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Extreme Reduction of Chromosome-Specific Α-Satellite Array Is Unusually Common in Human Chromosome 21

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Extreme Reduction of Chromosome-Specific Α-Satellite Array Is Unusually Common in Human Chromosome 21 Downloaded from genome.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Research Extreme Reduction of Chromosome-Specific ␣-Satellite Array Is Unusually Common in Human Chromosome 21 Anthony W.I. Lo,1 Gregory C.-C. Liao,1 Mariano Rocchi,2 and K.H. Andy Choo1,3 1The Murdoch Institute, Royal Children’s Hospital, Parkville, Victoria 3052, Australia; 2Instituto di Genetica, 70126 Bari, Italy Human centromeres contain large arrays of ␣-satellite DNA that are thought to provide centromere function. The arrays show size and sequence variation, but the extent to which extremely low levels of this DNA can occur on normal centromeres is unclear. Using a set of chromosome-specific ␣-satellite probes for each of the human chromosomes, we performed interphase fluorescence in situ hybridization (FISH) in a population-screening study. Our results demonstrate that extreme reduction of chromosome-specific ␣ satellite is unusually common in chromosome 21 (screened with the ␣RI probe), with a prevalence of 3.70%, compared to Յ0.12% for each of chromosomes 13 and 17, and 0% for the other chromosomes. No analphoid centromere was identified in >17,000 morphologically normal chromosomes studied. All of the low-alphoid centromeres are fully functional as indicated by their mitotic stability and binding to centromere proteins CENP-B, CENP-C, and CENP-E. Sensitive metaphase FISH analysis of the low-alphoid chromosome 21 centromeres established the presence of residual ␣RI as well as other non-␣RI ␣-satellite DNA suggesting that centromere function may be provided by (1) the residual ␣RI DNA, (2) other non-␣RI ␣-satellite sequences, (3) a combination of 1 and 2, or (4) an activated neocentromere DNA. The low-alphoid centromeres, in particular those of chromosome 21, should provide unique opportunities for the study of the evolution and the minimal DNA requirement of the human centromere. The centromere is a specialized structure on a chromo- ruption of normal chromosome segregation, and asso- some that plays an essential role in chromosomal seg- ciation with the ␣-satellite DNA-binding protein regation during mitosis and meiosis. The most abun- CENP-B (Haaf et al. 1992; Larin et al. 1994). In the dant DNA element in the human centromere is the ␣ remaining two studies, transfection of ␣-satellite DNA satellite, which constitutes as much as 3%–4% of chro- with other genomic DNA, in particular human telo- mosomal DNA. The significance of ␣ satellite in cen- mere sequences, into human cell cultures has resulted tromere function has been the subject of active re- in the formation of stable minichromosomes contain- search for over two decades. Its apparent ubiquitous ing functional centromeres that can be attributed to presence at the cytogenetically defined primary con- the introduced ␣-satellite DNA (Harrington et al. 1997; strictions of all normal human chromosomes implies a Ikeno et al. 1998). priori a possible functional role. Analysis of rearranged Although the above evidence points strongly to a (Tyler-Smith et al. 1993) or fragmented (Brown et al. positive centromere role for ␣ satellite, it is now clear 1994) centromeres of the human Y chromosome has that this DNA is not always, on its own, sufficient to demonstrated that sequences necessary for centromere elicit centromere activity. For example, in human di- function are localized to a region containing 150–200 centric chromosomes, normal amounts of ␣ satellite kb of ␣-satellite DNA. Five different studies involving are present on two distinct chromosomal sites and yet the introduction of exogenous ␣ satellite into cultured only one of these sites will form an active centromere mammalian cells have provided further evidence in fa- (Earnshaw et al. 1989; Page et al. 1995; Sullivan and vor of ␣-satellite DNA having a functional centromere Schwartz 1995). Furthermore, an increasing number of role. In three of these studies, transfection of ␣ satellite functional neocentromeres have been detected in into hamster, simian, or human cells has led to the marker chromosomes that are formed from interstitial appearance of integration-associated centromere chromosomal sites that are devoid of ␣-satellite se- manifestation such as increase in the number of dicen- quences (for review, see Choo 1997b), suggesting that tric and ring chromosomes per cell (Heartlein et al. ␣-satellite DNA is, in certain situations, unnecessary for 1988) or the formation of a primary constriction, dis- centromere activity. A well-characterized example of such neocentromeres is the one derived from band 3Corresponding author. q25.2 of human chromosome 10 in which the core E-MAIL [email protected]; FAX 61-3-9348-1391. centromeric protein binding region has been localized 9:895–908 ©1999 by Cold Spring Harbor Laboratory Press ISSN 1054-9803/99 $5.00; www.genome.org Genome Research 895 www.genome.org Downloaded from genome.