Chromosomal translocations and palindromic AT-rich repeats

doi:10.1016/j.gde.2012.02.004

Current Opinion in Genetics & Development

Volume 22, Issue 3, June 2012, Pages 221-228

https://doi.org/10.1016/j.gde.2012.02.004 Get rights and content

Repetitive DNA sequences constitute 30% of the human genome, and are often sites of genomic rearrangement. Recently, it has been found that several constitutional translocations, especially those that involve chromosome 22, take place utilizing palindromic sequences on 22q11 and on the partner chromosome. Analysis of translocation junction fragments shows that the breakpoints of such palindrome-mediated translocations are localized at the center of palindromic AT-rich repeats (PATRRs). The presence of PATRRs at the breakpoints indicates a palindrome-mediated mechanism involved in the generation of these constitutional translocations. Identification of these PATRR-mediated translocations suggests a universal pathway for gross chromosomal rearrangement in the human genome. De novo occurrences of PATRR-mediated translocations can be detected by PCR in normal sperm samples but not somatic cells. Polymorphisms of various PATRRs influence their propensity for adopting a secondary structure, which in turn affects de novo translocation frequency. We propose that the PATRRs form an unstable secondary structure, which leads to double-strand breaks at the center of the PATRR. The double-strand breaks appear to be followed by a non-homologous end-joining repair pathway, ultimately leading to the translocations. This review considers recent findings concerning the mechanism of meiosis-specific, PATRR-mediated translocations.

Section snippets

The genomic structure of 22q11 mediates rearrangements

It was previously thought that most genomic rearrangements were formed randomly, but more recent data indicate that is not the case. The 22q11 region is a hotspot for nonrandom chromosomal rearrangements. Deletions, duplications and translocations at 22q11 occur in greater than 1/3000–4000 livebirths [1]. Rearrangements of 22q11 include deletions or duplications associated with congenital developmental defects. The 22q11 deletion syndrome includes DiGeorge, velocardiofacial and conotruncal

Identification of PATRR sequences at the breakpoints of palindrome-mediated translocations

Detailed analysis of the genomic configuration of the chromosome 11 and 22 breakpoint regions was initially quite difficult because the palindromic sequence is highly unstable, representing a hotspot for deletion and recombination in bacteria, yeast, and mammals [20, 21, 22, 23••]. To overcome these difficulties, we established a permissive PCR strategy, sequencing by RNA polymerase and cloning in recombination-deficient E. coli cells to accomplish PATRR genotyping [24]. Using these methods, we

Detection of de novo t(11;22)s in the sperm of normal males by translocation-specific PCR

Because t(11;22) translocations have a tightly confined recurrent breakpoint region, we hypothesized that de novo translocations might be detectable in sperm from normal males by PCR [8•, 10]. Utilizing the information derived from translocation carriers, we established t(11;22) translocation-specific PCR methodology to assess translocation prevalence in sperm from normal individuals [32^••] (Figure 4a). When we amplified multiple aliquots of sperm DNA, translocation-specific PCR products were

PATRR polymorphisms affect the de novo translocation propensity of several PATRRs

Previously, we demonstrated that PATRR11 manifests size polymorphisms as a result of deletions within the PATRR, and that this polymorphism influences the frequency of de novo t(11;22)s in sperm [33^••]. Long symmetrical PATRR11s (L-PATRR11, 442–450 bp) produce de novo translocations in approximately 10⁻⁵ gametes. The translocation frequencies of symmetrical short alleles (SS-PATRR11, 292–386 bp) are approximately 10-fold lower than L-PATRR11s, while asymmetrical short alleles (AS-PATRR11, 212–434

Chromosomal instability mediated by unusual DNA structures-several scenarios

As mentioned previously, de novo t(11;22)s can only be detected in sperm and not in other somatic tissues [32^••]. Further, all de novo t(11;22)s examined have been determined to be paternal in origin [39]. From these results, we hypothesize that PATRRs form secondary structures, which in turn induce translocations during gametogenesis, especially spermatogenesis. The timing and mechanisms of secondary structure and translocation formation in male germ cells are potentially threefold (1) before

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

The authors wish to thank Molly B. Sheridan, April M. Hacker and Colleen P. Franconi for suggestions. These studies were supported by Award Number R01CA039926 from the National Cancer Institute (B.S.E.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The studies were also supported by funds from the Charles E.H. Upham Chair (B.S.E.). One of the authors (T.K.) was

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The repair of potentially lethal DNA breaks can lead to mutations as well as chromosome rearrangements including translocations, large deletions, and gene amplifications. The human genome carries multiple recombinogenic palindromes known to cause specific DNA rearrangements which are the underlying cause of a series of diseases and syndromes such as the Emanuel syndrome [2,3] and can even instigate the development of tumours [4]. Palindrome recombinogenicity is caused by the ability of palindromes to form secondary structures due to intrastrand base pairing which in turn leads to double strand breaks.
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Chromosomal translocations and palindromic AT-rich repeats

Section snippets

The genomic structure of 22q11 mediates rearrangements

Identification of PATRR sequences at the breakpoints of palindrome-mediated translocations

Detection of de novo t(11;22)s in the sperm of normal males by translocation-specific PCR

PATRR polymorphisms affect the de novo translocation propensity of several PATRRs

Chromosomal instability mediated by unusual DNA structures-several scenarios

References and recommended reading

Acknowledgements

Curr Opin Genet Dev

Trends Genet

Am J Hum Genet

Hum Genet

Hum Genet

Hum Mol Genet

Nat Genet

Mol Cytogenet

Nat Rev Genet

Cell

Nat Genet

J Med Genet

Exp Cell Res

Nat Genet

Molecular mechanisms and diagnosis of chromosome 22q11.2 rearrangements

Dev Disabil Res Rev

A common molecular basis for rearrangement disorders on chromosome 22q11

Hum Mol Genet

Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis

Hum Mol Genet

Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms

Genome Res

Long AT-rich palindromes and the constitutional t(11;22) breakpoint

Hum Mol Genet

Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22)

Hum Mol Genet

Clustered 11q23 and 22q11 breakpoints and 3:1 meiotic malsegregation in multiple unrelated t(11;22) families

Am J Hum Genet

Site-specific reciprocal translocation, t(11;22) (q23;q11), in several unrelated families with 3:1 meiotic disjunction

Am J Med Genet

A palindrome-driven complex rearrangement of 22q11.2 and 8q24.1 elucidated using novel technologies

Genome Res

A palindrome-mediated recurrent translocation with 3:1 meiotic nondisjunction: the t(8;22)(q24.13;q11.21)

Am J Hum Genet

The constitutional t(17;22): another translocation mediated by palindromic AT-rich repeats

Am J Hum Genet

A palindrome-mediated mechanism distinguishes translocations involving LCR-B of chromosome 22q11.2

Hum Mol Genet

Molecular cloning of a translocation breakpoint hotspot in 22q11

Genome Res

Palindrome resolution and recombination in the mammalian germ line

Mol Cell Biol

Instability of long inverted repeats within mouse transgenes

EMBO J

Inverted DNA repeats: a source of eukaryotic genomic instability

Mol Cell Biol

Long DNA palindromes, cruciform structures, genetic instability and secondary structure repair

Bioessays

Palindromic AT-rich repeat in the NF1 gene is hypervariable in humans and evolutionarily conserved in primates

Hum Mutat