February 12, 2001
Human Genome Analysis Hints at New Proteins Involved in Gene Expression
An early search of the draft human genome sequence has revealed
promising evidence that the completed genome will yield new proteins
involved in gene expression. The researchers who performed the analysis
found previously unknown genes that appear to encode proteins involved
in gene expression.
The researchers also found evidence that the human gene expression
machinery is more complex than that of lower animals. This discovery
suggests that the more sophisticated machinery for translating genetic
information "may be particularly important for shaping human
development and physiology," wrote the researchers.
“This search illustrates how the human genome sequence will provide many new factors that may be involved in gene expression, although their roles remain unknown.”
Michael R. Green
Howard Hughes Medical Institute investigator Michael R.
Green at the University of Massachusetts Medical School and
co-authors Rossella Tupler at the Universitá degli Studi di
Pavia and Giovanni Perini at the University of Bologna published their
analysis in the February 15, 2001, issue of the journal Nature.
The analysis is part of a collection of papers published by
Nature that discusses the implications of efforts to sequence
the human genome.
"The availability of the human genome and other genome sequences
will revolutionize all fields of biomedical research," wrote the
scientists. "But, as the genome itself is the object of gene
expression, the impact may be particularly profound for those of us
studying this process."
In an interview discussing the Nature article, Green added,
"in studying gene expression, as opposed to most other biological
processes it is the genome itself that is being explored. The genome
contains both the sequences of the players involved—the
proteins—and the sequences of all the signals that govern the
expression of the genes."
In their analyses, the scientists searched for genes governing three
steps in gene expression—the transcription of the gene into
messenger RNA (mRNA); the early splicing of mRNA to produce the final
molecule that will specify a protein; and the addition of the poly(A)
"tail" to one end of the mRNA that is necessary for its processing by
the protein machinery.
In searching the human genome for gene sequences that specify
general transcription factors (GTFs), and transcriptional activators,
the researchers found sequences for numerous genes that were similar to
those in yeast and the fruitfly Drosophila. However, they also
found many more human gene sequences than in the Drosophila
genome that appear to be related to a particular GTF, called TFIID,
"indicating that the potential diversity of human TFIID is much greater
than that of Drosophila."
In searching for transcriptional activators, the researchers found
more than 2,000 genes that could code for these proteins—far more
than they found in genome databases for Drosophila and the
roundworm C. elegans. "This search illustrates how the human
genome sequence will provide many new factors that may be involved in
gene expression, although their roles remain unknown," wrote the
scientists.
Similarly in a search for genes that encode proteins involved in
assembling the mRNA splicing machinery, the scientists found
"significantly greater complexity than is found in Drosophila."
And, in searching for genes that encode proteins involved in adding the
poly(A) tail to mRNA, the researchers unexpectedly found new genes,
which, again, suggests that humans have a more complex gene expression
machinery.
Green said, "in each case, the surprises are of the same type. When
we looked for genes for certain types of proteins that were homologs to
Drosophila, there was no reason to believe there would be more
than a single protein. But in fact, we found homologs that there was no
reason to suspect would be there."
The researchers pointed out, however, that "although these searches
highlight the power of the new genomic information, they also reveal
important limitations. In particular, the existence of a related gene
does not mean that there is a corresponding protein: the sequence could
be a non-expressed pseudogene."
Green explained that pseudogenes are "fossils" of real genes. "But
the genome hasn’t expressed them," he said. "It has kept them
there, but they don’t do anything.
"I suspect that many of these new genes are not pseudogenes. In some
cases we can find them in databases of expressed genes. And, they are
conserved to a higher degree than I would have predicted if they were
pseudogenes. If they were just not expressed, there would be no
evolutionary constraint to maintain sequence conservation."
The findings raise a number of intriguing questions that will take
time to sort out, says Green. "These findings are very interesting and
exciting, but, of course, now we really have to figure out what they
mean in the context of gene expression. Are these additional proteins
made during certain times of development? In certain cells? What are
they doing? What are their target genes? But we wouldn’t be in a
position to ask these questions if we didn’t know these
candidates existed."
Many of the new genes appear to express subunits of larger protein
complexes. Further study will be needed to understand how they are
involved in those complexes. "As with any discovery, it opens up a
whole series of new questions and approaches that we can explore,"
Green said.
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