Abstract: Background: Large palindromes (inverted repeats) make up substantial proportions of mammalian sex chromosomes, often contain genes, and have high rates of structural variation arising via ectopic recombination. As a result, they underlie many genomic disorders. Maintenance of the palindromic structure by gene conversion between the arms has been documented, but over longer time periods, palindromes are remarkably labile. Mechanisms of origin and loss of palindromes have, however, received little attention. Results: Here, we use fiber-FISH, 10x Genomics Linked-Read sequencing, and breakpoint PCR sequencing to characterize the structural variation of the P8 palindrome on the human Y chromosome, which contains two copies of the VCY (Variable Charge Y) gene. We find a deletion of almost an entire arm of the palindrome, leading to death of the palindrome, a size increase by recruitment of adjacent sequence, and other complex changes including the formation of an entire new palindrome nearby. Together, these changes are found in ~ 1% of men, and we can assign likely molecular mechanisms to these mutational events. As a result, healthy men can have 1–4 copies of VCY. Conclusions: Gross changes, especially duplications, in palindrome structure can be relatively frequent and facilitate the evolution of sex chromosomes in humans, and potentially also in other mammalian species.