Application of principles regulating evolutionary genetics, testis determination (TD) & chromosome biology confirm induction of Y rearrangements & epigenetic modifications in interspecific (IS) combinations of mouse genomes & Y chromosomes. Chimeric adult males with >90% XX somatic & testicular cells confirm Sry dispensability. This & 3 methods confirmed genetically modulated rearrangements in the direct & inverted repeat (DR/IR) dense ~200 kb TD Sxr-region spanning the 34 kb IR Sry locus/gene of fertile males, at high frequency in all tissues, germlines & species. This is consistent with the spectrum of high frequency serendipitous subversions of chromosome biology (SHFSSCB) reported in IS mice from natural hybrid zones (NHZ) & lab matings. Induction by unbiased, evolutionary divergence, rather than by drug or heteroduplex selection, retains the pathological relevance of errors in endogenous sequences, native loci & developmental contexts - with systematization & control of inducing networks by mouse genetics. Also isolated is a putative retrotransposon encoded fusion ORF: SRY-HMG (splice site?)-LINE-1 transposase. Sry & yeast (S.c.) IR are similar as known sites of double strand breaks (DSB) processed into double Holliday Junctions (dHJ) & their rearrangement products. In S.c. (& mouse?) the choice between dissolution (& repair) or resolution (& deletions) of dHJ is a consequence of the interactions of the Sgs1 helicase/Top3 topoisomerase/Rmi1 heteromer with Rad51. EMSA & ‘Pull Down’ assays confirm that Rmi1 & Top3/Rmi1 preferentially (>10x) bind HJ over 10 synthetic recombinational or replicational structures. The dimer but neither monomer, stimulates Sgs-1N/HJ complex formation. Complexes with HJ have ~6x> affinity than with pseudoreplication forks (pRF) & so this choice between the 2 activities of Sgs1 at stalled forks may be imposed by DNA structure & the dimer. Structural similarity with unstable replication slow zones (RSZ)/fragile sites (FS) & cis suppressors of viral Oris may also predict Sxr instability. These results are a basis for an unbiased & integrative approach to systematizing, surveilling & controlling mammalian genome biology, preempting (disease) mutations & shifting therapeutic paradigms!