title: 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.
abstract: 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.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom. CooperDN@cardiff.ac.uk
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Albino
authors.initials: A
authors.lastname: Bacolla
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Karen M
authors.initials: KM
authors.lastname: Vasquez
authors.forename: Hildegard
authors.initials: H
authors.lastname: Kehrer-Sawatzki
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
mesh_terms: D020087:Alu Elements; D001483:Base Sequence; D056915:DNA Copy Number Variations; D042622:DNA Repeat Expansion; D005796:Genes; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D054629:Genome, Mitochondrial; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic; D011995:Recombination, Genetic; D018626:Retroelements / Q000235:genetics
chemical_list: D018626:Retroelements