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Genetica 117: 209–215, 2003.
© 2003 Kluwer Academic Publishers. Printed in the Netherlands.
209
Vital genes in the heterochromatin of chromosomes 2 and 3 of Drosophila
melanogaster
Patrizio Dimitri1, Nicoletta Corradini1 , Fabrizio Rossi1 , Fiammetta Vernı̀1 , Giovanni Cenci2 ,
Giorgio Belloni1 , Igor F. Zhimulev3 & Dmitry E. Koryakov4
1 Dipartimento
di Genetica e Biologia Molecolare ‘Charles Darwin’ Università ‘La Sapienza’, Piazzale A. Moro
5, 00185, Roma, Italy (Phone: 39-0649912856; Fax: 39-06-4456866; E-mail: [email protected]);
2 Dipartimento di Scienze Tecnologiche, Biologiche ed Ambientali-ECOTEKNE 73100, Lecce, Italy; 3 Institute of
Cytology and Genetics, 630090, Novosibirsk, Russia; 4 Department of Cytology and Genetics, Novosibirsk State
University, 630090, Novosibirsk, Russia
Key words: Drosophila, heterochromatic genes, heterochromatin
Abstract
Heterochromatin has been traditionally regarded as a genomic wasteland, but in the last three decades extensive
genetic and molecular studies have shown that this ubiquitous component of eukaryotic chromosomes may perform
important biological functions. In D. melanogaster, about 30 genes that are essential for viability and/or fertility
have been mapped to the heterochromatin of the major autosomes. Thus far, the known essential genes exhibit a
peculiar molecular organization. They consist of single-copy exons, while their introns are comprised mainly of
degenerate transposons. Moreover, about one hundred predicted genes that escaped previous genetic analyses have
been associated with the proximal regions of chromosome arms but it remains to be determined how many of these
genes are actually located within the heterochromatin. In this overview, we present available data on the mapping,
molecular organization and function of known vital genes embedded in the heterochromatin of chromosomes 2
and 3. Repetitive loci, such as Responder and the ABO elements, which are also located in the heterochromatin of
chromosome 2, are not discussed here because they have been reviewed in detail elsewhere.
Introduction
It is now clear that heterochromatin performs important cellular functions such as gene regulation,
centromere and telomere function and meiotic chromosome transmission (Weiler & Wakimoto, 1995;
McKee, 1998; Eissemberg & Hilliker, 2000; Henikoff,
2000; Grewal & Elgin, 2002). In particular, the heterochromatin of D. melanogaster contains several essential genetic loci (Gatti & Pimpinelli, 1992; Weiler
& Wakimoto, 1995). About 30 genes required for viability and fertility have been mapped to the heterochromatin of major autosomes (Hilliker, 1976; Dimitri,
1991; Schulze et al., 2001; Koryakov, Zhimulev &
Dimitri, 2002). The early prediction that these genes
correspond to unique sequences (Hilliker, 1976) has
been confirmed by molecular analyses. At least light,
concertina, rolled and Nipped-B in chromosome 2
and l(3)80Fh, l(3)80Fi and l(3)80Fj in chromosome
3 consist of single copy exons (Devlin, Bingham &
Wakimoto, 1990; Parks & Weischaus, 1991; Biggs
et al., 1994; Rollins, Morcillo & Dorsett, 1999). Recently, the computational analysis of the sequence of
D. melanogaster genome identified about one hundred
new predicted genes associated with the proximal regions of the chromosome arms. These genes may have
escaped previous genetic analysis and it remains uncertain whether they are indeed located in heterochromatin or correspond to proximal euchromatic genes.
Vital genes located in the heterochromatin
of chromosome 2
Sixteen vital genes identified by recessive lethal alleles have been thus far mapped to the constitutive
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Figure 1. Cytological mapping of vital genes in the heterochromatin of chromosomes 2 and 3. (A) Gene distribution within chromosome
2 heterochromatin; note that the l(2)41Aa gene maps to the h41 region proximally to rolled and is separated from it by the breakpoint of
Df(2Rh)Rsp1 . (B) Gene distribution within chromosome 3 heterochromatin. Black color and hues of gray color correspond to the intensity
of DAPI staining. 2L = left arm of chromosome 2; 2R = right arm of chromosome 2. 3L = left arm of chromosome 3; 3R = right arm of
chromosome 3. C = centromeric region.
