Rearrangements of our genome can be responsible for inherited as well as sporadic traits. The analyses of chromosome breakpoints in the proximal short arm of Chromosome 17 (17p) reveal nonallelic homologous recombination (NAHR) as a major mechanism for recurrent rearrangements whereas nonhomologous end-joining (NHEJ) can be responsible for many of the nonrecurrent rearrangements. Genome architectural features consisting of low-copy repeats (LCRs), or segmental duplications, can stimulate and mediate NAHR, and there are hotspots for the crossovers within the LCRs. Rearrangements introduce variation into our genome for selection to act upon and as such serve an evolutionary function analogous to base pair changes. Genomic rearrangements may cause Mendelian diseases, produce complex traits such as behaviors, or represent benign polymorphic changes. The mechanisms by which rearrangements convey phenotypes are diverse and include gene dosage, gene interruption, generation of a fusion gene, position effects, unmasking of recessive coding region mutations (single nucleotide polymorphisms, SNPs, in coding DNA) or other functional SNPs, and perhaps by effects on transvection.
Citation: Lupski JR, Stankiewicz P (2005) Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes. PLoS Genet 1(6): e49. https://doi.org/10.1371/journal.pgen.0010049
Published: December 30, 2005
Copyright: © 2005 Lupski and Stankiewicz. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abbreviations: 17p, proximal short arm of Chromosome 17; AHR, allelic homologous recombination; CMT1A, Charcot-Marie-Tooth disease type 1A; CNP, copy-number polymorphism; CNV, copy number variation; HNPP, hereditary neuropathy with liability to pressure palsies; HR, homologous recombination; LCR, low-copy repeat; LCV, large-segment copy-number variation; MEPS, minimal efficient processing segment; NAHR, nonallelic homologous recombination; NHEJ, nonhomologous end-joining; RAI1, , retinoic acid inducible 1; ; SMS, Smith-Magenis syndrome
Whereas Watson–Crick DNA base pair changes have long been recognized as a mechanism for mutation, rearrangements of the human genome including deletions, duplications, and inversions have been appreciated only more recently as a significant source for genetic variation. Deletion and duplication mutations can vary in size from thousands to hundreds of thousands of base pairs in length and may require specialized technologies to visualize. Structural features, or the architecture, of the human genome can result in region-specific susceptibility to rearrangements and thus genomic instability. The molecular mechanisms by which rearrangement mutations of the human genome occur, and how such rearrangements convey phenotypes, are only beginning to be unraveled.
During the last decade it has become apparent that the molecular genetic mechanisms for many disease traits consist of genomic rearrangements rather than point mutations of single genes. Such conditions, in which the clinical phenotype is a consequence of abnormal dosage or dysregulation of one or more genes resulting from rearrangement of the genome, have been referred to as genomic disorders [1–4]. DNA rearrangements occur by both homologous and nonhomologous recombination mechanisms; however, homologous recombination (HR) appears to be the predominant pathway underlying recurrent rearrangements of our genome. Regardless of mechanism, structural features of the genome can predispose a particular region to rearrangement. Determining the architectural features that result in the instability of the genomic regions has profound consequences for clinical genetics as new technologies enable high-resolution analysis of the human genome. This review will focus on the information culled from, and molecular mechanisms elucidated by, breakpoint analyses of disease-associated rearrangements involving proximal 17p. Although the focus is 17p, such mechanisms appear to be generally applicable to all regions of the human genome. We also describe the many mechanisms by which rearrangements can convey phenotypes and discuss rearrangements as the basis for introducing variation in our genome.
Proximal 17p Dosage Changes Convey Phenotypes—An Assay for Rearrangements
Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are dysmyelinating peripheral neuropathies that result from an altered dosage of PMP22, which encodes peripheral myelin protein. CMT1A results from heterozygous duplication of a 1.4-Mb segment that includes the PMP22 gene, whereas HNPP results from a heterozygous deletion of the same genomic interval. The rearrangements cause altered dosage of PMP22 that subsequently results in neuropathy; overexpression causes CMT1A whereas underexpression (i.e., haploinsufficiency) leads to HNPP. Experimental evidence in support of the PMP22 dosage hypothesis is substantive (reviewed in [5,6]). Suffice it to say that rare nonduplication CMT1A patients have been identified with heterozygous apparent gain-of-function PMP22 point mutations, and rare nondeletion HNPP patients have loss-of-function PMP22 mutations (nonsense or frameshift alleles) consistent with haploinsufficiency . Animal models that overexpress PMP22 recapitulate the CMT1A phenotype, and the neuropathy can be clinically, electrophysiologically, and neuropathologically corrected by abrogation of the overexpression using epigenetic manipulation of PMP22 gene expression [7,8].
Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation disorder usually associated with a cytogenetically visible heterozygous deletion of sub-band 17p11.2, i.e., del(17)(p11.2p11.2) (reviewed in [9,10]). Rare patients without deletion have been identified, and some were found to have heterozygous point mutations in the retinoic acid inducible 1 (RAI1) gene [11–13]. As would be anticipated, most of these are frameshift or nonsense mutations consistent with a haploinsufficiency mechanism. Chromosome-engineered mouse models that delete one copy of the mouse Chromosome 11 region syntenic to human 17p11.2 (i.e., Df(11)17 and other derivative deficiencies) [14–16], as well as targeted disruption of Rai1 , recapitulate much of the SMS phenotype. Animal models that are compound heterozygotes for deletion and duplication (Df(11)17/Dp(11)17) have a normal phenotype; this “rescue” is consistent with a dosage mechanism for the phenotypes observed in the mice harboring heterozygous rearrangements . A syndrome associated with heterozygous duplication of the genomic interval deleted in SMS, dup(17)(p11.2p11.2), has been described . The dup(17)(p11.2p11.2) phenotype likely results from a dosage-sensitive gene in the human Chromosome 17p11.2 region. This dosage-sensitive gene is probably RAI1 since Dp(11)17/Rai1− animals, who have a normal Rai1 gene copy number but three copies for all the other genes in the rearranged intervals, have a normal phenotype (i.e., the knockout allele appears to rescue the duplication phenotypes; unpublished data), although this hypothesis awaits formal verification.
