August 10, 2001
A Closer Look at the Genome’s ‘Black Holes’
The centromeres of chromosomes — considered by some to be the
genomic equivalent of black holes — may hold the answers to many
scientific questions, according Howard Hughes Medical Institute
investigator Steven
Henikoff. For example, studies of the centromere may help in
understanding the paradox that while centromeric DNA is evolving with
extraordinary rapidity, it is still stable enough to perform its job
during cell division.
In a review article published in the August 10, 2001, issue of the
journal Science, Henikoff and colleagues Kami Ahmad and Harmit
S. Malik at the Fred Hutchinson Cancer Research Center theorize that
the rapid evolution of centromeric DNA may provide a mechanism by which
newly evolving species rapidly become genetically incompatible with one
another.
“Current methodology really doesn’t allow the sequencing of centromeric DNA. Thus, nobody has sequenced the centromeres of the human genome, the fly genome, or that of any other complex organism. They remain big black holes often millions of bases in length in every chromosome.”
Steven Henikoff
Each chromosome possesses a centromere, which is the site at which
sister chromatids are held together. During mitosis and meiosis, the
chromatid pair separates, and the centromere is the point of attachment
of spindle fibers that pull each chromosome to opposite poles of the
dividing cell. "While the centromere is a locus on the chromosome, it
is different than a gene, because it is a locus that is acted upon by
the apparatus of cell division," said Henikoff.
And unlike genes, which are amenable to mapping and sequencing,
probing the genetic makeup of the centromere has proved to be a dead
end because of the centromere’s unusual structure. "The
centromere has remained enigmatic ever since it was discovered that
centromeric DNA is highly repetitive," said Henikoff. "Current
methodology really doesn’t allow the sequencing of centromeric
DNA. Thus, nobody has sequenced the centromeres of the human genome,
the fly genome, or that of any other complex organism. They remain big
black holes often millions of bases in length in every chromosome."
The wide variability of centromeric DNA across different species has
led some researchers to dismiss its importance. According to Henikoff,
the centromere shouldn’t be dismissed so casually. “Some
believe that centromeric DNA sequence is not all that important,
because it is not conserved in evolution," said Henikoff. "That lack of
conservation has led to the centromere paradox where stable inheritance
occurs despite rapidly evolving DNA. Normally, the elements of the
mitotic segregation machinery would be expected to be highly conserved,
as are other essential cellular machines, such as ribosomes. But the
central question with centromeric DNA is why it hasn't found some
optimal sequence and just stayed there.”
A key to stable centromere inheritance might be found in the
proteins called histones, with which all DNA in the nucleus must
associate in order for it to form beadlike structures called
nucleosomes that bind DNA into compact packages. In the Science
article, Henikoff and his colleagues suggest that the uniqueness of the
centromeric histone H3 may teach researchers some interesting lessons
about evolution.
"While histones are crucial, they are thought to be boring, because
they are so highly conserved," said Henikoff. "Because the histones
must interact reliably with the entire genome, there are few amino acid
differences in these proteins between plants and animals." Centromeric
histones, however, have evolved to be profoundly different among
organisms.
"The idea that we explore in the Science review is that the
centromeric histone and centromeric DNA are evolving rapidly, but in
step, since the histone must interact with the centromeric DNA,”
said Henikoff.
Analysis of centromeric histones has revealed that they seem to be
adapting constantly to the changing centromeric DNA. These evolutionary
changes are occurring in parts of the histone that interact with DNA,
Henikoff says, "so that tells us that it's the interaction with the DNA
that's driving the evolution of the protein.”
Henikoff and his colleagues theorize that this continuous evolution
is being driven by a sort of competition among centromeric DNA that
occurs during meiosis in the egg. Three of the four products of meiosis
are discarded, and only one survives to become the oocyte nucleus. The
"winning" centromeres are those whose chromosomes may show even a
slight advantage in orienting themselves during meiosis, said
Henikoff.
"What's important about this competitive process among centromeres
is that it can result in fixation of winning centromeres. This process
can be deleterious to the host genome, and so centromeric histones
would evolve to restore parity between competing centromeres,”
Henikoff said. Bringing together incompatible centromeres and histones
in hybrids would lead to their sterility or inviability. "Understanding
the basis of the sterility of cross-species breeding has been a huge
problem in evolution ever since Darwin," he said. "The rapidly evolving
centromeric DNA and histones and their incompatibility with their
counterparts in another species might account for this phenomenon. We
can test these ideas by analyzing the centromeric histones in emerging
species.”
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