Table 1. The vital genes located in the heterochromatin of chromosome 2
Gene
Mitotic map
Size (kb)
Function
Overlaps
l(2)40Fa
l(2)40Fc
light
concertina
l(2)40Fd
l(2)40Fe
l(2)40F
l(2)40Fg
l(2)41Ab
l(2)41Aa
rolled
l(2)41Ad
l(2)41Ae
l(2)41Af
l(2)41Ah
Nipped-B
h35
h35
h35
h35
h35
h35
h35
h35
h39–40
h41
h41
h43–h44
h46
h46
h46
h46
–
–
16
10.5
–
–
–
–
–
–
∼80
–
–
–
–
39
Unknown
Unknown
Cellular-protein trafficking
Gastrulation
Unknown
Unknown
Unknown
Unknown
Unknown
Chromosome condensation
Sevenless signal transduction pathway
Legs and wing morphogenesis
Unknown
Unknown
Unknown
Chromosomal adherin
–
–
AE002734
AE002743
–
–
–
–
–
–
AE003090 AE002642
–
–
–
AE003040
All the genes have been identified by genetic analysis. Molecular data are available only for light, concertina, rolled and
Nipped-B.
heterochromatin of chromosome 2 (Hilliker, 1976;
Dimitri, 1991; Rollins, Morcillo & Dorsett, 1999).
Here we will present available data on their cytological mapping, molecular organization and functions
(Figure 1(A) and Table 1).
Mapping and molecular organization
The vital genes are nonrandomly distributed throughout the mitotic heterochromatin of chromosome 2
(Figure 1(A)): l(2)41Aa, l(2)41Ab, rolled (l(2)41Ac)
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and l(2)41Ad are clearly located within the proximal
heterochromatin of 2R, while eight loci in the left
arm (l(2)40Fa, l(2)40Fc, concertina, light, l(2)40Fd,
l(2)40Fe, l(2)40Ff and l(2)40Fg) and four in the right
arm (l(2)41Ae l(2)41Af, l(2)41Ah and Nipped-B) are
clustered within h35 and h46, respectively. These two
regions represent the most distal portions of mitotic
heterochromatin of chromosome 2 (Dimitri, 1991)
and, based on the total DNA content of the heterochromatin (Adams et al., 2000), we estimated that
they are roughly 2 and 1.5 Mb of DNA long, respectively. Interestingly, most of the genes thus far
detected are located in DAPI-dull fluorescent chromosomal regions. FISH experiments on mitotic chromosomes have shown that those gene-rich regions
harbor clusters of transposable element-homologous
sequences and are devoid of highly repetitive satellite
DNAs (Carmena & Gonzales, 1995; Pimpinelli et al.,
1995; Dimitri, 1997).
After the release of D. melanogaster genome sequence (Adams et al., 2000), we have a more detailed
picture of the molecular structure of some heterochromatic genes of chromosome 2 (Table 1). The light
gene (scaffold AE002734) it is about 16 kb long and
has 11 introns in agreement with previous work of
Devlin, Bingham and Wakimoto (1990); concertina
(scaffold AE002743) is about 10.5 kb long and contains four introns. The rolled gene encompasses about
80 kb and has six introns (W. Biggs and K. Zavitz,
unpublished). A significant, but incomplete, portion
of rolled is present in two different non-overlapping
scaffolds (AE003090 and AE002642). Finally, the
Nipped-B gene (scaffold AE003040) is 39 kb long
and has 23 introns. In general, the introns encompass a major portion of the entire genomic region of
those genes. Most of the introns belong to the category of short introns as they range from 50 to 70 bp,
while others are longer and their size can reach up
20 kb. Interestingly, the intronic and flanking portions
of those genes are enriched in transposable elementhomologous sequences. This peculiar organization
was originally shown for light (Devlin, Bingham &
Wakimoto, 1990). We have recently performed sequence analysis of the introns from rolled, Nipped-B,
light and concertina and found that about 50% of
the large introns is composed of degenerate retroelements and DNA transposons (Dimitri, Junakovic &
Arcà, submitted). Moreover, comparative analysis of
introns from orthologues of the same genes in closely
related Drosophila species revealed intron size variation which might result from rearrangements and
instability of TE-related sequences. Our findings suggest that the structure of those genes evolve rapidly
possibly as a consequence of TE-mediated changes.
Functions
It appears that single-copy genes on chromosome 2
are involved in several important cellular processes
(Table 1). Among 2Lh genes the light gene product is
involved in cellular-protein trafficking (Warner et al.,
1998), while concertina encodes a maternal α-like
subunit of a G protein essential for gastrulation (Parks
& Wieschaus, 1991). Among the 2Rh genes, molecular data are available for rolled and Nipped-B. The
rolled gene was originally found to be required for
imaginal disc development and suggested to be involved in cell proliferation (Hilliker, 1976; Dimitri,
1991). Subsequent studies have shown that the rolled
product is a mitogen-activated protein (MAP) kinase
which is required in the sevenless signal transduction
pathway (Biggs et al., 1994) and may also be implicated in mediating the spindle integrity checkpoint
(Inoue & Glover, 1998). The Nipped-B gene encodes
a protein which is homologous to a family of chromosomal adherins and may be also involved in sister
chromatid cohesion, chromosome condensation, and
DNA repair (Rollins, Morcillo & Dorsett, 1999).
