日本人類遺伝学会第64回大会

長崎ブリックホール

2019年11月08日

APCHG-5

口頭発表

精子形成過程における一過性多焦点性ゲノムクライシスは、クロモスリプシス依存的および非依存的染色体再編成を招く Transient multifocal genomic crisis creates chromothriptic and non-chromothriptic rearrangements in male germ cells

Atsushi Hattori1,2, Kohji Okamura3, Yumiko Terada4, Rika Tanaka5, Yuko Katoh-Fukui1, Yoichi Matsubara6, Keiko Matsubara1, Masayo Kagami1, Reiko Horikawa4, Maki Fukami1 1Mol. Endocrinol., NCCHD, 2Adv. Pediatr. Med., Grad. Sch. Med., Tohoku Univ., 3Sys. BioMed., NCCHD, 4Endocrinol. and Metab., NCCHD, 5Neonat., Aiiku Hosp., 6NRICHD, NCCHD

To date, the cause of multiple de novo copy-number variations (CNVs) has poorly been understood, although an “organismal CNV mutator phenotype” has recently been shown to underlie transient genomic instability in primary oocytes and early-stage zygotes. Subjects and Methods: We analyzed genome data from approximately 2,100 individuals. A boy with multiple de novo CNVs was subjected to extensive molecular analyses including synthetic long-read whole-genome sequencing and haplotype-phasing. Multiple CNVs were detected in a one-year-old boy. His CNVs included simple inversion, multiple duplications, and chromothriptic changes, which independently affected five paternally derived chromosomes. Postzygotic genomic instability was ruled out. Duplicated regions contained both diallelic and triallelic loci, indicating that the duplications occurred during premeiotic mitosis and subsequently modified by physiological meiotic recombination. Nucleotide sequences around breakpoints indicated that the rearrangements were caused by non-homologous end joining, replication-based error, and chromothripsis. These results indicate that a multifocal genomic crisis in prezygotic germ cells can induce chromothriptic and non-chromothriptic changes into the genome. This unique mutagenic event appears to be etiologically and consequentially different from the previously documented “organismal CNV mutator phenotype” and occurs exclusively during spermatogenesis. This study suggests a novel mechanism for altering the global chromosomal architecture of human embryos.