Recombination-Associated Sequence Homogenization of Neighboring Alu Elements: Signature of Nonallelic Gene Conversion

Abstract

Recently, researchers have begun to recognize that, in order to establish neutral models for disease association and evolutionary genomics studies, it is crucial to have a clear understanding of the genomic impact of nonallelic gene conversion. Drawing on previous successes in characterizing this phenomenon over protein-coding gene families, we undertook a computational analysis of neighboring Alu sequences in the genome scale. For this purpose, we developed adjusted comutation rate (aCMR), a novel statistical method measuring the excess number of identical point mutations shared by adjacent Alu sequences, vis-à-vis random pairs. Using aCMR, we uncovered a remarkable genome-wide sequence homogenization of neighboring Alus, with the strongest signal observed in the pseudoautosomal regions of the X and Y chromosomes. The magnitude of sequence homogenization between Alu pairs is greater with shorter interlocus distance, higher sequence identity, and parallel orientation. Moreover, shared substitutions show a strong directionality toward GC nucleotides, with multiple substitutions tending to cluster within the Alu sequence. Taken together, these observed recombination-associated sequence homogenization patterns are best explained by frequent ubiquitous gene conversion events between neighboring Alus. We believe that these observations help to illuminate the nature and impact of the enigmatic phenomenon of gene conversion.