Asymmetry in chromosome pairing: a major factor in de novo mutation and the production of genetic disease in man

Abstract

At the outset of the meiotic pairing process in man, trial and error mismatching and misalignment, both within homologous pairs and between heterologues, can be observed cytologically. Pairing starts at early zygotene principally within subtelomeric regions where the synaptonemal complex initiates. In the present paper, evidence for the primary role in synaptic initiation of a GC rich minisatellite in the human XY pseudoautosomal segment is presented, and circumstantial evidence is provided to support the view that GC rich sequences (minisatellites and Alu repeats) function to promote pairing within autosomes. The known sequence hypervariability of proterminal human minisatellites, it is suggested, arises as a secondary consequence of unequal exchange after misalignment between tandem repeats at the outset of the pairing process. Unequal exchange within misaligned repeat sequences at early prophase of meiosis could make a major contribution to de novo germinal mutation (conversion, duplication, deficiency, inversion, translocation), with serious consequences in man for the production of hereditary disease. For somatic tissues, rare mispairing between G rich repeats followed by unequal exchange could be a key step in cancer progression. It might also explain somatic mosaicism in some non-neoplastic clinical conditions.