Dynamics and processes of copy number instability in human gamma-globin genes

Copy number variation in the human genome is prevalent but relatively little is known about the dynamics of DNA rearrangement. We therefore used the duplicated gamma-globin genes as a simple system to explore de novo copy number changes. Rearrangements that changed gene number were seen in both germline and somatic DNA, and mainly arose by unequal sister chromatid exchange between homologous sequences, with evidence from recurrent mosaic rearrangements that many, if not all, of these events in sperm arise before meiosis. Unequal exchange frequencies are apparently controlled primarily by the degree of sequence identity shared by the duplicate genes, leading to substantial variation between haplotypes in copy number instability. Additional, more complex rearrangements generated by mechanisms not involving homologous recombination, and in some cases showing DNA transfer between chromosomes, were also detected but were rare. Sequence changes were also seen in gamma-globin DNA molecules, with strong evidence that some were genuine de novo base substitutions. They were present in sperm at a frequency far higher than predicted from current estimates of germline mutation rates, raising interesting questions about base mutation dynamics in the male germline.