Mechanisms of insertion and deletion mutations: Rate variation, context specificity, and impact on primate sex chromosome evolution.

摘要

Despite substantial progress in understanding the molecular mechanisms of origin for nucleotide substitutions, at present we have only a rudimentary understanding of these processes for insertions and deletions. Such knowledge is important because almost a third of all mutations in the Human Gene Mutation Database (http://www.hgmd.org/) are insertions and deletions (indels).;Here we use the tools of bioinformatics, statistics and comparative genomics to study indel mutagenesis in detail. We have established a novel computational pipeline to accurately detect insertions and deletions in whole-genome human-chimpanzee alignments using the macaque sequence as an outgroup. This platform has allowed us to address several key questions pertaining to the formation of indels. In particular, this dissertation is organized around three specific questions: (1) What determines the variation in small insertion and deletion rates across the human genome? Genomic factors delineated here distinguish insertion vs. deletion mutagenesis. (2) What are the specific local contexts that contribute to rate differences in small insertions vs. deletions? Specific local sequences are hypothesized to facilitate indel mutations, and to differ between insertions and deletions. (3) What is the mechanism(s) contributing to the observed distribution of transposable elements (TEs) on primate sex chromosomes? Comparisons of sex chromosomes vs. autosomes (combining both their sequence features and retrotransposition history) serve to narrow the alternative scenarios for the evolution of the observed distribution.;Results from this research directly contribute to understanding the biological basis for insertion and deletion mutagenesis, with its implications for human genetic diseases. In addition, it aids in the development of improved gap modeling, which is crucial for improving alignment methodology and thus the accuracy of inferences regarding genome evolution.