Structure and Evolution of the Smith-Magenis Syndrome Repeat Gene Clusters, SMS-REPs

Park, Sung Sup; Stankiewicz, Paweł; Bi, Weimin; Shaw, Christine J.; Lehoczky, Jessica A.; Dewar, Ken; Birren, Bruce; Lupski, James R.

doi:10.1101/gr.82802

Cited by 87 publications

(102 citation statements)

References 46 publications

(78 reference statements)

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“…1). Also of interest, the directly oriented LCR17pA/D and LCR17pD are 98.7% identical (Table 1) and can act as alternative homologous recombination substrates resulting in an ∼5 Mb deletion associated with SMS in about 4% of patients (Shaw et al 2004b), whereas the directly oriented distal and proximal SMS-REP copies are the substrates for the common ∼4 Mb deletion observed in 70%-80% of SMS patients (Chen et al 1997;Park et al 2002).…”

Section: Structure and Orientation Of Lcr17p Repeatsmentioning

confidence: 99%

“…Recent data suggest that LCR-associated genome architecture does not represent simple segmental duplications but rather reflects complex rearrangements that are potentially the end product of multiple events (van Geel et al 2002). These serial segmental duplications can result in a complex shuffling of genomic sequences (Babcock et al 2003;.The gene-and LCR-rich human genomic region 17p11.2-p12 is rearranged in a variety of different constitutional, evolutionary, and cancer-associated structural chromosome aberrations, and thus appears to be an excellent model to investigate the role of genome architecture in DNA rearrangements (Pentao et al 1992;Chance et al 1994;Chen et al 1997; Reiter et al 1998;Potocki et al 2000;Stankiewicz et al 2001;Park et al 2002;Bi et al 2003;Barbouti et al 2004). Recently, we documented that LCRs in proximal 17p constitute >23% of ∼7.5 Mb of genome sequence (Fig.…”

mentioning

confidence: 99%

“…In some regions, they constitute up to 23%-45% of the examined sequence (Hurles and Jobling 2003;Stankiewicz et al 2003). Because of their repeat nature, LCRs have been a significant challenge to the Human Genome Project and many of the remaining gaps in euchromatic regions are associated with LCRs (Stankiewicz and Lupski 2002;Eichler et al 2004).…”

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confidence: 99%

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Serial segmental duplications during primate evolution result in complex human genome architecture

Stankiewicz¹,

Shaw²,

Withers³

et al. 2004

Genome Res.

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The human genome is particularly rich in low-copy repeats (LCRs) or segmental duplications (5%-10%), and this characteristic likely distinguishes us from lower mammals such as rodents. How and why the complex human genome architecture consisting of multiple LCRs has evolved remains an open question. Using molecular and computational analyses of human and primate genomic regions, we analyzed the structure and evolution of LCRs that resulted in complex architectural features of the human genome in proximal 17p. We found that multiple LCRs of different origins are situated adjacent to one another, whereas each LCR changed at different time points between >25 to 3-7 million years ago (Mya) during primate evolution. Evolutionary studies in primates suggested communication between the LCRs by gene conversion. The DNA transposable element MER1-Charlie3 and retroviral ERVL elements were identified at the breakpoint of the t(4;19) chromosome translocation in Gorilla gorilla, suggesting a potential role for transpositions in evolution of the primate genome. Thus, a series of consecutive segmental duplication events during primate evolution resulted in complex genome architecture in proximal 17p. Some of the more recent events led to the formation of novel genes that in human are expressed primarily in the brain. Our observations support the contention that serial segmental duplication events might have orchestrated primate evolution by the generation of novel fusion/fission genes as well as potentially by genomic inversions associated with decreased recombination rates facilitating gene divergence. The genome architecture resulting from the size, orientation, and arrangement of LCRs was shown to be responsible for genomic instability (Lupski 1998;Emanuel and Shaikh 2001;Stankiewicz and Lupski 2002a). Serving as substrates for nonallelic (or "ectopic") homologous recombination (NAHR), LCRs facilitate meiotic and potentially mitotic DNA rearrangements associated with several diseases that are referred to as genomic disorders. Genomic rearrangements can be responsible for Mendelian traits, contiguous gene syndromes, and whole-arm chromosome aberrations (Lupski 1998Stankiewicz and Lupski 2002a). During the last decade, substantial molecular data have emerged documenting that LCR-mediated NAHR is a major mechanism for human disease (Emanuel and Shaikh 2001;Stankiewicz and Lupski 2002a;Shaw and Lupski 2004).Several studies have shown that LCRs arose recently, apparently during primate evolution (Stankiewicz and Lupski 2002b). Recent data suggest that LCR-associated genome architecture does not represent simple segmental duplications but rather reflects complex rearrangements that are potentially the end product of multiple events (van Geel et al. 2002). These serial segmental duplications can result in a complex shuffling of genomic sequences (Babcock et al. 2003;.The gene-and LCR-rich human genomic region 17p11.2-p12 is rearranged in a variety of different constitutional, evolutionary, and cancer-associated structural chromoso...

