AT-rich repeats associated with chromosome 22q11.2 rearrangement disorders shape human genome architecture on Yq12

Abstract

Low copy repeats (LCRs; segmental duplications) constitute ∼5% of the sequenced human genome. Nonallelic homologous recombination events between LCRs during meiosis can lead to chromosomal rearrangements responsible for many genomic disorders. The 22q11.2 region is susceptible to recurrent and nonrecurrent deletions, duplications as well as translocations that are mediated by LCRs termed LCR22s. One particular DNA structural element, a palindromic AT-rich repeat (PATRR) present within LCR22-3a, is responsible for translocations. Similar AT-rich repeats are present within the two largest LCR22s, LCR22-2 and LCR22-4. We provide direct sequence evidence that the AT-rich repeats have altered LCR22 organization during primate evolution. The AT-rich repeats are surrounded by a subtype of human satellite I (HSAT I), and an AluSc element, forming a 2.4-kb tripartite structure. Besides 22q11.2, FISH and PCR mapping localized the tripartite repeat within heterochromatic, unsequenced regions of the genome, including the pericentromeric regions of the acrocentric chromosomes and the heterochromatic portion of Yq12 in humans. The repeat is also present on autosomes but not on chromosome Y in other hominoid species, suggesting that it has duplicated on Yq12 after speciation of humans from its common ancestor. This demonstrates that AT-rich repeats have shaped or altered the structure of the genome during evolution.[Supplemental material is available online at www.genome.org.]The human 22q11.2 region is susceptible to chromosome rearrangements leading to multiple congenital malformation disorders (for review, see McDermid and Morrow 2002). The most well recognized is velo-cardio-facial syndrome/DiGeorge syndrome (22q11.2 deletion syndrome, 22q11DS; MIM 192430; MIM 601,362) associated with a recurrent 3-Mb hemizygous deletion (Morrow et al. 1995;Carlson et al. 1997;Shaikh et al. 2000). A newly described developmental disorder occurs in individuals with a duplication of the same region that is deleted Ensenauer et al. 2003). The deletion and duplication result from nonallelic homologous recombination events between two 240-kb low copy repeats (LCRs) termed LCR22-2 and LCR22-4 ( Fig. 1; Babcock et al. 2003). Approximately 7% of 22q11DS patients have a nested distal deletion endpoint in a third LCR22, LCR22-3a, lying equidistant between LCR22-2 and LCR22-4 (Fig. 1). In addition to deletions and duplications, translocations also occur in 22q11.2, some within LCR22s. The constitutional t(11;22) translocation is the most common nonRobertsonian recurrent translocation in humans and the breakpoint on 22q11.2 is in LCR22-3a (Fraccaro et al. 1980;Zackai and Emanuel 1980;Funke et al. 1999). Another, more rare recurrent translocation, the t(17;22) translocation occurs in the same region as well (Kehrer-Sawatzki et al. 1997;Edelmann et al. 2001). In addition, other de novo translocations also occur on 22q11.2, several in the vicinity of LCR22s . The chromosome breakpoints on 22q11.2 for the recurrent translocations are in the center of an A...

The role of fork stalling and DNA structures in causing chromosome fragility

“…These data suggest that translocations at PATRRs in germ cells and deletions in somatic cells occur through separate mechanisms. PATRRs 11 and 22 are both associated with non‐recurrent translocations as well, and have been proposed to play a role in genome evolution …”

“…PATRRs 11 and 22 are both associated with non-recurrent translocations as well, and have been proposed to play a role in genome evolution. 108 IRs are two sequences with complementary DNA on the same strand that are facing toward one another across a center of symmetry ( Figure 2). Note that many dinucleotide repeats are also IRs.…”

Distinct karyotypes in two offspring of a man with jumping translocation karyotype 45,XY,der(16)t(16;22)(q24;q11.2), −22 [59]/45,XY,der(1)t(1;22)(p36;q11.2), −22 [11]/45,XY,der(22)t(22;22)(p13;q11.2), −22 [10]

“…On 22q11.2, HSAT I/Alu/AT-rich regions are common and have altered the structure of the genome during evolution, leading to instability [Babcock et al, 2007]. Thus, it may play an important role in mediating translocations during meiosis.…”

FISH and array CGH characterization of de novo derivative Y chromosome (Yq duplication and partial Yp deletion) in an azoospermic male

“…without an IR sequence. It could only be suggested that in this particular case an interchromatid crossing-over took place within sequences which could potentially constitute translocation ‘hot spots’, as for example are chromosomal subtelomeric regions (Babcock et al, 2007; Kirsch et al, 2008; Linardopoulou et al, 2005; Rosser et al, 2009). …”