title: Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes.
abstract: Massive palindromes in the human Y chromosome harbor mirror-image gene pairs essential for spermatogenesis. During evolution, these gene pairs have been maintained by intrapalindrome, arm-to-arm recombination. The mechanism of intrapalindrome recombination and risk of harmful effects are unknown. We report 51 patients with isodicentric Y (idicY) chromosomes formed by homologous crossing over between opposing arms of palindromes on sister chromatids. These ectopic recombination events occur at nearly all Y-linked palindromes. Based on our findings, we propose that intrapalindrome sequence identity is maintained via noncrossover pathways of homologous recombination. DNA double-strand breaks that initiate these pathways can be alternatively resolved by crossing over between sister chromatids to form idicY chromosomes, with clinical consequences ranging from spermatogenic failure to sex reversal and Turner syndrome. Our observations imply that crossover and noncrossover pathways are active in nearly all Y-linked palindromes, exposing an Achilles' heel in the mechanism that preserves palindrome-borne genes.
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute, and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Lange
authors.forename: Helen
authors.initials: H
authors.lastname: Skaletsky
authors.forename: Saskia K M
authors.initials: SK
authors.lastname: van Daalen
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Embry
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Korver
authors.forename: Laura G
authors.initials: LG
authors.lastname: Brown
authors.forename: Robert D
authors.initials: RD
authors.lastname: Oates
authors.forename: Sherman
authors.initials: S
authors.lastname: Silber
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Repping
authors.forename: David C
authors.initials: DC
authors.lastname: Page
mesh_terms: D043171:Chromosomal Instability; D041322:Chromosomes, Human, Y; D003434:Crossing Over, Genetic; D005260:Female; D006801:Humans; D055029:Inverted Repeat Sequences; D008297:Male; D011995:Recombination, Genetic; D012689:Sequence Homology, Nucleic Acid; D025064:Sex Chromosome Disorders / Q000235:genetics; D013091:Spermatogenesis; D014424:Turner Syndrome / Q000235:genetics