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Section: Structure and Orientation Of Lcr17p Repeatsmentioning

confidence: 99%

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confidence: 99%

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Serial segmental duplications during primate evolution result in complex human genome architecture

Stankiewicz¹,

Shaw²,

Withers³

et al. 2004

Genome Res.

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“…These appear to have formed relatively recently during primate evolution (Keller et al 1999;Park et al 2002). In contrast, pericentromeric interchromosomal duplications characterized to date have no associated pathology.…”

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confidence: 92%

Genomic Sequence and Transcriptional Profile of the Boundary Between Pericentromeric Satellites and Genes on Human Chromosome Arm 10p

et al. 2003

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Contiguous finished sequence from highly duplicated pericentromeric regions of human chromosomes is needed if we are to understand the role of pericentromeric instability in disease, and in gene and karyotype evolution. Here, we have constructed a BAC contig spanning the transition from pericentromeric satellites to genes on the short arm of human chromosome 10, and used this to generate 1.4 Mb of finished genomic sequence. Combining RT-PCR, in silico gene prediction, and paralogy analysis, we can identify two domains within the sequence. The proximal 600 kb consists of satellite-rich pericentromerically duplicated DNA which is transcript poor, containing only three unspliced transcripts. In contrast, the distal 850 kb contains four known genes (ZNF248, ZNF25, ZNF33A, and ZNF37A) and up to 32 additional transcripts of unknown function. This distal region also contains seven out of the eight intrachromosomal duplications within the sequence, including the p arm copy of the ∼ 250-kb duplication which gave rise to ZNF33A and ZNF33B. By sequencing orthologs of the duplicated ZNF33 genes we have established that ZNF33A has diverged significantly at residues critical for DNA binding but ZNF33B has not, indicating that ZNF33B has remained constrained by selection for ancestral gene function. These results provide further evidence of gene formation within intrachromosomal duplications, but indicate that recent interchromosomal duplications at this centromere have involved transcriptionally inert, satellite rich DNA, which is likely to be heterochromatic. This suggests that any novel gene structures formed by these interchromosomal events would require relocation to a more open chromatin environment to be expressed.[Supplemental material is available online at www.genome.org and also at

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“…Three low-copy repeat gene clusters were identified previously inside and flanking the SMS deletion region . Clones specific to an individual SMS-REP were identified based on cis-morphisms, sequence differences among repeats on the same chromosome (Park et al 2002). From the DNA sequence of these clones, we deduced that the size of the common deletion region including the three SMS-REPs is ∼3.7 Mb and the sizes of the SMS-REPs are between 176 and 256 kb.…”

Section: Construction Of the Bac/pac Contig Of The Sms Common Deletiomentioning

confidence: 99%

Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17p11.2 and the Syntenic Region of the Mouse

Bi¹,

Yan²,

Stankiewicz³

et al. 2002

Genome Res.

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Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with behavioral abnormalities and sleep disturbance. Most patients have the same ∼4 Mb interstitial genomic deletion within chromosome 17p11.2. To investigate the molecular bases of the SMS phenotype, we constructed BAC/PAC contigs covering the SMS common deletion interval and its syntenic region on mouse chromosome 11. Comparative genome analysis reveals the absence of all three ∼200-kb SMS-REP low-copy repeats in the mouse and indicates that the evolution of SMS-REPs was accompanied by transposition of adjacent genes. Physical and genetic map comparisons in humans reveal reduced recombination in both sexes. Moreover, by examining the deleted regions in SMS patients with unusual-sized deletions, we refined the minimal Smith-Magenis critical region (SMCR) to an ∼1.1-Mb genomic interval that is syntenic to an ∼1.0-Mb region in the mouse. Genes within the SMCR and its mouse syntenic region were identified by homology searches and by gene prediction programs, and their gene structures and expression profiles were characterized. In addition to 12 genes previously mapped, we identified 8 new genes and 10 predicted genes in the SMCR. In the mouse syntenic region of the human SMCR, 16 genes and 6 predicted genes were identified. The SMCR is highly conserved between humans and mice, including 19 genes with the same gene order and orientation. Our findings will facilitate both the identification of gene(s) responsible for the SMS phenotype and the engineering of an SMS mouse model.

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Structure and Evolution of the Smith-Magenis Syndrome Repeat Gene Clusters, SMS-REPs

Cited by 87 publications

References 46 publications

Serial segmental duplications during primate evolution result in complex human genome architecture

Serial segmental duplications during primate evolution result in complex human genome architecture

Genomic Sequence and Transcriptional Profile of the Boundary Between Pericentromeric Satellites and Genes on Human Chromosome Arm 10p

Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17p11.2 and the Syntenic Region of the Mouse

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