Extensive variation between inbred mouse strains due to endogenous L1 retrotransposition

Abstract

Numerous inbred mouse strains comprise models for human diseases and diversity, but the molecular differences between them are mostly unknown. Several mammalian genomes have been assembled, providing a framework for identifying structural variations. To identify variants between inbred mouse strains at a single nucleotide resolution, we aligned 26 million individual sequence traces from four laboratory mouse strains to the C57BL/6J reference genome. We discovered and analyzed over ten thousand intermediate-length genomic variants (from 100 nucleotides to 10 kilobases) distinguishing these strains from the C57BL/6J reference. Approximately 85% of such variants are due to recent mobilization of endogenous retrotransposons, predominantly L1 elements, greatly exceeding that reported in humans. Many genes' structure and expression are altered directly by polymorphic L1 retrotransposons, including Drosha, Parp8, Scn1a, Arhgap15 and others including novel genes. L1 polymorphisms are distributed non-randomly across the genome, as they are excluded significantly from the X chromosome and from genes associated with the cell cycle, but are enriched in receptor genes. Thus, recent endogenous L1 retrotransposition has diversified genomic structures and transcripts significantly, distinguishing mouse lineages and driving a major portion of natural genetic variation.