Thus, alterations of the copy number of either PMP22 or RAI1 convey a clinical phenotype that usually elicits a visit to a physician. Therefore, rearrangements involving these genes can be readily ascertained.
Recurrent Rearrangement Breakpoints Map to LCRs
The CMT1A duplication  and HNPP deletion  are transmitted through the germ line and cosegregate with their respective neuropathy phenotypes as an autosomal dominant trait. However, both de novo duplication and deletion can occur in association with sporadic disease. The vast majority of unrelated patients from families segregating CMT1A, as well as sporadic cases, have the same size duplication. This common duplication rearrangement has recurrent breakpoints that map to LCRs called CMT1A-REPs  (Figure 1). Similarly, HNPP patients have a common deletion rearrangement with recurrent (i.e., clustered) breakpoints that map to CMT1A-REPs. It has been shown that the CMT1A duplication and HNPP deletion represent alternative products of a NAHR utilizing CMT1A-REPs as recombination substrates [21,22].
The horizontal line represents proximal 17p with the telomere (TEL) to the left, the centromere (circle) to the right, and LCRs demarcated. The genomic regions duplicated in CMT1A (green horizontal rectangle) and deleted in HNPP (red horizontal rectangle) are shown above, and the recurrent deletions associated with SMS and duplication associated with dup(17)(p11.2p11.2) are shown below. The position of the isochromosome 17q breakpoint cluster region within a large cruciform structure (consisting of five subunits of ~40–50 kb each) is also shown.
Detection of the CMT1A duplication or HNPP deletion has turned out to be a useful molecular diagnostic test for the evaluation of patients with neuropathy. Thousands of tests that detect a junction fragment (i.e., a novel band that reflects the rearrangement and can be identified at the breakpoint junction) specific to either the duplication or deletion have been performed since the early 1990s. Essentially all CMT1A and HNPP patients with a rearrangement mutation, with the exception of three reported CMT1A patients harboring a smaller duplication and a couple of HNPP patients with smaller deletions (reviewed in ), have had the common recurrent rearrangement. Thus, in greater than 99% of the families with rearrangements the new mutation appears to have occurred by NAHR. However, it is important to note that the molecular test that assays for a specific junction fragment may not detect some smaller or larger sized duplications.
In contrast to CMT1A and HNPP, which usually segregate as dominant traits, SMS is essentially always a sporadic disease associated with a de novo del(17)(p11.2p11.2) [23–26]. In the majority of SMS patients with cytogenetically visible deletions, the breakpoints are recurrent and cluster in LCRs termed SMS-REPs [25–28] (Figure 1). The common recurrent SMS deletion occurs by NAHR utilizing SMS-REPs as the recombination substrates [29,30]. A common recurrent rearrangement occurs in 70%–80% of deletion patients with SMS .
Approximately 20%–30% of SMS patients do not harbor the common deletion, but instead have uncommon sized deletions. Interestingly, some of the uncommon deletion rearrangements [32,33], representing about 4% of the total SMS deletions studied, were also found to have recurrent breakpoints. As anticipated, these recurrent breakpoints mapped to yet another LCR family—LCR17ps  (Figure 1). These uncommon recurrent SMS rearrangements also occur by NAHR, utilizing LCR17p flanking repeats as recombination substrates. Whereas the predicted reciprocal duplication of the common SMS deletion mediated by SMS-REP has been identified , the predicted reciprocal duplication for this uncommon recurrent deletion remains to be found.
Recombination Hotspots Associated with Strand Exchanges
Theoretically, HR can occur whenever there is a shared stretch of homology providing substrates. There does appear to be a minimal stretch of identity, referred to as a minimal efficient processing segment (MEPS), required among substrates to enable HR to occur. The MEPSs that enable HR to occur in cultured mouse cells have been determined to be between 132 and 232 bp of perfect shared sequence identity [35,36]. The MEPS requirements for HR in human meiosis remain to be elucidated. Nevertheless, for an LCR of several thousand base pairs in length and more than 98% identity, a strand exchange could occur potentially wherever there are the required MEPSs. However, experimental observations from multiple NAHR studies document positional preferences, or recombination hotspots, wherein the crossovers preferentially occur . This was initially observed within the 24-kb CMT1A-REP [37,38], but found also in the ~200-kb SMS-REP  and ~125-kb LCR17p . Interestingly, hotspots for strand exchange have been documented also for allelic HR (AHR) across the human genome [39–41]. Common features shared among NAHR and AHR hotspots include the following: clustering within small (<1 kb) genomic regions, coincidence with apparent gene conversion events, and no obvious sequence similarities with one another . This last feature distinguishes mammalian HR from HR in prokaryotes, wherein a cis-acting recombinogenic heptameric sequence motif (χ or chi ) stimulates recombination. Whether NAHR and AHR hotspots are coincident in the human genome remains to be determined. It is also not clear if recombination hotspots reflect cis-acting sequence motifs, positional preference of trans-acting factors, or unusual non-B DNA structures , or rather just denote genomic regions more susceptible to DNA double-strand breaks.
