Genetic Variation Affects de Novo Translocation Frequency

Abstract

Translocation is one of the most frequently occurring human chromosomal aberrations. Balanced carriers usually manifest no phenotype but experience problems with reproduction. These include infertility, recurrent abortion, and offspring with chromosomal imbalance. The constitutional t(11;22)(q23;q11) is a balanced translocation between chromosomes 11 and 22, with breakpoints at bands 11q23 and 22q11. It is the only known recurrent non-Robertsonian translocation and represents a good model for studying translocations in humans (1). The recurrent nature of this translocation prompted us to examine t(11;22) breakpoints for a specific genomic structure. The analysis of many unrelated t(11;22) cases revealed that the breakpoints occur within palindromic AT-rich repeats (PATRRs) on 11q23 and 22q11 (PATRR11 and PATRR22) (2-4). The majority of the breakpoints are localized at the center of the PATRRs, suggesting that the center of the palindrome is susceptible to double-strand breaks (DSBs), thereby inducing illegitimate chromosomal rearrangement (3,5). Recent findings of PATRRlike sequences at the breakpoints of other translocations support the possibility that palindromemediated chromosomal translocation is a general pathway for human genomic rearrangements (6-8).The PATRR11 is variable in size in normal healthy individuals ( Fig. 1 and table S1). The most common allele is a ~450-base pair (bp) PATRR11 (L-PATRR11) that forms a nearly perfect palindrome (5). Several types of short variants were identified (S-PATRR11) that appear to be derived from the longer version primarily by deletion near the symmetric center of the palindromic structure. We can classify the S-PATRR11s into four groups. The most frequent 350-bp variant, S1-PATRR11, has a 50-bp deletion at both of the palindromic arms but still remains completely symmetrical. S2-PATRR11 has an asymmetric deletion at its center, but the new center manifests a symmetric palindrome. S3-PATRR11 does not possess palindromic features by virtue of a deletion at the center of the palindrome. We identified a rare 434-bp S-PATRR11, which sustained an asymmetric central deletion followed by the insertion of an ATrich sequence of unknown origin (S4-PATRR11). We also identified another rare allele with a duplication of the proximal arm, which constitutes a 603-bp asymmetric palindrome (EL-PATRR11). On the basis of the palindrome-mediated mechanism of the translocation, it is reasonable to hypothesize that the polymorphism of the PATRR11 could affect the frequency of de novo t(11;22) translocations.

Molecular cloning of a translocation breakpoint hotspot in 22q11

“…This finding is in contrast to what has been observed for the PATRR11 or PATRR17 (Inagaki et al 2005;Kato et al 2006). One possibility is that the PATRR22 emerged more recently in the history of primate evolution.…”

Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations

“…In addition, de novo t(11;22)s (1.0-0.1 Â 10 À 4 ) are found in sperm from healthy males 11 . The PATRRs manifest size polymorphisms, and the symmetry and length of the PATRRs greatly influence the de novo translocation frequency 12,13 . Thus, we proposed that the palindromic sequences form a cruciform conformation in vivo, and this conformation could induce DNA breakage that results in illegitimate joining, leading to a reciprocal translocation.…”

Recent advance in our understanding of the molecular nature of chromosomal abnormalities

“…Longer and more symmetric PATRR alleles with potent cruciform-forming propensity in vitro show a strong predisposition to translocation events. 41,42 It is proposed that the secondary structures adopted by palindromic DNA induce a greater susceptibility to DSBs thus leading to recurrent chromosomal translocations in humans. 26 This hypothesis has been recently verified using a plasmid-based model system that recapitulates PATRR-mediated translocation.…”