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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

Cooper, David Neil, Bacolla, Albino, Férec, Claude, Vasquez, Karen M., Kehrer-Sawatzki, Hildegard and Chen, Jian-Min 2011. 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. Human Mutation 32 (10) , pp. 1075-1099. 10.1002/humu.21557

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RB Pathology
Uncontrolled Keywords: Inherited disease ; Human genome ; Disease genes ; Mutational mechanisms, Mutation hotspots ; DNA sequence motifs ; Genome architecture ; Non-B DNA structures
Publisher: John Wiley & Sons
ISSN: 1059-7794
Last Modified: 04 Jun 2017 03:34
URI: http://orca.cf.ac.uk/id/eprint/22847

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