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Vol. 11, Issue 4, 513-516, April 2001
INSIGHT/OUTLOOK
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The centromeres of primate chromosomes are composed of
complex arrays of alphoid sequences that are organized from tandemly repeating units of 171 bp. The ubiquity of alphoid DNA at the centromeric regions suggests a preference for repetitive DNA in the
assembly of the kinetochore. Nevertheless, recent analyses of ectopic
centromeres (neocentromeres) at non-alphoid-containing chromosomal
sites suggest that centromeres can be "repositioned" along a
chromosome through a still poorly understood epigenetic mechanism of
"activation" of hitherto noncentromeric genomic DNA (Choo 1997
). In
this issue, Ventura et al. (2001) present evidence for centromere
repositioning along the X chromosome during primate evolution that
raises interesting mechanistic possibilities.
Centromere Repositioning Via Neocentromere Emergence?
The study of Ventura et al. (2001) is based on comparison of the
conservation of DNA sequences on the X chromosomes of humans and two of
the Lemuridae: the black lemur and the ringtailed lemur. Lemurs are
small primates related to the monkey and are found mainly in
Madagascar. Unlike the submetacentric human X chromosome, the black and
ringtailed lemur chromosomes are telocentric and metacentric,
respectively. Ventura et al. have performed FISH analysis on the lemur
X chromosomes using human chromosomal paints and a panel of
BACs/cosmids spanning the entire X chromosome. Based on the relative
map positions of these probes, they conclude that the lemur X
chromosomes are isosequential to the human X chromosome (Fig.
1). They then propose that neocentromere
activation may account for the centromere repositioning that has given
rise to the acrocentric, metacentric, and submetacentric configurations in the three different species (Fig. 2).
Because the corresponding chromosomal regions at which the
neocentromeres putatively originated do not contain the large arrays of
repetitive sequences that are now found at the repositioned
centromeres, Ventura et al. suggest that heterochromatic materials may
have gradually accumulated at the neocentromere sites. In addition, the
investigators indicate that there has been a loss of repetitive DNA
materials from the original centromeres of the X chromosomes.
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Ventura et al. do not favor the alternate possibility of insertional transposition of normal centromere DNA, based on the observation that no crosshybridization was detected on the human X chromosome when probes amplified from the dissected lemur centromeric segments were used in FISH analysis. However, the fact that the centromere sequences of the X chromosomes in humans and in the black lemur are common to those found on the centromeres of other chromosomes within the same cell raises the possibility that the chromosome-X centromeres may have originated by transposition or acquisition of a functional centromere from another chromosome (Fig. 3). Nevertheless, it remains possible that any transposition or acquisition of centromere repeats may have occurred subsequent to the activation of a neocentromere, therefore still identifying neocentromerization as the primary trigger for centromere repositioning (Fig. 2). The data do not allow these possibilities to be discerned.
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In the ringtailed lemur X chromosome, the centromere sequence is unique
in regard to other centromeres, although slight homology to the
interstitial heterochromatin of various chromosomes in this species,
and to the pericentromeric heterochromatin of chromosomes 3 and 6 of
the black lemur, was described. In this case, direct transposition of
centromeric DNA is less likely to have occurred, and
neocentromerization probably provides a better explanation. The low
level of crosshybridization with the heterochromatin of other
chromosomes suggests a possibility of transposition of noncentromeric heterochromatic DNA during the evolution of this neocentromere (Fig.
2). The transposition of such DNA may have occurred either prior to the
formation of a neocentromere or following an independent neocentromerization event. A recent study demonstrating that
noncentromeric heterochromatic DNA is a good substrate for
neocentromerization (Henikoff et al. 2000; see below) adds some support
to the possibility of the transposition of heterochromatic DNA in
inducing neocentromere formation. It is also possible, although
unlikely, that the acquisition of such heterochromatin-related DNA may
simply be an incidental occurrence that has nothing to do with the
evolution of this centromere. Further discrimination between these
possibilities will require the identification of the functional DNA
sequences within the repositioned centromere and comparison of this
sequence with those found in the corresponding euchromatic portion of
the other primate X chromosomes or the heterochromatic DNA of other chromosomes.
What Triggers the Formation of a Neocentromere?
In humans, the appearance of a neocentromere and the inactivation
of a pre-existing centromere go hand in hand (Choo 1997; Warburton et
al. 2000). Epigenetic modifications that are known to induce
higher-order chromatin repackaging have been proposed to account for
the observed assembly of kinetochores on noncentromeric sequences in
various species, including Drosophila and humans, suggesting
that the mechanisms may be universal (Steiner and Clark 1994; du Sart
et al. 1997; Williams et al. 1998). Possible epigenetic modifications
include deposition of centromere DNA-binding protein that results in
higher-order chromatin reorganization or occur via chemical
modification of centromeric DNA or its associated histones and
nonhistone proteins, such as methylation, polyribosylation, acetylation/deacetylation, phosphorylation, and ubiquitination (Choo
2000). In Drosophila, neocentromere formation has been
proposed to be a consequence of cis-spreading of centromeric
epigenetic modifications to juxtaposed DNA during chromosomal
rearrangements (Williams et al. 1998). This cis-spreading
model postulates that an altered centromere-specific chromatin
conformation is being imposed onto an euchromatic region. Partridge et
al. (2000) have also demonstrated the cis-spreading of fission
yeast centromere proteins and suggested that the plasticity in
centromere formation may be mediated in part by spreading of
chromatin-associated proteins beyond the nucleation point, possibly via
underacetylated or methylated chromatin. However, it is conceivable
that activation may also occur via trans-spreading of
epigenetic information through interaction between two noncontiguous
chromosome regions.