NAHR—A General Mechanism for Generating Rearrangements of Our Genome
With the description of the reciprocity for NAHR, e.g., the CMT1A duplication/HNPP deletion and the SMS deletion/dup(17)(p11.2p11.2), it is anticipated that all deletion syndromes in which the rearrangement breakpoints cluster in flanking LCRs will likely have reciprocal duplication syndromes. One challenge is to identify such reciprocal duplications and document their role in causing a specific phenotype. In addition to deletion/duplication rearrangements mediated by NAHR using directly oriented LCRs as substrates, NAHR can also produce inversion rearrangements if inverted LCRs are utilized as the recombination substrates. Such inversion rearrangements can disrupt genes and cause disease traits , predispose DNA to deleterious genomic rearrangements [45–48], or be responsible for haplotype blocks essentially creating a balancer chromosome that suppresses recombination . Somatic NAHR between nonsister chromatids can result in the formation of an isochromosome .
The breakpoints of ~20%–30% of deletions in patients with SMS do not map to the proximal and distal copies of SMS-REP as in the common recurrent deletions [32,33] (Figure 2). Such deletion patients are readily ascertained because their phenotype also results from RAI1 haploinsufficiency. Interestingly, the breakpoints of these nonrecurrent rearrangements often map to LCRs . However, the observation that the two breakpoints could be in different LCRs is inconsistent with homology mediating these events. Thus, LCRs may stimulate but do not appear to mediate nonrecurrent rearrangements. Sequencing the breakpoint junctions to examine the products of recombination for four such nonrecurrent rearrangements revealed NHEJ as the mechanism in two whereas the other two represented Alu–Alu recombinations between closely related (i.e., sharing a high degree of sequence identity) Alu sequences .
Proximal 17p with its complex genome architecture and multiple LCRs. The centromere (cen) is to the right, telomere (tel) to the left. Filled, hatch-marked, and color-coded rectangles depict LCR regions of greater than 97% sequence identity, with horizontal arrows depicting orientation. The locations of the RAI1 gene and isochromosome 17q breakpoint cluster regions are demarcated. Above is shown the region deleted in SMS patients with uncommon nonrecurrent deletions—the breakpoints are denoted by arrowheads. Below are shown the regions contained in the supernumerary marker chromosomes (SMCs). Also, below are shown the 17p11.2 breakpoints of the translocations.
LCRs have also been identified at the breakpoints of three of four small marker Chromosomes 17 [52–54] and in some apparently balanced translocations with breakpoints in 17p  (Figure 2), but the DNA sequence at these breakpoints has not been determined so the exact recombination mechanism remains to be elucidated. Interestingly, breakpoints for small marker chromosomes and translocations also often map to (peri)centromeric sequences.
NHEJ—An Alternative Pathway
It is clear that not all rearrangements in our genome are mediated by HR. As documented above, evidence for NHEJ has been found by examining breakpoints for some deletions causing SMS. However, this represents less than 20%–25% of SMS deletion cases. Nevertheless, it remains to be determined to what extent NHEJ is a mechanism for genome rearrangement. NHEJ may potentially have a more prominent role in nonrecurrent rearrangements [55–57].
The molecular investigations of somatic rearrangements pose additional challenges to those encountered in the study of constitutional rearrangements. In constitutional rearrangements the tissue used for a source of DNA is usually uniform in its genetic constitution. In a somatic rearrangement event, the tissue source for isolating the DNA to study by molecular methods may represent a mosaic mixture of cells that contain the rearrangement with cells that have a normal, or wild-type, genome. This may be further complicated in a tumor, wherein multiple different and serial rearrangement events can occur. Nevertheless, for one somatic 17p rearrangement, molecular analyses revealed complex genomic architecture at clustered breakpoints and led to a model that explains the molecular mechanism for its formation .
Isochromosome 17q is a common recurrent genomic rearrangement observed in human neoplasms and was shown earlier to be isodicentric with clustered breakpoints . Subsequently, a complex genomic architecture characterized by large (38–49 kb) cruciform LCRs was identified at the breakpoint cluster region . DNA breaks generated in the hairpin/cruciform structures were postulated to trigger the double-strand-break repair pathway. A subsequent NAHR event between repeats of opposite orientation on sister chromatids (i.e., sister chromatid exchange) can result in the formation of an isodicentric Chromosome 17 and an acentric fragment . The recognition of breakpoint clustering and determination of the mechanism for isochromosome formation enabled the development of a FISH-based test to assay the rearrangement event .
Molecular Mechanisms by Which Constitutional Rearrangements Convey Phenotypes
Deletion and duplication rearrangements can cause a phenotype by several molecular mechanisms (Figure 3A–3D), including altering the copy number of a gene (or genes) sensitive to a dosage effect, as exemplified by PMP22 and RAI1. The breakpoint of the rearrangement may interrupt a gene and cause a loss-of-function by inactivating a gene. Alternatively, a fusion gene can form at the breakpoint generating a gain-of-function mutation; a mechanism prominent amongst cancers associated with specific chromosomal translocations. Rearrangements can also manifest through a position effect . Such position effects have been documented for apparently balanced translocations that even exert their influence when the breakpoints map as far as ~1 Mb away either upstream or downstream from the culprit gene . Position effects have been observed also with deletion  and duplication  rearrangements that occur outside the intact gene.
Six models are depicted and include (A) gene dosage, where there is a dosage sensitive gene within the rearrangement; (B) gene interruption, wherein the rearrangement breakpoint interrupts a gene; (C) gene fusion whereby a fusion gene is created at the breakpoint that either fuses coding sequences or a novel regulatory sequence to the gene; (D) position effect, in which the rearrangement has effects on expression/regulation of a gene near the breakpoint, potentially by removing or altering a regulatory sequence; (E) unmasking recessive allele, where a deletion results in hemizygous expression of a recessive mutation or further uncovers/exacerbates effects of a functional polymorphism; and (F) by potentially interrupting effects of transvection, where the deletion of a gene and its surrounding regulatory sequences affects the communication between alleles. In each model, both chromosome homologs are depicted as horizontal lines. The rearranged genomic interval is enclosed by brackets—dashed lines indicate genomic regions either deleted or duplicated, an absent line indicates deletion with phenotypic effects from the remaining allele unmasked because of the rearrangement, and a dotted line represents deletion but where phenotypic effects result from the absence of interactions between alleles (i.e., transvection effects). Gene is depicted by filled horizontal rectangle, while regulatory region is shown as a hatch-marked rectangle. Asterisks denote point mutations.
