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Proteins are
Better Biomarkers
than Genes
T
he costs of sequencing the order of nucleotide bases
in the DNA strands found in chromosomes have
plummeted by a million-fold over the last 25 years.
The entire sequence of 2.9 billion nucleotide base-pairs in a
single human genome can now be determined for less than
$1000. Complete genomes of hundreds of thousands of
people are expected to be sequenced over the next decade.
While the acquisition of such genomic knowledge was
originally forecasted to herald better diagnostics and
therapeutic treatments, the actual deliverables for improved
health care have been disappointing. Excluding cancer, it
has become apparent that only about 10% of the cases of
the most common diseases that afflict our population have a
genetic basis that can be ascribed to hereditary mutations in
the DNA sequences of specific genes.
Over 100 million single nucleotide variants appear to exist
in the human population, and perfectly healthy people
appear to commonly harbour about 100 or so serious
disease-associated mutations without any apparent
manifestations of these particular diseases. Studies, with
over 50,000 genetically identical twins, have shown no
increased risks for the 24 most common diseases amongst
the twins than for a twin with the general population.
Over 95% of the known 21,300 genes carried in the human
genome serve as the blue-prints for the construction of all
of the cellular proteins, known as the proteome. These
proteins function like molecular robots to regulate and carry
out all of the biochemical reactions needed to keep cells
alive. Their programming for specific tasks is partly
hardwired into the structures of these proteins as dictated by
their gene sequences. But, they are also tightly controlled
by reversible modifications after they are initially
manufactured, which are added on by regulatory proteins
that operate within cellular intelligence systems.
While gene sequences can provide some clues as to the
potential functions and interactions of proteins with each
other and other molecules, this information is extremely
limited. Even now, we do not have a real sense of what over
a third of these diverse proteins do, and less than 20% of
these proteins have received any real serious attention in
research labs.
The disconnect between genetic information and the actual
occurrence of disease is due to the high impact of
environmental factors such as diet, life style and exposure
to agents in the environment that can affect the proteome.
Proteomes are immensely complex and dynamic. For
example, blood plasma may contain as many as 40,000
different protein products, and their individual
concentrations can range over a trillion-fold. Consequently,
tracking proteins offers much better insights into the
occurrence of diseases than genetic profiling, and
importantly the opportunity for more rational therapeutic
intervention.
While about 21,300 genes encode proteins in the human
genome, the actual number of distinct protein entities in the
proteome may actually exceed several million, largely due
to the range and degree of added modifications and other
processing. More than 50 types of modifications have been
|November 2018 | 18