LINE-1-Derived Poly(A) Microsatellites Undergo Rapid Shortening and Create Somatic and Germline Mosaicism in Mice

Abstract

Interspersed and tandem repeat sequences comprise the bulk of mammalian genomes. Interspersed repeats result from successive replication by transposable elements, such as Alu and long interspersed element type 1 (L1). Microsatellites are tandem repeats of 1-6 base pairs, among which poly(A) microsatellites are the most abundant in the human genome. The rise and fall of a microsatellite has been depicted as a life cycle. Previous studies have demonstrated that Alu and L1 insertions are a major source of A-rich microsatellites owing to the concurrent formation of a poly(A) DNA tract at the 3'-end of each insertion. The fate of such poly(A) tracts has been studied by surveying the length distribution of genomic resident Alu and L1 insertions. However, these cross-sectional studies provide no information about the tempo of mutation immediately after birth. In this study, de novo L1 insertions were created using a transgenic L1 mouse model and traced through generations to investigate the early life of poly(A) microsatellites. High frequencies of intra-individual and intergenerational shortening were observed for long poly(A) tracts, creating somatic and germline mosaicism at the insertion site, whereas little variation was observed for short poly(A) alleles. As poly(A) microsatellites are the major intrinsic signal for nucleosome positioning, their remarkable abundance and variability make them a significant source of epigenetic variation. Thus, the birth of poly(A) microsatellites from retrotransposons and the subsequent rapid and variable shortening represent a new way with which retrotransposons can modify the genetic and epigenetic architecture of our genome.