 122 such “potentially compensated mutations” (PCMs) identified, 88 were deemed “ancestral” on the basis that the reported wild‐type Neanderthal nucleotide was identical to that of the chimpanzee. Another 33 PCMs were deemed to be “derived” in that the Neanderthal wild‐type nucleotide matched the human but not the chimpanzee wild‐type. For the remaining PCM, all three wild‐type states were found to differ. Whereas a derived PCM would require compensation only in the chimpanzee, ancestral PCMs are useful as a means to identify sites of possible adaptive differences between modern humans on the one hand, and Neanderthals and chimpanzees on the other. Ancestral PCMs considered to be disease‐causing in humans were identified in two Neanderthal genes (DUOX2, MAMLD1). Because the underlying mutations are known to give rise to recessive conditions in human, it is possible that they may also have been of pathological significance in Neanderthals. Hum Mutat 31:1–8, 2010. © 2010 Wiley‐Liss, Inc.     

Rates of nucleotide substitution,mutation at a locus,and the "beanbag" gene number in man

We estimated the number of different human genes by relating the patterns of spontaneous mutation at the population and individual level. A geometric distribution model of mutation was used in which the average rates of nucleotide replacement (P) and mutation at a locus (p), obtained by experiment, were used to determine the estimate of the physical size of the coding genome (n) in man. The probabilistic relation used, P = (1 −p) ⁿ⁻¹ p, integrates two different referential time scales of mutation, that of a nucleotide and year and that of a coding gene and generation. The estimates of n, for different values of P and p, are compatible with the experimentally determined genome sizes. The size of the coding portion of the genome appears to be evolutionarily constrained by an interplay between the rate of nucleotide replacement and the pattern of mutation at the level of the individual locus. The evolution of the size of the coding genome may be more dependent on the number of generations than on time. Received: October 26, 2001 / Accepted: January 16, 2002     

Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions

Serial replication slippage in cis (SRScis) provides a plausible explanation for many complex genomic rearrangements that underlie human genetic disease. This concept, taken together with the intra- and intermolecular strand switch models that account for mutations that arise via quasipalindrome correction, suggest that intrachromosomal SRS in trans (SRStrans) mediated by short inverted repeats may also give rise to a diverse series of complex genomic rearrangements. If this were to be so, such rearrangements would invariably generate inversions. To test this idea, we collated all informative mutations involving inversions of >or=5 bp but <1 kb by screening the Human Gene Mutation Database (HGMD; www.hgmd.org) and conducting an extensive literature search. Of the 21 resulting mutations, only two (both of which coincidentally contain untemplated additions) were found to be incompatible with the SRStrans model. Eighteen (one simple inversion, six inversions involving sequence replacement by upstream or downstream sequence, five inversions involving the partial reinsertion of removed sequence, and six inversions that occurred in a more complicated context) of the remaining 19 mutations were found to be consistent with either two steps of intrachromosomal SRStrans or a combination of replication slippage in cis plus intrachromosomal SRStrans. The remaining lesion, a 31-kb segmental duplication associated with a small inversion in the SLC3A1 gene, is explicable in terms of a modified SRS model that integrates the concept of "break-induced replication." This study therefore lends broad support to our postulate that intrachromosomal SRStrans can account for a variety of complex gene rearrangements that involve inversions.     

Meta-analysis of indels causing human genetic disease: mechanisms of mutagenesis and the role of local DNA sequence complexity

A relatively rare type of mutation causing human genetic disease is the indel, a complex lesion that appears to represent a combination of micro-deletion and micro-insertion. In the absence of meta-analytical studies of indels, the mutational mechanisms underlying indel formation remain unclear. Data from the Human Gene Mutation Database (HGMD) were therefore used to compare and contrast 211 different indels underlying genetic disease in an attempt to deduce the processes responsible for their genesis. Each indel was treated as if it were the result of a two-step insertion/deletion process and was assessed in the context of 10 base-pairs DNA sequence flanking the lesion on either side. Several indel hotspots were noted and a GTAAGT motif was found to be significantly over-represented in the vicinity of the indels studied. Previously postulated mechanisms underlying micro-deletions and micro-insertions were initially explored in terms of local DNA sequence regularity as measured by its complexity. The change in complexity consequent to a mutation was found to be indicative of the type of repeat sequence involved in mediating the event, thereby providing clues as to the underlying mutational mechanism. Complexity analysis was then employed to examine the possible intermediates through which each indel could have occurred and to propose likely mechanisms and pathways for indel generation on an individual basis. Manual analysis served to confirm that the majority of indels (>90%) are explicable in terms of a two-step process involving established mutational mechanisms. Indels equivalent to double base-pair substitutions (22% of the total) were found to be mechanistically indistinguishable from the remainder and may therefore be regarded as a special type of indel. The observed correspondence between changes in local DNA sequence complexity and the involvement of specific mutational mechanisms in the insertion/deletion process, and the ability of generated models to account for both the number and identity of the bases deleted and/or inserted, makes this approach invaluable not only for the analysis of indel formation, but also for the study of other types of complex lesion.