Multi-modal investigation of the schizophrenia-associated 3q29 genomic interval reveals global genetic diversity with unique haplotypes and segments that increase the risk for non-allelic homologous recombination
Feyza YilmazGurusamy UmamaheswaranTrenell J. MosleyYulia MostovoyTamim H. ShaikhMichael E. ZwickPui–Yan KwokCharles LeeJennifer G. Mullé
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Abstract Chromosomal rearrangements that alter the copy number of dosage-sensitive genes can result in genomic disorders, such as the 3q29 deletion syndrome. At the 3q29 region, non-allelic homologous recombination (NAHR) between paralogous copies of segmental duplications (SDs) leads to a recurrent ∼1.6 Mbp deletion or duplication, causing neurodevelopmental and psychiatric phenotypes. However, risk factors contributing to NAHR at this locus are not well understood. In this study, we used an optical mapping approach to identify structural variations within the 3q29 interval. We identified 18 novel haplotypes among 161 unaffected individuals and used this information to characterize this region in 18 probands with either the 3q29 deletion or 3q29 duplication syndrome. A significant amount of variation in haplotype prevalence was observed between populations. Within probands, we narrowed down the breakpoints to a ∼5 kbp segment within the SD blocks in 89% of the 3q29 deletion and duplication cases studied. Furthermore, all 3q29 deletion and duplication cases could be categorized into one of five distinct classes based on their breakpoints. Contrary to previous findings for other recurrent deletion and duplication loci, there was no evidence for inversions in either parent of the probands mediating the deletion or duplication seen in this syndrome.Keywords:
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Non-allelic homologous recombination
Segmental duplication
Copy number variation is surprisingly common among humans and can be involved in phenotypic diversity and variable susceptibility to complex diseases, but little is known of the extent of copy number variation in nonhuman primates. We have used two array-based comparative genomic hybridization platforms to identify a total of 355 copy number variants (CNVs) in the genomes of 20 wild-born chimpanzees (Pan troglodytes) and have compared the identified chimpanzee CNVs to known human CNVs from previous studies. Many CNVs were observed in the corresponding regions in both chimpanzees and humans; especially those CNVs of higher frequency. Strikingly, these loci are enriched 20-fold for ancestral segmental duplications, which may facilitate CNV formation through nonallelic homologous recombination mechanisms. Therefore, some of these regions may be unstable "hotspots" for the genesis of copy number variation, with recurrent duplications and deletions occurring across and within species.
Segmental duplication
Comparative genomic hybridization
Structural Variation
Non-allelic homologous recombination
Copy number analysis
Variation (astronomy)
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Segmental duplication
Structural Variation
Sequence (biology)
Copy number analysis
Gene dosage
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Breakpoint
Comparative genomic hybridization
Human genetics
Segmental duplication
Non-allelic homologous recombination
Positional cloning
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Chromosomal inversion
Segmental duplication
Non-allelic homologous recombination
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Chromosome regions
Chromosomal rearrangement
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Subtelomere
Segmental duplication
Human genetics
Non-homologous end joining
Gene rearrangement
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Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling, or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. Additionally, patient R609021 had Lisch nodules, whereas patient R653070 exhibited two inguinal freckles. The mother and sister of patient R609021 also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nine NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high-resolution breakpoint analysis that indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors the type-1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events.
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Abstract The human genome contains many different types of repetitive DNA elements that vary by size and copy number. Segmental duplications (SDs) are one such class of repetitive elements that are relatively large in size, have low copy number in the genome and their copies share high levels of sequence identity with each other. These characteristic features of SDs make them excellent substrates for genomic rearrangements, resulting from aberrant recombination between the highly identical copies. Several of the genomic rearrangements mediated by SDs lead to copy number variations of large genomic regions containing many genes. Consequently, SD‐mediated rearrangements are often associated with genetic diseases that manifest as syndromes characterised by multiple congenital anomalies due to dosage imbalance of one or more genes. Key Concepts Segmental duplications are repetitive DNA elements in the human genome. Segmental duplications mediate genomic rearrangements associated with many genomic diseases. Segmental duplications mediate genomic rearrangements via nonallelic homologous recombination (NAHR), or they can stimulate or promote rearrangements via nonhomologous end‐joining (NHEJ) or replication‐based mechanism (RBM). Segmental duplications have been associated with both recurrent and nonrecurrent chromosomal rearrangements including microdeletions, microduplications, translocations, inversions and other complex rearrangements. Segmental duplications have played an important role in the human genome evolution, genetic variation and disease predisposition.
Segmental duplication
Non-allelic homologous recombination
Structural Variation
Comparative genomic hybridization
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Array-based methods have enabled the detection of many genomic gains and losses. These are stated as copy number variants (CNVs) and comprise up to 13% of the human genome. Based on their breakpoints and modes of formation CNVs are termed recurrent or nonrecurrent. Recurrent CNVs are flanked by low copy repeats and are of a fixed size. They arise as a result of misalignment during meiosis by a mechanism named nonallelic homologous recombination. Several of such recurrent CNVs have been linked to human diseases. Nonrecurrent CNVs, which are not flanked by low copy repeats, are of variable size and may arise via mechanisms like nonhomologous end joining and replication-based mechanisms described by the fork stalling and template switching and microhomology-mediated break-induced replication models. It is becoming clear that most disease-causing CNVs are nonrecurrent and generally arise via replication-based mechanisms. Furthermore, it is now appreciated that genomic features other than low copy repeats play a role in the formation of nonrecurrent CNVs. This review will discuss the different mechanisms of CNV formation and how high resolution analyses of CNV breakpoints have added to our knowledge of their precise structure.
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