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.

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