Molecular Cytogenetic Evidence for a Common Breakpoint in the Largest Inverted Duplications of Chromosome 15 A.E. Wandstrat, J. Leana-Cox, L. Jenkins,

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Molecular Cytogenetic Evidence for a Common Breakpoint in the Largest Inverted Duplications of Chromosome 15 A.E. Wandstrat, J. Leana-Cox, L. Jenkins, S. Schwartz The American Journal of Human Genetics Volume 62, Issue 4, Pages 925-936 (April 1998) DOI: 10.1086/301777 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 Types of inv dup(15) chromosomes. A, Normal chromosome 15, with band designations (left) and probes utilized in this study (right). Types I–III represent those inv dup(15) chromosomes that are associated with a normal phenotype. Type I represents the inv dup(15) that is monocentric and that has only one copy of the D15Z1 locus. Type II represents the inv dup(15) that is dicentric, that has two copies of the D15Z1 locus, and that breaks in 15q11, proximal to the D15S18 locus (Cheng et al. 1994; Huang et al. 1997). Type III represents the inv dup(15) that is dicentric, that has two copies of the D15Z1 locus, and that breaks in 15q11, distal to D15S18 (Huang et al. 1997). Types IV–VI represent those inv dup(15) chromosomes that contain euchromatic material from the PWS/AS commonly deleted region and that are associated with an abnormal phenotype. Type IV represents the inv dup(15) that breaks in 15q13, distal to P93C9 (D15S12) and proximal to B94H7 (D15S24) (cases 1–6 in this study; Mignon et al. 1996). Type V represents the inv dup(15) that breaks in 15q13, distal to B94H7 (D15S24) and proximal to pIR29-1 (D15S17) (Mignon et al. 1996). Type VI represents the inv dup(15) that breaks at or near sequences detected by YAC 810f11 (cases 8–20 in this study). B, All the microsatellite markers and YAC clones used in this study are listed (based on information from the Whitehead (http://www-genome.wi.mit.edu) and Genome (http://gdbwww.gdb.org) databases, as well as from the study by Christian et al. [1995]), and lines between the physical and genetic maps have been used to connect loci. The jagged lines indicate the breakpoint regions seen in the common deletion found in PWS/AS patients. The two classes of proximal deletions have been designated “I” and “II” (boxed). The American Journal of Human Genetics 1998 62, 925-936DOI: (10.1086/301777) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 FISH results for the inv dup(15) that breaks between D15S12 and D15S24. All chromosomes were counterstained with DAPI and appear blue, and all probes were labeled with fluorescein isothiocyanate (FITC) and appear green. a, Partial metaphase spread from case 3. P93C9 (D15S12) appears on both normal chromosomes 15, as well as on the inv dup(15) (indicated by the arrow). b, Partial metaphase spread from case 5. B94H7 (D15S24) appears on both normal chromosomes 15 but not on the inv dup(15) (indicated by the arrow). The American Journal of Human Genetics 1998 62, 925-936DOI: (10.1086/301777) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 FISH results for the largest inv dup(15)s. All chromosomes and cells were counterstained with DAPI and appear blue. a, Partial metaphase spread from case 18, hybridized with YAC 810f11 (FITC labeled [green]) from the D15S144 locus. The signal from YAC 810f11 appears on both normal chromosomes 15, as well as on the inv dup(15) (indicated by the arrow). The signal intensity from the inv dup(15) appears to be reduced, when compared with that from the normal chromosomes 15. b, Another example of a partial metaphase spread, from case 12, hybridized with YAC 810f11 (FITC labeled [green]) from the D15S144 locus. The signal from YAC 810f11 appears on both normal chromosomes 15, as well as on the inv dup(15) (indicated by the arrow). Again, the signal intensity appears to be reduced, when compared with that from the normal chromosomes 15. c, Interphase cell from case 8, hybridized with both YAC 810f11 (FITC labeled [green]) and the cosmid from the D15S11 locus (rhodamine labeled [red]). The signal from the inv dup(15) is clear, and two signals from the D15S11 cosmid and only one, reduced signal from YAC 810f11 (indicated by the arrow) are shown. d, Partial metaphase spread from case 8, hybridized with YAC 920a7 (FITC labeled [green]), also from the D15S144 locus. The signal from YAC 920a7 appears on both normal chromosomes 15 but not on the inv dup(15) (indicated by the arrow). The American Journal of Human Genetics 1998 62, 925-936DOI: (10.1086/301777) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 4 Diagram showing the order of STSs (D15S1010, D15S144, and D15S1007) and YACs 810f11 and 920a7, which are located in the breakpoint region of the largest inv dup(15). The American Journal of Human Genetics 1998 62, 925-936DOI: (10.1086/301777) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 5 Alu fingerprinting of YACs 810f11 and 920a7, using PCR primers CL1 and CL2, which were derived from the Alu family of repeats. A negative control YAC from the X chromosome is shown for comparison. Clearly, YACs 810f11 and 920a7 have many bands in common, indicating a high degree of homology. The American Journal of Human Genetics 1998 62, 925-936DOI: (10.1086/301777) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 6 PCR microsatellite analysis, with polymorphic CA repeats for D15S18, of case 8. The proband has inherited only one allele from the father and two alleles from the mother. The American Journal of Human Genetics 1998 62, 925-936DOI: (10.1086/301777) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 7 Methylation analysis at SNRPN exon 1. The 4.3-kb and 0.9-kb bands correspond to the maternal and paternal alleles, respectively, in normal individuals. Clearly, the 4.3-kb band is increased in intensity, compared with the 0.9-kb band, in the inv dup(15) cases, when compared with the intensity ratios generated from normal individuals, as well as with those from PWS/AS-deletion–patient controls. The American Journal of Human Genetics 1998 62, 925-936DOI: (10.1086/301777) Copyright © 1998 The American Society of Human Genetics Terms and Conditions