Other molecular mechanisms by which rearrangements of the genome may convey or alter a disease phenotype result from how the rearrangement on one chromosome affects or is affected by the allele on the other chromosome at that locus (Figure 3E and 3F). These include the unmasking of either recessive mutations (reviewed in ) or functional polymorphisms  of the remaining allele when a deletion occurs, and potential transvection (communication between alleles on homologous chromosomes) [16,17] effects via deletion of regulatory elements required for communication between alleles.
Recent excitement has been generated by the observation that individuals may vary for large segments of their genome, with evidence for both decreased and increased copy number [65–67]. This revelation has been enabled by array technologies that allow high-resolution screening of the entire human genome simultaneously. It is not clear to what extent such genomic changes are responsible for Mendelian or complex disease traits and common traits (including behavioral traits), or represent only benign polymorphic variation. In fact, it is impossible to assay individuals with such genomic changes for all potential phenotypes that can occur. Furthermore, some phenotypes caused by genomic rearrangements (e.g., HNPP) may not present until late adulthood—if at all [5,6]. This age-dependent penetrance confounds the interpretation of genomic copy-number changes. Copy-number changes have been associated with phenotypes that are often difficult to ascertain such as susceptibility to HIV infection .
Copy-number variations (CNVs), alternatively referred to as large-segment copy-number variations (LCVs)  or copy-number polymorphisms (CNPs) , of genomic regions have been reported to occur near segmental duplications or LCRs [65,66,69]. However, the involvement of segmental duplications, perhaps by an LCR/NAHR mechanism, is yet to be determined. Segmental duplications account for some 5%–10% of the human genome [70–72], and CNVs may be coincident with LCRs by chance. Nevertheless, it is clear that LCR/NAHR-generated rearrangements occur throughout the genome [1,2], and therefore it is not unreasonable to assume that such rearrangements or CNVs could be associated with inherited or sporadic (de novo rearrangement) disease, susceptibility to disease, complex traits, or common benign traits, or could represent polymorphic variation with no apparent phenotypic consequences (Figure 4), depending on whether or not dosage-sensitive genes are affected by the rearrangement. In fact, analogous to base pair changes, rearrangements introduce variations into the genome for selection to act upon (Figure 5). Perhaps LCR/NAHR is analogous to the changes introduced by a replication error at a nucleotide base: both are endogenous molecular mechanisms that introduce variation into our genome. Early comparative genomics studies among bacterial species revealed substantive evidence for genome rearrangements and insertion/deletion events that accompany genome evolution [73,74].
Above is shown a gradient/threshold for trait manifestation. Whether or not a trait is manifested is a function of the dosage sensitivity of the gene(s) affected by the rearrangement. Below are examples of traits that can be due to DNA rearrangements. DGS, DiGeorge syndrome; dz, disease; IP, incontientia pigmenti; MR, mental retardation; PWS/AS, Prader-Willi syndrome/Angelman syndrome; WBS, Williams-Beuren syndrome.
The two major mechanisms by which variation is introduced into our genome are shown. Such variations can be introduced by both endogenous and exogenous means. These mutations can cause a disease trait if they affect gene structure, function, or regulation, as well as through the alteration of dosage. SNP, single nucleotide polymorphism.
During the previous decade, we have witnessed the uncovering of recurrent submicroscopic rearrangements as a cause of disease. High-resolution analysis of the human genome has allowed detection of genome changes not observed previously because of technology limitations . The availability of the “finished” human genome sequence  and genomic microarrays have enabled approaches to resolve changes in the genome heretofore impossible to assess, particularly on a global genome scale, i.e., simultaneously examining the entire genome rather than discreet segments . During the past five decades, since the elucidation of the chemical basis of heredity by Watson and Crick, base pair changes have dominated our thinking with regard to mutation and variation. Rearrangements of our genome are perhaps introducing mutation and variation to a greater extent than was recognized previously.
We apologize to colleagues whose work was not cited due to space limitations. This work was supported in part by the National Institutes of Health (NINDS, NICHD, NCI, and NIDCR), the Muscular Dystrophy Association, the Charcot-Marie-Tooth Association, and the March of Dimes.
- 1. Lupski JR (1998) Genomic disorders: Structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14: 417–422.JR Lupski1998Genomic disorders: Structural features of the genome can lead to DNA rearrangements and human disease traits.Trends Genet14417422
- 2. Stankiewicz P, Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends Genet 18: 74–82.P. StankiewiczJR Lupski2002Genome architecture, rearrangements and genomic disorders.Trends Genet187482
- 3. Shaw CJ, Lupski JR (2004) Implications of human genome architecture for rearrangement-based disorders: The genomic basis of disease. Hum Mol Genet 13(Spec No 1): R57–R64.CJ ShawJR Lupski2004Implications of human genome architecture for rearrangement-based disorders: The genomic basis of disease.Hum Mol Genet13(Spec No 1)R57R64
- 4. Lupski JR (2003) 2002 Curt Stern Award Address. Genomic disorders recombination-based disease resulting from genomic architecture. Am J Hum Genet 72: 246–252.JR Lupski20032002 Curt Stern Award Address. Genomic disorders recombination-based disease resulting from genomic architecture.Am J Hum Genet72246252
- 5. Lupski JR, Garcia A (2001) Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, et al., editors. The metabolic and molecular bases of inherited diseases, 8th ed. New York: McGraw-Hill. pp. 5759–5788.JR LupskiA. Garcia2001Charcot-Marie-Tooth peripheral neuropathies and related disorders.In:. CR ScriverAL BeaudetWS SlyD. ValleB. Vogelstein The metabolic and molecular bases of inherited diseases, 8th edNew YorkMcGraw-Hillpp.57595788 pp.
