Sequence structure and evolution of the mouse Y centromere

© 2013 Dr. Mark Domenic PertileThe centromere is a fundamental structure required for the faithful segregation of eukaryotic chromosomes during cell division. Despite this function being highly conserved, centromere sequences evolve rapidly, and are frequently diverged between even closely related species. While the centromere sequences of many model multicellular eukaryotes are now well characterised, one centromere sequence, namely that of the mouse Y chromosome, has remained unidentified. This lack of sequence information has left a significant gap in our knowledge of centromere biology and chromosome evolution in this important mammalian model organism. In mouse, the centromere sequence of all chromosomes except the Y chromosome consists of a highly conserved, tandemly repeated minor satellite DNA. Why the Y centromere should lack minor satellite DNA is unknown, but this observation suggests that the Y centromere DNA has evolved in relative isolation from the minor satellite sequence. Here, a bioinformatics approach has been used to identify a putative Y centromere DNA that has led to the complete molecular characterisation of the C57BL/6J mouse Y centromere. This newly identified satellite DNA (Ymin) is composed of a complex, highly diverged minor satellite-like sequence that is organised as a 2.3 kb higher-order repeat (HOR) unit. The homogeneous HOR units are tandemly repeated across the core of the Y centromere array and are flanked by diverged multimeric and monomeric Ymin repeats. This sequence architecture is more reminiscent of the organisation of the human centromeres and is quite distinct from the minor satellite sequence organisation found at all other mouse centromeres. The complete characterisation of the C57BL/6J (M.m. molossinus) mouse Y centromere DNA has been facilitated by the entire 90 kb Ymin array being contained within a single, fully sequenced BAC clone; RP24-110P17. The sequence conservation of the Ymin DNA was also investigated in other mouse strains. This led to the characterisation of a new, 1.6 kb HOR unit that is specific for the Y centromere of the subspecies M.m. domesticus. A comparative sequence analysis between the canonical HOR units from M.m. molossinus and M.m. domesticus mice indicates the Y centromere DNA is diverging at an accelerated rate, with major turnover of the HOR arrays driving rapid divergence of sequence and higher-order structure at the mouse Y centromere. A comparative sequence analysis of the human and chimpanzee centromeres indicates a similar rapid divergence for the primate Y centromere relative to other primate centromeres. Together, these data suggest that accelerated divergence of the Y centromere DNA may be a general feature of mammalian Y chromosome evolution. Somewhat paradoxically, an analysis of inbred mice transmitting the same Y chromosome over several hundred inbred generations provided no evidence for a change in Y centromere array length. This is despite considerable evidence for unequal sister chromatid exchange, which drives the expansion and contraction of tandem repeat arrays, being pervasive in the evolution of the mouse Y centromere DNA. The identification and molecular characterisation of the mouse Y centromere sequence fills a significant and long standing void in centromere biology and chromosome evolution. The diverged nature of the Y centromere DNA and its unique organisational architecture is consistent with this sequence evolving independently from the centromeres of all other mouse chromosomes