Origin-Dependent Inverted-Repeat Amplification: Tests of a Model for Inverted DNA Amplification

摘要: DNA replication errors are a major driver of evolution--from single nucleotide polymorphisms to large-scale copy number variations (CNVs). Here we test specific replication-based model explain the generation interstitial, inverted triplications. While no genetic information is lost, novel inversion junctions and increased included sequences create potential for adaptive phenotypes. The model--Origin-Dependent Inverted-Repeat Amplification (ODIRA)-proposes that error at pre-existing short, interrupted, repeats in genomic generates an extrachromosomal, dimeric, autonomously replicating intermediate; subsequent integration dimer yields this class CNV without loss distal chromosomal sequences. We used combination vitro vivo approaches feasibility proposed its downstream consequences on chromosome structure yeast Saccharomyces cerevisiae. show error-the ligation leading lagging nascent strands "closed" forks-can occur interrupted repeats. removal molecules with two closed forks results hairpin-capped linear duplex replicates inverted, dimeric plasmid subsequently integrates into genome by homologous recombination, creating triplication. other models have been triplications their derivatives, our can also human, de novo, amplicons 2:1 mixture from both homologues parent--a feature readily explained intermediate arises one homologue prior meiosis. Our tests key features ODIRA lend support mechanism suggest further avenues enquiry unravel origins CNVs pivotal human health evolution.