- 6. JR LupskiPF Chance 2005 Hereditary motor and sensory neuropathies involving altered dosage or mutation of PMP22: The CMT1A duplication and HNPP deletion. In:. PJ DyckPK Thomas Peripheral neuropathy Philadelphia Elsevier Science pp. 1659 1680.
- 7. Sereda MW, Meyer zu Hörste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med 9: 1533–1537.MW SeredaG. Meyer zu HörsteU. SuterN. UzmaKA Nave2003Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A).Nat Med915331537
- 8. Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J, et al. (2004) Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med 10: 396–401.E. PassageJC NorreelP. Noack-FraissignesV. SanguedolceJ. Pizant2004Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease.Nat Med10396401
- 9. Chen KS, Potocki L, Lupski JR (1996) The Smith-Magenis syndrome [del(17)p11.2]: Clinical review and molecular advances. In: McCabe ERB, editor. Mental retardation and developmental disabilities research reviews. pp. 122–129.KS ChenL. PotockiJR Lupski1996The Smith-Magenis syndrome [del(17)p11.2]: Clinical review and molecular advances.In:. ERB McCabeMental retardation and developmental disabilities research reviewspp.122129 pp.
- 10. Greenberg F, Lewis RA, Potocki L, Glaze D, Parke J, et al. (1996) Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am J Med Genet 62: 247–254.F. GreenbergRA LewisL. PotockiD. GlazeJ. Parke1996Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2).Am J Med Genet62247254
- 11. Slager RE, Newton TL, Vlangos CN, Finucane B, Elsea SH (2003) Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet 33: 466–468.RE SlagerTL NewtonCN VlangosB. FinucaneSH Elsea2003Mutations in RAI1 associated with Smith-Magenis syndrome.Nat Genet33466468
- 12. Bi W, Saifi GM, Shaw CJ, Walz K, Fonseca P, et al. (2004) Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum Genet 115: 515–524.W. BiGM SaifiCJ ShawK. WalzP. Fonseca2004Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome.Hum Genet115515524
- 13. Girirajan S, Elsas LJ 2nd, Devriendt K, Elsea SH (2005) RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. J Med Genet 42: 820–828.S. GirirajanLJ Elsas 2ndK. DevriendtSH Elsea2005RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions.J Med Genet42820828
- 14. Walz K, Caratini-Rivera S, Bi W, Fonseca P, Mansouri DL, et al. (2003) Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: Phenotypic consequences of gene dosage imbalance. Mol Cell Biol 23: 3646–3655.K. WalzS. Caratini-RiveraW. BiP. FonsecaDL Mansouri2003Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: Phenotypic consequences of gene dosage imbalance.Mol Cell Biol2336463655
- 15. Walz K, Spencer C, Kaasik K, Lee CC, Lupski JR, et al. (2004) Behavioral characterization of mouse models for Smith-Magenis syndrome and dup(17)(p11.2p11.2). Hum Mol Genet 13: 367–378.K. WalzC. SpencerK. KaasikCC LeeJR Lupski2004Behavioral characterization of mouse models for Smith-Magenis syndrome and dup(17)(p11.2p11.2).Hum Mol Genet13367378
- 16. Yan J, Keener VW, Bi W, Walz K, Bradley A, et al. (2004) Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith-Magenis syndrome. Hum Mol Genet 13: 2613–2624.J. YanVW KeenerW. BiK. WalzA. Bradley2004Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith-Magenis syndrome.Hum Mol Genet1326132624
- 17. Bi W, Ohyama T, Nakamura H, Yan J, Visvanathan J, et al. (2005) Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome. Hum Mol Genet 14: 983–995.W. BiT. OhyamaH. NakamuraJ. YanJ. Visvanathan2005Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome.Hum Mol Genet14983995
- 18. Potocki L, Chen KS, Park SS, Osterholm DE, Withers MA, et al. (2000) Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 24: 84–87.L. PotockiKS ChenSS ParkDE OsterholmMA Withers2000Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion.Nat Genet248487
- 19. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, Pentao L, Guzzetta V, et al. (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66: 219–232.JR LupskiRM de Oca-LunaS. SlaugenhauptL. PentaoV. Guzzetta1991DNA duplication associated with Charcot-Marie-Tooth disease type 1A.Cell66219232
- 20. Chance PF, Alderson MK, Leppig KA, Lensch MW, Matsunami N, et al. (1993) DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72: 143–151.PF ChanceMK AldersonKA LeppigMW LenschN. Matsunami1993DNA deletion associated with hereditary neuropathy with liability to pressure palsies.Cell72143151
- 21. Pentao L, Wise CA, Chinault AC, Patel PI, Lupski JR (1992) Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nat Genet 2: 292–300.L. PentaoCA WiseAC ChinaultPI PatelJR Lupski1992Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit.Nat Genet2292300
- 22. Chance PF, Abbas N, Lensch MW, Pentao L, Roa BB, et al. (1994) Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17. Hum Mol Genet 3: 223–228.PF ChanceN. AbbasMW LenschL. PentaoBB Roa1994Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17.Hum Mol Genet3223228
- 23. Smith AC, McGavran L, Robinson J, Waldstein G, Macfarlane J, et al. (1986) Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am J Med Genet 24: 393–414.AC SmithL. McGavranJ. RobinsonG. WaldsteinJ. Macfarlane1986Interstitial deletion of (17)(p11.2p11.2) in nine patients.Am J Med Genet24393414
- 24. Stratton RF, Dobyns WB, Greenberg F, DeSana JB, Moore C, et al. (1986) Interstitial deletion of (17)(p11.2p11.2): Report of six additional patients with a new chromosome deletion syndrome. Am J Med Genet 24: 421–432.RF StrattonWB DobynsF. GreenbergJB DeSanaC. Moore1986Interstitial deletion of (17)(p11.2p11.2): Report of six additional patients with a new chromosome deletion syndrome.Am J Med Genet24421432