In the release of D. melanogaster genome sequence, only limited portions of the 60 Mb of heterochromatin have been sequenced (Adams et al., 2000).
Thus, the structure and function of most of the heterochromatic genes thus far detected by conventional
genetic analysis remains unknown. Among the genes
in 2Rh, l(2)41Aa and l(2)41Ad are of particular interest and the analysis of phenotypic defects exhibited
by their lethal alleles may help shed some light on
their function. Flies mutant for l(2)41Aa survive until
third instar larvae (Hilliker, 1976) and have severely
defective imaginal discs (Dimitri, 1991). The phenotypes of late lethality and poorly developed imaginal
discs are diagnostic of lesions in essential cell-cycle
genes (Gatti & Baker, 1989). The cytological analysis of both mitotic and meiotic cell divisions showed
that l(2)41Aa mutants affect proper chromosome condensation (Cenci, Belloni & Dimitri, submitted). In
particular, in larval brain, a high proportion of cells
(∼30–60%) showed irregularly condensed metaphase
chromosomes (Figure 2). These results suggest that
the l(2)41Aa product may be required for chromosome
condensation in both mitosis and meiosis.
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Figure 2. Mitotic defects associated with l(2)41Aa mutations. (a) Colchicine treated control metaphase stained with DAPI; (b) Phenotype of
colchicine treated metaphase of l(2)41Aa mutants stained with DAPI.
As previously mentioned, the l(2)41Ad gene maps
to the h43–h44 regions of mitotic heterochromatin of
2R. It has been shown that lethal mutations of this
gene result in death at the late pupae or pharate adult
stage with individuals exhibiting malformed legs and
unextended wings (Hilliker, 1976; Dimitri, 1989).
This phenotype strongly resembles that of mutations
in Drosophila genes involved in morphogenesis suggesting that l(2)41Ad has a similar function. One
of those genes is vulcan which encodes a product
that is required for proper legs and wings morphogenesis and is a putative component of the septate
junction (Spradling et al., 1999; Gates & Thummel,
2000; http://fly.ebi.ac.uk:7081/.bin/fbidq.html?FBgn
0010633). Intriguingly, vulcan has been assigned to
2R in the polytene region 41F. However, complementation tests ruled out the possibility that vulcan and l(2)41Ad are alleles (P. Dimitri & F. Rossi,
unpublished).
heterochromatin appears to be devoid of known genes
or satellite DNAs.
Three of the genes from the left arm, l(3)80Fh,
l(3)80Fi and l(3)80Fj, have been cloned and found
to correspond to single-copy sequences. Interestingly,
l(3)80Fh and l(3)80Fj genes appear to be members of
the trithorax group (trxG) genes, while the l(3)80Fi
gene may have key functions in growth and development (Schulze et al., 2001). In addition, other
single-copy genes such as α-Cat, rp21, SCP, DSK,
QIII, ziti, Dbp80 and PARP map to regions 80 and
81 (Kelly et al., 1977; Sinclair, Suzuky & Grigliatti,
1981; Kay, Zhang & Jacobs-Lorena, 1988; Nichols,
Schneuwly & Dixon, 1988; Oda et al., 1993; Dej &
Spradling, 1997; Eisen et al., 1998; Hanai et al., 1998),
but it is unclear whether or not they are allelic to the
genes described by Marchant and Holm (1988).
Predicted genes associated with the proximal
regions of the arms
Vital genes located in the heterochromatin
of chromosome 3
A group of 12 vital genes, identified by EMS, Pelement and γ-rays mutageneses, has been associated
with the heterochromatin of chromosome 3 (Schulze
et al., 2001). A detailed cytogenetic mapping of those
genes on mitotic chromosomes has been recently performed (Koryakov, Zhimulev & Dimitri, 2002; see
Figure 1(B)). The results showed that at least seven
genes of the left arm (from l(3)80Fd to l(3)80Fj) map
to segment h49–h51 and that the most distal genes
(from l(3)80Fa to l(3)80Fc) are located within regions h47–h49. The two essential genes on the right
arm, l(3)81Fa and l(3)81Fb map to the distal h58 segment. Intriguingly, a large portion of chromosome 3
Several predicted genes located in the proximal regions of the arms of chromosomes 2 ans 3 have been
recently identified by the computational analysis of the
sequence of D. melanogaster genome (Adams et al.,
2000; http://fly.ebi.ac.uk:7081/annot/bands/band41.
html; http://fly.ebi.ac.uk:7081/annot/bands/band40.
html; http://fly.ebi.ac.uk:7081/annot/bands/band80.
