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Background  Numerous human genes encode potentially active DNA transposases or recombinases, but our understanding of their functions remains limited due to shortage of methods to profile their activities on endogenous genomic substrates.    Results  To enable functional analysis of human transposase-derived genes, we combined forward chemical genetic hypoxanthine-guanine phosphoribosyltransferase 1 ( HPRT1 ) screening with massively parallel paired-end DNA sequencing and structural variant genome assembly and analysis. Here, we report the  HPRT1  mutational spectrum induced by the human transposase PGBD5, including PGBD5-specific signal sequences (PSS) that serve as potential genomic rearrangement substrates.    Conclusions  The discovered PSS motifs and high-throughput forward chemical genomic screening approach should prove useful for the elucidation of endogenous genome remodeling activities of PGBD5 and other domesticated human DNA transposases and recombinases.    Electronic supplementary material  The online version of this article (doi:10.1186/s12864-016-2877-x) contains supplementary material, which is available to authorized users.

Forward genetic screen of human transposase genomic rearrangements