- 25. Greenberg F, Guzzetta V, Montes de Oca-Luna R, Magenis RE, Smith AC, et al. (1991) Molecular analysis of the Smith-Magenis syndrome: A possible contiguous-gene syndrome associated with del(17)(p11.2). Am J Hum Genet 49: 1207–1218.F. GreenbergV. GuzzettaR. Montes de Oca-LunaRE MagenisAC Smith1991Molecular analysis of the Smith-Magenis syndrome: A possible contiguous-gene syndrome associated with del(17)(p11.2).Am J Hum Genet4912071218
- 26. Juyal RC, Figuera LE, Hauge X, Elsea SH, Lupski JR, et al. (1996) Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients. Am J Hum Genet 58: 998–1007.RC JuyalLE FigueraX. HaugeSH ElseaJR Lupski1996Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients.Am J Hum Genet589981007
- 27. Chen KS, Manian P, Koeuth T, Potocki L, Zhao Q, et al. (1997) Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat Genet 17: 154–163.KS ChenP. ManianT. KoeuthL. PotockiQ. Zhao1997Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome.Nat Genet17154163
- 28. Park SS, Stankiewicz P, Bi W, Shaw C, Lehoczky J, et al. (2002) Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs. Genome Res 12: 729–738.SS ParkP. StankiewiczW. BiC. ShawJ. Lehoczky2002Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs.Genome Res12729738
- 29. Shaw CJ, Bi W, Lupski JR (2002) Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2. Am J Hum Genet 71: 1072–1081.CJ ShawW. BiJR Lupski2002Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2.Am J Hum Genet7110721081
- 30. Bi W, Park SS, Shaw CJ, Withers MA, Patel PI, et al. (2003) Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2. Am J Hum Genet 73: 1302–1315.W. BiSS ParkCJ ShawMA WithersPI Patel2003Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2.Am J Hum Genet7313021315
- 31. Potocki L, Shaw CJ, Stankiewicz P, Lupski JR (2003) Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]. Genet Med 5: 430–434.L. PotockiCJ ShawP. StankiewiczJR Lupski2003Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)].Genet Med5430434
- 32. Trask BJ, Mefford H, van den Engh G, Massa HF, Juyal RC, et al. (1996) Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients. Hum Genet 98: 710–718.BJ TraskH. MeffordG. van den EnghHF MassaRC Juyal1996Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients.Hum Genet98710718
- 33. Stankiewicz P, Shaw CJ, Dapper JD, Wakui K, Shaffer LG, et al. (2003) Genome architecture catalyzes nonrecurrent chromosomal rearrangements. Am J Hum Genet 72: 1101–1116.P. StankiewiczCJ ShawJD DapperK. WakuiLG Shaffer2003Genome architecture catalyzes nonrecurrent chromosomal rearrangements.Am J Hum Genet7211011116
- 34. Shaw CJ, Withers MA, Lupski JR (2004) Uncommon deletions of the Smith-Magenis syndrome region can be recurrent when alternate low-copy repeats act as homologous recombination substrates. Am J Hum Genet 75: 75–81.CJ ShawMA WithersJR Lupski2004Uncommon deletions of the Smith-Magenis syndrome region can be recurrent when alternate low-copy repeats act as homologous recombination substrates.Am J Hum Genet757581
- 35. Liskay RM, Letsou A, Stachelek JL (1987) Homology requirement for efficient gene conversion between duplicated chromosomal sequences in mammalian cells. Genetics 115: 161–167.RM LiskayA. LetsouJL Stachelek1987Homology requirement for efficient gene conversion between duplicated chromosomal sequences in mammalian cells.Genetics115161167
- 36. Waldman AS, Liskay RM (1988) Dependence of intrachromosomal recombination in mammalian cells on uninterrupted homology. Mol Cell Biol 8: 5350–5357.AS WaldmanRM Liskay1988Dependence of intrachromosomal recombination in mammalian cells on uninterrupted homology.Mol Cell Biol853505357
- 37. Lupski JR (2004) Hotspots of homologous recombination in the human genome: Not all homolgous sequences are equal. Genome Biol 5: 242.JR Lupski2004Hotspots of homologous recombination in the human genome: Not all homolgous sequences are equal.Genome Biol5242
- 38. Reiter LT, Murakami T, Koeuth T, Pentao L, Muzny DM, et al. (1996) A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nat Genet 12: 288–297.LT ReiterT. MurakamiT. KoeuthL. PentaoDM Muzny1996A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element.Nat Genet12288297
- 39. Kauppi L, Jeffreys AJ, Keeney S (2004) Where the crossovers are: Recombination distributions in mammals. Nat Rev Genet 5: 413–424.L. KauppiAJ JeffreysS. Keeney2004Where the crossovers are: Recombination distributions in mammals.Nat Rev Genet5413424
- 40. Crawford DC, Bhangale T, Li N, Hellenthal G, Rieder MJ, et al. (2004) Evidence for substantial fine-scale variation in recombination rates across the human genome. Nat Genet 36: 700–706.DC CrawfordT. BhangaleN. LiG. HellenthalMJ Rieder2004Evidence for substantial fine-scale variation in recombination rates across the human genome.Nat Genet36700706
- 41. McVean GA, Myers SR, Hunt S, Deloukas P, Bentley DR, et al. (2004) The fine-scale structure of recombination rate variation in the human genome. Science 304: 581–584.GA McVeanSR MyersS. HuntP. DeloukasDR Bentley2004The fine-scale structure of recombination rate variation in the human genome.Science304581584
- 42. G. Smith 1998 Chi sites and their consequences. In:. FJ de BruijnJR LupskiGM Weinstock Bacterial genomes New York Chapman and Hall pp. 49 66.