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Lo et al. to a genomic sequence of ∼80 kb (Voullaire et al. 1993; 1997). Although these studies have unequivocally es- du Sart et al. 1997; Cancilla et al. 1998; Barry et al. tablished the quantitative heteromorphic nature of 1999). ␣-satellite DNA, it is unclear to what extent extreme Structurally, centromeric ␣-satellite DNA is com- reductions of these arrays are tolerated in the normal posed of huge arrays of tandemly repeated monomers centromeric regions of different human chromosomes. of 171 bp (Waye and Willard 1987; Choo et al. 1991). In the present study, we addressed this question in a Arrays of ␣ satellite on different chromosomes are population study employing FISH and a battery of highly heterogeneous both in the sequence of the chromosome-specific ␣-satellite DNA probes for each monomer as well as in their higher-order organization. of the human chromosomes. Our results indicated that Such heterogeneity has led to the evolution of chro- extreme reduction of this DNA is rare for the different mosome-specific subfamilies of ␣ satellite within the chromosomes with the exception of chromosome 21. human genome, in which a particular subfamily may A similar analysis was performed on a cohort of Down be specific to a single chromosome or shared by two or syndrome (DS) patients. The implications of our obser- more chromosomes, or where multiple subfamilies of vations in the light of the evolution and minimal DNA this DNA may be present on a single chromosome (for requirement of ␣ satellite, and the etiology of meiotic review, see Choo et al. 1991; Choo 1997a). nondisjunction in DS, are discussed. In addition to sequence heterogeneity, ␣-satellite arrays also demonstrate extensive size variation be- tween nonhomologous as well as homologous chro- RESULTS mosomes. This variation has been recognized at both The study was divided into two phases. The first in- the molecular and cytogenetic levels. Using pulsed- volved the use of each of the ␣-satellite probes to de- field gel electrophoresis (PFGE), significant differences termine the distribution profile of cells that exhibited in the size of individual ␣-satellite DNA arrays have the expected number of FISH signals within a sample been observed between homologs of various human population. In the second phase, a more rapid inter- chromosomes, such as the X chromosome (array size phase FISH screening of a larger population sample was range: 1380–3730 kb; Mahtani and Willard 1990), Y undertaken with the specific aim of identifying ex- chromosome (array size range: 285–1020 kb; Tyler- Smith 1987; Abruzzo et al. Table 1. Interphase FISH Screening for Low-Alphoid Cell Lines 1996), or chromosome 21 Chromosome- No. of cell lines No. of low-alphoid centromeres (array size range, 420 to specific >2650 kb; Marcais et al. Chromo- ␣-satellite phase phase phase phase prevalencea 1991; Trowel et al. 1993; some probes I II total I II total (%) Ikeno et al. 1994). Other 1 pZ5.1 — 328b 328b ——— — studies of individual chro- 2 pX2 78 290 368 — — — — mosomes 1 (Waye et al. 3 pAE0.68 62 301 363 — — — — 4 p4n1/4 74 243 317 — — — — 1987b), 3 (Waye and 5 pZ5.1 — 328b 328b ——— — Willard 1989), 7 (Wevrick 6 pEDZ6 76 245 321 — — — — et al. 1992), 8 (Ge et 7 pZ7.5 77 319 396 — — — — al.1992), 10 (Jackson et al. 8 pZ8.4 76 227 303 — — — — 9 pMR9A 65 320 385 — — — — 1993), 11 (Waye et al. 10 pZ10-2.3 70 266 336 — — — — 1987a), 13 (Trowell et al. 11 Oncor D11Z1 76 312 388 — — — — 1993), 14 (Trowell et al. 12 pB12 78 306 384 — — — — ␣ 1993), and 16 (Greig et al. 13 RI 53 366 419 — 1 1 0.12 14 ␣XT 73 321 394 — — — — 1989) have indicated a 15 pTRA20 58 328 386 — — — — broad centromeric ␣-satel- 16 pZ16A-2 67 241 308 — — — — lite size spectrum ranging 17 TR17 78 357 435 — 1 1 0.11 ∼ 18 L1.84 69 239 308 — — — — from 200 kb to 4Mb.At 19 pZ5.1 — 328b 328b ——— — the cytogenetic level, inter- 20 pZ20 77 268 345 — — — — phase and metaphase FISH 21 ␣RI 53 366 419 6 25 31 3.70 analyses have similarly re- 22 ␣XT 73 321 394 — — — — XY XY ␣-mixc 67 294 361 — — — — vealed noticeable varia- tions in ␣-satellite array sig- aPrevalence is expressed in terms of the total number of chromosomes. nals in functionally normal bFor chromosomes 1, 5 and 19, screening for low-alphoid centromeres was done on metaphase centromeres (e.g., Shelby et chromosomes. cThis mix contains the X- and Y-specific probes, pLAX and pLAY5.5, respectively. al. 1996; Verma et al. 896 Genome Research www.genome.org Downloaded from genome.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Low-alphoid Centromere in Human Chromosome 21 treme cases of ␣-satellite DNA reduction on each of the chromosomes. Phase I: Determination of FISH Profiles for Different ␣-Satellite Probes Table 1 lists the different chromosome- specific ␣-satellite probes used in the present study.
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