Two Functional Copies of the DGCR6 Gene Are Present on Human Chromosome 22q11 Due to a Duplication of an Ancestral Locus

Edelmann, Lisa; Stankiewicz, Pavel; Spiteri, Elizabeth; Pandita, Raj K.; Shaffer, Lisa G.; Lupski, James R.; Morrow, Bernice E.

doi:10.1101/gr.gr-1431r

Cited by 31 publications

(20 citation statements)

References 27 publications

(50 reference statements)

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“…Computational analyses of human genome sequence suggest the generation of fusion/ fission transcripts accompanying segmental duplication in many genomic regions (Courseaux and Nahon 2001;Edelmann et al 2001;Eichler 2001;Bailey et al 2002). These findings illustrate the potential role of DNA rearrangements during mammalian genome evolution in the generation of new genes Inoue and Lupski 2002).…”

Section: Dna Rearrangements Generate New Genesmentioning

confidence: 77%

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

Stankiewicz¹,

Shaw²,

Withers³

et al. 2004

Genome Res.

100

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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: Dna Rearrangements Generate New Genesmentioning

confidence: 77%

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

Stankiewicz¹,

Shaw²,

Withers³

et al. 2004

Genome Res.

100

View full text Add to dashboard Cite

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“…The genes in these two regions are variably hemizygous depending on the individual subject's breakpoints. DGCR6 is expressed in all adult and fetal tissues thus far examined (Edelmann et al, 2001) but no function has been determined. The PRODH gene, deleted in 16 of our 20 subjects studied, may be important in the 30% of 22q deletion patients with schizophrenia (Murphy et al, 1999;Kates et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH

Bittel

Yu²,

Newkirk³

et al. 2009

Cytogenet Genome Res

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Hemizygous deletions of the chromosome 22q11.2 region result in the 22q11.2 deletion syndrome also referred to as DiGeorge, Velocardiofacial or Shprintzen syndromes. The phenotype is variable but commonly includes conotruncal cardiac defects, palatal abnormalities, learning and behavioral problems, immune deficiency, and facial anomalies. Four distinct highly homologous blocks of low copy number repeat sequences (LCRs) flank the deletion region. Mispairing of LCRs during meiosis with unequal meiotic exchange is assumed to cause the recurrent and consistent deletions. The proximal LCR is reportedly located at 22q11.2 from 17.037 to 17.083 Mb while the distal LCR is located from 19.835 to 19.880 Mb. Although the chromosome breakpoints are thought to localize to the LCRs, the positions of the breakpoints have been investigated in only a few individuals. Therefore, we used high resolution oligonucleotide-based 244K microarray comparative genomic hybridization (aCGH) to resolve the breakpoints in a cohort of 20 subjects with known 22q11.2 deletions. We also investigated copy number variation (CNV) in the rest of the genome. The 22q11.2 breaks occurred on either side of the LCR in our subjects, although more commonly on the distal side of the reported proximal LCR. The proximal breakpoints in our subjects spanned the region from 17.036 to 17.398 Mb. This region includes the genes DGCR6 (DiGeorge syndrome critical region protein 6) and PRODH (proline dehydrogenase 1), along with three open reading frames that may encode proteins of unknown function. The distal breakpoints spanned the region from 19.788 to 20.122 Mb. This region includes the genes GGT2 (gamma-glutamyltransferase-like protein 2), HIC2 (hypermethylated in cancer 2), and multiple transcripts of unknown function. The genes in these two breakpoint regions are variably hemizygous depending on the location of the breakpoints. Our 20 subjects had 254 CNVs throughout the genome, 94 duplications and 160 deletions, ranging in size from 1 kb to 2.4 Mb. The presence or absence of genes at the breakpoints depending on the size of the deletion plus variation in the rest of the genome due to CNVs likely contribute to the variable phenotype associated with the 22q11.2 deletion or DiGeorge syndrome.

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“…1S). Two functional copies of the DGCR6 gene are present on human Chromosome 22q11 and are due to a duplication of an ancestral locus (Edelmann et al 2001). LCR22-2 contains three large intra-LCR duplications denoted dupA-C (Fig.…”

Section: Polymorphisms In Lcr22-2 and Lcr22-4mentioning

confidence: 99%

Traffic of genetic information between segmental duplications flanking the typical 22q11.2 deletion in velo-cardio-facial syndrome/DiGeorge syndrome

et al. 2005

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Velo-cardio-facial syndrome/DiGeorge syndrome results from unequal crossing-over events between two 240-kb low-copy repeats termed LCR22 (LCR22-2 and LCR22-4) on Chromosome 22q11.2, comprised of modules, each of which are >99% identical in sequence. To delineate regions in the LCR22s that might contain hotspots for 22q11.2 rearrangements, we scanned the interval for increased rates of recombination with the hypothesis that these regions might be more prone to breakage. We generated an algorithm to detect sites of altered recombination by searching for single nucleotide polymorphic positions in BAC clones from different libraries mapped to LCR22-2 and LCR22-4. This method distinguishes single nucleotide polymorphisms from paralogous sequence variants and complex polymorphic positions. Sites of shared polymorphism are considered potential sites of gene conversion or double cross-over between the two LCR22s. We found an inverse correlation between regions of paralogous sequence variants that are unique to a given position within one LCR22 and clusters of shared polymorphic sites, suggesting that these clusters depict altered recombination and not remnants of ancestral single nucleotide polymorphisms. We postulate that most shared polymorphic sites are products of past transfers of DNA information between the LCR22s, suggesting that frequent traffic of genetic material may induce genomic instability in the two LCR22s. We also found that gaps up to 1.5 kb long can be transferred between LCR22s.

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Two Functional Copies of the DGCR6 Gene Are Present on Human Chromosome 22q11 Due to a Duplication of an Ancestral Locus

Cited by 31 publications

References 27 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

Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH

Traffic of genetic information between segmental duplications flanking the typical 22q11.2 deletion in velo-cardio-facial syndrome/DiGeorge syndrome

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