Mutational dynamics of a haploid y-specific minisatellite

MSY1 is the only hypervariable minisatellite on the human Y chromosome. Arrays contain 22-114 AT-rich repeat units of 25bp in length, of which eighteen different sequence-variant types have been identified. MSY1 maintains >99% virtual heterozygosity despite the absence of interallelic processes on the haploid and non-recombining Y chromosome. This thesis aimed to determine the types and rates of mutation events that were occurring at MSY1. Single-molecule analysis was used to analyse mutation in the sperm and blood DNA of a single donor. Sperm mutation rate was 2.6%, and mutants were small-scale length changes and isometric mutations that alter the internal structure of arrays but not array length. Overall mutation rate in blood was similar (1.8%), but the spectrum of mutation types was markedly different, suggesting that somatic and germline mutation processes are distinct. Analysis of MSY1 diversity in the framework of the Y phylogeny defined by binary markers allowed inferences to be made about rarer mutation events. These include the generation of novel repeats by recurrent point mutations and conversion events involving a flanking half-repeat (processes with rates of ~10-5 per generation), as well as examples of the rapid spread of specific base substitutions within arrays. The mechanisms underlying this rich variety of mutations could include unequal sister chromatid exchange, replication slippage, synthesis-dependent strand annealing and patch gene conversion. MSY1 repeats are strongly predicted to form hairpins, and this secondary structure is likely to be important in mutation at this unique locus.