html). Moreover, it is still unclear whether all the
predicted coding sequences correspond to true functional genes, since only few of the predicted genes
have mutant alleles. Thus far, the actual location of
most predicted genes remains uncertain since they
have been incorporated into gadFly with inferred mapping (http://www.fruitfly.org/sequence/faq.html#seq14). How many predicted genes are located within
213
heterochromatin? Do some of them corresponds to
the genetically identified single-copy genes mapped
to the mitotic heterochromatin of chromosome 2 and
3? We have preliminary results based on FISH mapping of BACs suggesting that only a small group of
the predicted genes mapping to 41C-F is included in
h46, the most distal region of 2R mitotic heterochromatin (N. Corradini, F. Rossi, F. Vernì & P. Dimitri,
in preparation). Moreover, 3 genes on 2L such as
chitinase-3 (CG18140), chitinase-1 (CG17682) (De la
Vega et al., 1998) and CG18117 can be mapped on
the basis of their linkage with concertina. The concertina gene is found in the scaffold AE002743.1 together
with chitinase-3, chitinase-1 and CG1811. Both concertina and chitinase-3 are separated by about 20 kb,
while chitinase-1 and CG18117 are even closer to
concertina. Since concertina maps to the h35 of 2L
mitotic heterochromatin (see the map in Figure 1) it
is then conceivable that chitinase-3, chitinase-1 and
CG18117 are also located in the same region.
Transposon tagging of single-copy genes
located in heterochromatin
In addition to EMS or γ-rays, the vital heterochromatic
genes of chromosomes 2 and 3 can be mutated by insertional mutagenesis with transposable elements, that
may greatly facilitate genetic and molecular studies
of the disrupted genes. Alleles of the light gene have
been induced by P-element transposition and this has
allowed the cloning of the gene (Devlin, Bingham
& Wakimoto, 1990). More recently, P–M hybrid
dysgenesis-induced mutations were also recovered in
heterochromatic genes of 3L (Schulze et al., 2001).
Transposon tagging using strains carrying single-P
element marked with the rosy, white or both white
and yellow sequences has been proved to be successful in the recovery of heterochromatic insertions
(Zhang & Spradling, 1994; Roseman et al., 1995). A
collection of lines carrying single-P inserts in heterochromatin was produced by the Berkeley Drosophila
Genome Project (BDGP). Among those insertions,
l(2)02047 was shown to be an allele of the NippedB gene which allowed the molecular characterization
of the gene (Rollins, Morcillo & Dorsett, 1999). Although P-element mutagenesis represents a powerful
tool for the analysis of genes, it is still unclear whether
P-elements can mutate all single-copy genes in heterochromatin. Other dysgenic systems may be also
used for mutating those genes. I–R hybrid dysgen-
esis, where transposition of the I elements is activated
(Busseau et al., 1994), was also found to be very efficient in generating mutations at heterochromatic loci
of chromosome 2 (Dimitri et al., 1997). About 65%
of the heterochromatic lethals recovered in this work
affected individual loci and may be due to I factor insertion within the gene, as shown in the case of the
rolledIR1 allele. The remaining lethals were associated with chromosome rearrangements which mostly
correspond to large deletions spanning megabases of
DNA. Interestingly, nine out of 40 (21%) were alleles
of the l(2)41Ad gene suggesting that this gene is particularly prone to mutation following I–R dysgenesis.
How can the apparent hypermutability of l(2)41Ad be
explained? This may result from a highly accessible
chromatin state, or to a particularly large size of the
gene. Moreover, preexisting I-element sequences in
region h44 (Dimitri et al., 1997) may also have a role
in this phenomenon perhaps in inducing some kind of
‘homing’.
Unfortunately, a limitation to the use of I–R dysgenesis for tagging heterochromatic genes is the lack
of a marked I factor construct that can be induced to
transpose efficiently.
Conclusions
Joint efforts are now required to complete the molecular characterization of the heterochromatic genome
of D. melanogaster and to extend the work to other
Drosophila species. This may allow us to characterize new heterochromatic genes and to learn how
they have evolved. An important goal is also to solve
the apparent paradox of the ‘functional heterochromatin’. Although it is well know that heterochromatic
genes such as light and rolled genes require a heterochromatic environment to function (Wakimoto &
Hearn, 1990; Eberl, Duyf & Hilliker, 1993), we
still need to understand how heterochromatic domains
of gene expression are organized and what accounts
for the differences between heterochromatic and euchromatic domains. To this regard it is worth noting
that active heterochromatic genes might show a nucleosome array characteristic of euchromatin, while
being flanked by TE-sequences that are packaged in
a heterochromatic fashion, with long-range order (Sun
et al., 2001). Moreover, heterochromatin proteins such
as HP1 can be required for heterochromatic gene expression (Lu et al., 1999). Future research on these
topics should provide a more complete picture of the
214
functional domains present in the heterochromatin of
Drosophila.
Acknowledgement
We wish to thank Nicolaj Junakovic for helpful comments and discussions.
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