- 43. Bacolla A, Jaworski A, Larson JE, Jakupciak JP, Chuzhanova N, et al. (2004) Breakpoints of gross deletions coincide with non-B DNA conformations. Proc Natl Acad Sci U S A 101: 14162–14167.A. BacollaA. JaworskiJE LarsonJP JakupciakN. Chuzhanova2004Breakpoints of gross deletions coincide with non-B DNA conformations.Proc Natl Acad Sci U S A1011416214167
- 44. Lakich D, Kazazian HH Jr, Antonarakis SE, Gitschier J (1993) Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet 5: 236–241.D. LakichHH Kazazian JrSE AntonarakisJ. Gitschier1993Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A.Nat Genet5236241
- 45. Jobling MA, Williams GA, Schiebel GA, Pandya GA, McElreavey GA, et al. (1998) A selective difference between human Y-chromosomal DNA haplotypes. Curr Biol 8: 1391–1394.MA JoblingGA WilliamsGA SchiebelGA PandyaGA McElreavey1998A selective difference between human Y-chromosomal DNA haplotypes.Curr Biol813911394
- 46. Osborne LR, Li M, Pober B, Chitayat D, Bodurtha J, et al. (2001) A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet 29: 321–325.LR OsborneM. LiB. PoberD. ChitayatJ. Bodurtha2001A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome.Nat Genet29321325
- 47. Giglio S, Calvari V, Gregato G, Gimelli G, Camanini S, et al. (2002) Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. Am J Hum Genet 71: 276–285.S. GiglioV. CalvariG. GregatoG. GimelliS. Camanini2002Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation.Am J Hum Genet71276285
- 48. Gimelli G, Pujana MA, Patricelli MG, Russo S, Giardino D, et al. (2003) Genomic inversions of human chromosome 15q11-q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions. Hum Mol Genet 12: 849–858.G. GimelliMA PujanaMG PatricelliS. RussoD. Giardino2003Genomic inversions of human chromosome 15q11-q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions.Hum Mol Genet12849858
- 49. Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, et al. (2005) A common inversion under selection in Europeans. Nat Genet 37: 129–137.H. StefanssonA. HelgasonG. ThorleifssonV. SteinthorsdottirG. Masson2005A common inversion under selection in Europeans.Nat Genet37129137
- 50. Barbouti A, Stankiewicz P, Nusbaum C, Cuomo C, Cook A, et al. (2004) The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats. Am J Hum Genet 74: 1–10.A. BarboutiP. StankiewiczC. NusbaumC. CuomoA. Cook2004The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats.Am J Hum Genet74110
- 51. Shaw CJ, Lupski JR (2005) Non-recurrent 17p11.2 deletions are generated by homologous and non-homologous mechanisms. Hum Genet 116: 1–7.CJ ShawJR Lupski2005Non-recurrent 17p11.2 deletions are generated by homologous and non-homologous mechanisms.Hum Genet11617
- 52. Stankiewicz P, Park SS, Holder SE, Waters CS, Palmer RW, et al. (2001) Trisomy 17p10-p12 resulting from a supernumerary marker chromosome derived from chromosome 17: Molecular analysis and delineation of the phenotype. Clin Genet 60: 336–344.P. StankiewiczSS ParkSE HolderCS WatersRW Palmer2001Trisomy 17p10-p12 resulting from a supernumerary marker chromosome derived from chromosome 17: Molecular analysis and delineation of the phenotype.Clin Genet60336344
- 53. Shaw CJ, Stankiewicz P, Bien-Willner G, Bello SC, Shaw CA, et al. (2004) Small marker chromosomes in two patients with segmental aneusomy for proximal 17p. Hum Genet 115: 1–7.CJ ShawP. StankiewiczG. Bien-WillnerSC BelloCA Shaw2004Small marker chromosomes in two patients with segmental aneusomy for proximal 17p.Hum Genet11517
- 54. Yatsenko SA, Treadwell-Deering D, Krull K, Glaze D, Stankiewicz P, et al. (2005) Trisomy 17p10-p12 due to mosaic supernumery marker chromosome: Delineation of molecular breakpoints and clinical phenotype and comparison to other proximal 17p segmental duplications. Am J Med Genet 138: 175–180.SA YatsenkoD. Treadwell-DeeringK. KrullD. GlazeP. Stankiewicz2005Trisomy 17p10-p12 due to mosaic supernumery marker chromosome: Delineation of molecular breakpoints and clinical phenotype and comparison to other proximal 17p segmental duplications.Am J Med Genet138175180
- 55. Inoue K, Osaka H, Imaizumi K, Nezu A, Takanashi J, et al. (1999) Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: Molecular mechanism and phenotypic manifestations. Ann Neurol 45: 624–632.K. InoueH. OsakaK. ImaizumiA. NezuJ. Takanashi1999Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: Molecular mechanism and phenotypic manifestations.Ann Neurol45624632
- 56. Inoue K, Osaka H, Thurston VC, Clarke JTR, Yoneyama A, et al. (2002) Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am J Hum Genet 71: 838–853.K. InoueH. OsakaVC ThurstonJTR ClarkeA. Yoneyama2002Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females.Am J Hum Genet71838853
- 57. Nobile C, Toffolatti L, Rizzi F, Simionati B, Nigro V, et al. (2002) Analysis of 22 deletion breakpoints in dystrophin intron 49. Hum Genet 110: 418–421.C. NobileL. ToffolattiF. RizziB. SimionatiV. Nigro2002Analysis of 22 deletion breakpoints in dystrophin intron 49.Hum Genet110418421
- 58. Fioretos T, Strömbeck B, Sandberg T, Johansson B, Billström R, et al. (1999) Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations. Blood 94: 225–232.T. FioretosB. StrömbeckT. SandbergB. JohanssonR. Billström1999Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations.Blood94225232
