Human Chromosome 18 and Acrocentrics: A Dangerous Liaison

Abstract

The presence of thousands of repetitive sequences makes the centromere a fragile region subject to breakage. In this study we collected 31 cases of rearrangements of chromosome 18, of which 16 involved an acrocentric chromosome, during genetic screening done in three centers. We noticed a significant enrichment of reciprocal translocations between the centromere of chromosome 18 and the centromeric or pericentromeric regions of the acrocentrics. We describe five cases with translocation between chromosome 18 and an acrocentric chromosome, and one case involving the common telomere regions of chromosomes 18p and 22p. In addition, we bring evidence to support the hypothesis that chromosome 18 preferentially recombines with acrocentrics: (i) the presence on 18p11.21 of segmental duplications highly homologous to acrocentrics, that can justify a NAHR mechanism; (ii) the observation by 2D-FISH of the behavior of the centromeric regions of 18 respect to the centromeric regions of acrocentrics in the nuclei of normal subjects; (iii) the contact analysis among these regions on published Hi-C data from the human lymphoblastoid cell line (GM12878).

Keywords: acrocentric chromosomes; centromeric/pericentromeric regions; chromosome 18; chromosome territory; chromosome translocations; nuclear subcompartments.

Figure 1

Case 1. (A) Partial Q banded metaphase plate, the arrows indicate the two chromosomes involved in the balanced translocation t(13;18)(q10;q10), the numbers indicate the normal homologs. (B) Metaphase plate after FISH with mixture of telomeres specific for chromosomes 11 and 18p. The arrows indicate the two derivatives of translocation. Signals: green 11ptel; red 11qtel; yellow 18ptel; aqua D18Z1.

Figure 2

Case 2. (A) Chromosomes 18 and 22 from a GTG stained metaphase, left chromosome 18 translocated with 22q, right normal chromosomes 18 and the normal 22. (B) Partial metaphase after FISH with D18Z1, the arrow indicates t(18;22)(q10;q10). (C) FISH with probe D14Z1D22Z1, the arrow indicates t(18;22)(q10;q10). (D) FISH with BAC RP11 19M2 (18p 11.21), the arrow indicates t(18;22)(q10;q10). (E) FISH with BAC RP11 48H7 (18p 11.21), the arrow indicates t(18;22)(q10;q10).

Figure 3

Case 3. (A) Chromosomes 18, QFQ (left) and GTG (right) banded, the 18ps is on the right of the couple. (B) Family tree showing the paternal chromosomes 22 on the left, those maternal on the right, and the daughter with 18ps together with 22 on the bottom. The arrows indicate the 22 maternal chromosome probably involved in the translocation. (C) Partial metaphase after FISH with probe D18Z1, the arrow indicates the 18ps in association with other acrocentric chromosomes of D and G groups. (D) Partial metaphase after FISH with probe D14Z1D22Z1, the arrow indicates the 18ps. (E) Normal chromosome 18 showing hybridization after FISH with probe RP11-48H7 (18p11.21) and the arrowed 18ps without signal of hybridization. (F) Partial metaphase after FISH with beta satellite probe, the arrow indicates the 18ps showing signal of hybridization.

Figure 4

Case 4. (A) QFQ banded chromosomes 15 and 18 of the proband. From left to right: normal 15, derivative 15, derivative 18 and normal 18. (B) QFQ banded chromosomes 15 of the father (left), the foetus (middle) and the mother (right). #: indicates the normal chromosome 15; *: indicates the satellites of the paternal chromosome. (C) FISH with probe D15Z4, centromeric, alpha satellite, the arrow indicates the derivative 18 without signal of hybridization. (D) Multicolour FISH with probes D18Z1 (light blue) DXZ1 (green) DYZ3 (red). The arrow indicates the derivative 18 and the arrowhead indicates the derivative 15. (E) Multicolour FISH with probes D15Z1 (15p11.2, satellite III, light blue), SNRPN (15q11.2, red), PML (15q24, green). The arrow indicates the derivative 18 and the arrowhead indicates the derivative 15.

Figure 5

Case 5. (A) Reconstruction of karyotype in QFQ bands. (B) Family tree showing paternal (left), maternal (right), and foetus chromosomes 21. The arrowhead indicates the paternal chromosome 21, apparently without satellites.

Figure 6

Telomeric case. (A) QFQ banded chromosomes of the proband. From left to right: normal 18, derivative t(22;18), normal 22. (B) Proband’s partial karyotype showing an apparent breakage of stalk 22. (C) FISH with D18Z1 probe: the arrow indicates the translocation. The detail shows the same image without the probe, which shows the absence of primary constriction at the inactive centromere of 18 and the presence of the unique primary constriction of chromosome 22 (arrowed head). (D) FISH with D14Z1/D22Z1 probe: the normal chromosomes 14 and 22 and the harrowed derivative 22;18. (E) FISH with common telomeric sequences shows the presence of signal at 22q and 18q and the absence of interstitial signal at reunion point 22p;18p. (F) FISH with D18Z1 probe (green signals) and specific 18p subtelomeric probe (red signals). The arrow indicates the translocation. (G–I) Partial metaphases of proband’s father, blue circles evidence the derivative.

Figure 7

(A) Chromosome 18 ideogram modified from UCSC Human Genome Browser—hg19 assembly. The regions of chromosome 18 subjected to analysis are those involved in translocations with acrocentrics. The coloured arrows indicate segmental duplications (duplications of >1000 Bases of Non-RepeatMasked Sequence) with homology 90–98% with acrocentrics, as represented by the inset; the tip of the arrow pointing right indicates the strand +; the tip of the arrow pointing left indicates strand −. The arrows with the circle represent higher homology (98–99%). In particular, 18p11.32 band shows homology with segmental duplications in: 14q11.2, 22q11.1, 22q12.1, 22q13.33 and 21q22.3; 18p11.22 with 13q21.33; 18p11.21 with: 21p11.1-p11.2, 21q11.2, 22q11.1-q11.2, 14q11.1-q11.2, 15q11.2, 13q11.1, 22q13.3, 15q24.3, 14q12, 13q12, and 21q22.3. 18q11.2 with segmental duplications in: 13q14.3 and 15q23; 18q12.1 with 15q22.31, 15q14, 15q26.3, 13q12.11 and 13q14.3; 18q12.3 with 13q12.11; 18q21.31 with 14q23.3, 14q32.2, 14q26 and 15q22.2; 18q21.32 with 22q11.1, 15q23 and 14q31.3; 18q21.33 with 22q12.3. The red star indicates a ~47 Kb sequence with 93% identity between 18p11.21 (BAC RP11-681B3) and 21p11.2 satellite DNA I, II, III (BAC CR381670 [3]). (B) Histogram reporting the mean breakpoints number/100 Mb (see Tables S2 and S3). (C) 300-band resolution ideogram of chromosome 18 and distribution of breakpoints of translocations listed in Table 1 and Table S1. The colors indicate the different cytogenetic bands of chromosome 18 as in Table S1. The thicker edges of the circles show translocations with acrocentrics; the thinnest edges point out translocations with non-acrocentric chromosomes.