Alternatively, de novo formation of a centromere may simply begin with random imprinting or marking of a DNA sequence that favors the incorporation of some centromeric factors, such as the histone H3-like protein CENP-A. Once imprinted, the sequence can acquire additional proteins required for proper kinetochore assembly and propagate as a functional neocentromere regardless of the underlying nucleotide sequence composition. The initial state of the neocentromere may be imperfect for longterm evolutionary stability and may be subjected to further selection for improved kinetochore binding, for example, through repeated rounds of duplication of some crucial binding site, ultimately resulting in a new tandem array of repeats. Alternatively, as discussed above, the imperfect neocentromere may undergo an acquisition of a more preferred centromeric state through transposition of other centromeric or heterochromatic DNA.
Neocentromere Hotspots?
It is not known how a site is selected for neocentromere formation.
A recent study on a series of inv dup (13q) chromosomes containing
neocentromeres has identified specific "hotspots" for neocentromere
activation at 13q32 and 13q21 (Warburton et al. 2000). It is possible
that neocentromere sequences may share some sequence characteristics
with one another and with 
-satellite DNA, which has been shown to
be a preferred substrate for centromere formation (Harrington et al.
1997; Ikeno et al. 1998). The development of a rapid method for
identifying functionally critical neocentromere DNA, based on a
combined chromatin immunoprecipitation and array analysis procedure
described in Lo et al. (2001), should allow the in-depth investigation
of this possibility through in silico analysis and comparison of a
variety of cloned neocentromere DNA sequences.
Platero et al. (1999) have demonstrated that centromere competence can
be an innate characteristic of DNA containing heterochromatic blocks,
which may favor contacts for microtubule attachment and oscillation
during mitosis. This study raises the possibility of chromosomal
regions with heterochromatic properties being intrinsic sites for
neocentromere activation. Henikoff et al. (2000) have also shown that
the heterochromatic state facilitates the localization of CENP-A
proteins in both Drosophila and humans. Furthermore, it has
been reported that a dicentric Y chromosome is capable of forming a new
constriction in the q-terminal heterochromatic region of the chromosome
(Bukvic et al. 1996). Although most neocentromeres are localized at
euchromatic regions, heterochromatin-associated proteins have been
detected at neocentromeres, suggesting that neocentromeres, regardless
of whether they originate from heterohromatic DNA, carry some
properties of heterochromatin (Saffery et al. 2000). Thus, it appears
that a genomic region with intrinsic heterochromatic properties, or the
ability to acquire such properties, may be favored sites for neocentromerization.
Mechanisms for Accumulation of Repetitive DNA at Euchromatic Neocentromere
Recent molecular and cytological studies have identified the
occurrence of duplication and transposition of region-specific low-copy
repeat elements, or duplicons, at the pericentromeric regions of
chromosomes (Eichler et al. 1997; Horvath et al. 2000a,b). Analysis of
the molecular structure of a 160-kb DNA segment that separates
-satellite from non--satellite on human chromosome 16p11
reveals that this junction is composed of duplicated segments from Xq28
and 4q24 and that this DNA is found further amplified and spread to
other pericentromeric regions, resulting in the formation of large
blocks of sequences of high homology among nonhomologous chromosomes
(Horvath et al. 2000b). Guy et al. (2000) and Jackson et al. (1999)
have similarly identified distinct domains of duplicated sequences at
the proximal regions flanking chromosome 10 centromere, indicating
reorganization of human pericentromeric heterochromatin
and evolution of a boundary between pericentromeric repeats and
euchromatins. They suggest that pericentromeric duplication represents
a transient intermediate of duplication of euchromatin into centromeric
heterochromatin. Pericentromeric regions, therefore, may be preferred
sites for recruitment of repeats and DNA transposition, leading to
expansion of satellite blocks and the reconstruction of a more complex
repeat structure that results in the accumulation of heterochromatic
DNA at the repositioned centromeric sites described by Ventura et al. (2001).
Many Questions Remain Unanswered
The study of Ventura et al. (2001) and that of an earlier report
from the same group (Montefalcone et al. 1999) represent the first
attempts to understand the gain or loss of centromeres on a chromosome
on an evolutionary scale. These occurrences result in the apparent
repositioning of centromeres on chromosomes. Although the approach used
by these investigators has clearly provided useful insights into
various mechanistic possibilities, many unanswered questions remain.
What triggers the need to reposition a centromere? How are
neocentromeres activated and epigenetically inherited? Do the
pericentromeric heterochromatin contribute to this activation? How has
the heterochromatin evolved on a repositioned centromere? How are
functional higher-order neocentromere structures produced by a
diversity of underlying DNA sequences? What are the mechanisms for the
loss of a pre-existing centromere on a chromosome carrying a
repositioned centromere? There are, clearly, many experimental paths
that can be followed in search of answers to these questions, including
the use of different organisms ranging from single-cell eukaryotes
(Saccharomyces cerevisiae and Schizosaccharomyces
pombe) to the higher eukaryotes (such as Caenorhabditis
elegans, Drosophila, Arabidopsis, and primates). The choice of
primates as the subject of study by the Rocchi laboratory provides
evolutionary data that fill a relevant and important gap to meet these
challenging questions.
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ACKNOWLEDGMENTS |
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This work is supported by the National Health and Medical Research Council of Australia.
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FOOTNOTES |
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1 Corresponding author.
E-MAIL choo{at}cryptic.rch.unimelb.edu.au; FAX 61-3-93481391.
Article and publication are at www.genome.org/cgi/doi/10.1101/gr.183901.
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