- 59. Bien-Willner G, Stankiewicz P, Lupski JR, Northup JK, Velagaleti GVN (2005) Interphase FISH screening for the LCR-mediated common rearrangement of isochromosome 17q in primary myelofirosis. Am J Hematol 79: 309–313.G. Bien-WillnerP. StankiewiczJR LupskiJK NorthupGVN Velagaleti2005Interphase FISH screening for the LCR-mediated common rearrangement of isochromosome 17q in primary myelofirosis.Am J Hematol79309313
- 60. Kleinjan D, van Heynigen V (2005) Long-range control of gene expression: Emerging mechanisms and disruption in disease. Am J Hum Genet 76: 8–32.D. KleinjanV. van Heynigen2005Long-range control of gene expression: Emerging mechanisms and disruption in disease.Am J Hum Genet76832
- 61. Velagaleti GVN, Bien-Willner GA, Northup JK, Lockhart LH, Hawkins JC, et al. (2005) Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am J Hum Genet 76: 652–662.GVN VelagaletiGA Bien-WillnerJK NorthupLH LockhartJC Hawkins2005Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia.Am J Hum Genet76652662
- 62. Lee JA, Madrid RE, Sperle K, Ritterson CM, Hobson GM, et al. (2005) Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol. JA LeeRE MadridK. SperleCM RittersonGM Hobson2005Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect.Ann NeurolIn press. In press.
- 63. Shaffer LG, Ledbetter DH, Lupski JR (2001) Molecular cytogenetics of contiguous gene syndromes: Mechanisms and consequences. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, et al., editors. The metabolic and molecular bases of inherited diseases. New York: McGraw-Hill. pp. 6077–6096.LG ShafferDH LedbetterJR Lupski2001Molecular cytogenetics of contiguous gene syndromes: Mechanisms and consequences.In:. CR ScriverAL BeaudetWS SlyD. ValleB. VogelsteinThe metabolic and molecular bases of inherited diseasesNew YorkMcGraw-Hillpp.60776096 pp.
- 64. Kurotaki N, Shen JJ, Touyama M, Kondoh T, Visser R, et al. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet Med 7: 479–483.N. KurotakiJJ ShenM. TouyamaT. KondohR. Visser2005Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency.Genet Med7479483
- 65. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, et al. (2004) Detection of large-scale variation in the human genome. Nat Genet 36: 949–951.AJ IafrateL. FeukMN RiveraML ListewnikPK Donahoe2004Detection of large-scale variation in the human genome.Nat Genet36949951
- 66. Sebat J, Lakshmi B, Troge J, Alexander J, Young J, et al. (2004) Large-scale copy number polymorphism in the human genome. Science 305: 525–528.J. SebatB. LakshmiJ. TrogeJ. AlexanderJ. Young2004Large-scale copy number polymorphism in the human genome.Science305525528
- 67. Carter NP (2004) As normal as normal can be? Nat Genet 36: 931–932.NP Carter2004As normal as normal can be?Nat Genet36931932
- 68. Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, et al. (2005) The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307: 1434–1440.E. GonzalezH. KulkarniH. BolivarA. ManganoR. Sanchez2005The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility.Science30714341440
- 69. Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, et al. (2005) Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 77: 78–88.AJ SharpDP LockeSD McGrathZ. ChengJA Bailey2005Segmental duplications and copy-number variation in the human genome.Am J Hum Genet777888
- 70. Bailey JA, Yavor AM, Massa HF, Trask BJ, Eichler EE (2001) Segmental duplications: Organization and impact within the current human genome project assembly. Genome Res 11: 1005–1017.JA BaileyAM YavorHF MassaBJ TraskEE Eichler2001Segmental duplications: Organization and impact within the current human genome project assembly.Genome Res1110051017
- 71. Bailey JA, Liu G, Eichler EE (2003) An Alu transposition model for the origin and expansion of human segmental duplications. Am J Hum Genet 73: 823–834.JA BaileyG. LiuEE Eichler2003An Alu transposition model for the origin and expansion of human segmental duplications.Am J Hum Genet73823834
- 72. Eichler EE (2001) Recent duplication, domain accretion and the dynamic mutation of the human genome. Trends Genet 17: 661–669.EE Eichler2001Recent duplication, domain accretion and the dynamic mutation of the human genome.Trends Genet17661669
- 73. Versalovic J, Koeuth T, Britton R, Geszvain K, Lupski JR (1993) Conservation and evolution of the rpsU-dnaG-rpoD macromolecular synthesis operon in bacteria. Mol Microbiol 8: 343–355.J. VersalovicT. KoeuthR. BrittonK. GeszvainJR Lupski1993Conservation and evolution of the rpsU-dnaG-rpoD macromolecular synthesis operon in bacteria.Mol Microbiol8343355
- 74. Weinstock GM (1994) Bacterial genomes: Mapping and stability. ASM News 60: 73–78.GM Weinstock1994Bacterial genomes: Mapping and stability.ASM News607378
- 75. International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431: 931–945.International Human Genome Sequencing Consortium2004Finishing the euchromatic sequence of the human genome.Nature431931945
- 76. Carter NP, Vetrie D (2004) Applications of genomic microarrays to explore human chromosome structure and function. Hum Mol Genet 13(Spec No 2): R297–R302.NP CarterD. Vetrie2004Applications of genomic microarrays to explore human chromosome structure and function.Hum Mol Genet13(Spec No 2)R297R302