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09/29/2004

Junk It Ain't

Every so often, I get an urge to try to understand genes and
DNA. That urge struck last in March of 2003 (see columns of
3/20 and 3/27/2003 in the archives). The death of Francis Crick,
an article by John S. Mattick in the October issue of Scientific
American and a visit to the Department of Energy’s Human
Genome Project Web site stirred me to try once again.

Sixty years ago, Oswald Avery, Collin MacLeod and Maclyn
McCarthy published work in which they took some stuff from a
smooth-surfaced bacterium and put it into a rough-surfaced
bacterium. The result was a smooth surface. The stuff was
DNA. In 1953, Crick and James Watson proposed that DNA’s
structure was a double helix. That and the knowledge that the
four chemical bases adenine, cytosine, guanine and thymine (A,
C, G and T) form A-T and C-G bonds, the “base pairs” that are
the rungs between the two DNA ribbons in the helix ladder,
revealed the basic coding of life and how it propagates.

The next step was decoding the genome, the complete set of
DNA in an organism. The single-cell bacterium has the smallest
genome, about 600 thousand base pairs. Our human genome has
about 3 billion base pairs. The recent decoding of the human
genome is a tremendous achievement but, by itself, it’s like
having a dictionary of 3 billion letters all strung out without any
punctuation, spacing or grouping of the letters into words. Genes
are like words in that they are groupings of the A, C, G, T bases
with special meanings - they code for the proteins used in
constructing our bodies and in enzymes and the like that carry
out bodily functions.

Being such complex animals, it was expected that our genome
would contain lots of genes; estimates ranged from 80 to 140
thousand genes. It’s been a shock to find only about 25 or 30
thousand genes, give or take a few thousand. Why is it so
shocking? Our bodies are composed of trillions, maybe a
hundred trillion cells. The body of C. elegans, a much-studied
tiny nematode worm, has less than a thousand cells. Its genome
has 19 thousand genes. We have billions of times the number of
cells but don’t even have twice the number of genes. How can
we possibly be so much more complex than a microscopic worm
with so few additional genes?

Mattick’s Scientific American article, titled “The Hidden Genetic
Code of Complex Organisms”, makes it clear that genes are not
the only important “words” in the DNA string of 3 billion
“letters”. Mattick, former director of the Australian Genome
Research Facility, points out that the prevailing view has been
one based primarily on studies of single-cell bacteria. In this
“traditional” view, genes code for proteins. The proteins play
not only their roles in the organism’s structure and functioning
but also regulate when and how genes are “expressed”, that is,
when the gene is activated to initiate the process of forming a
protein.

Let’s see what a gene looks like. You might think that a gene is
just a …CTTAGCGGG… sequence in DNA lined up in the code
for a given protein. Not so, at least in more complicated
organisms. A gene is composed of “exons”, stretches of DNA
that code for segments of the protein, not the whole protein.
These exons are separated by “introns”, stretches of DNA that do
not code for proteins. The size of a gene varies greatly,
averaging around 3,000 bases, but one particular human gene
weighs in at more than 2 million bases!

The “traditional” view of the expression of a gene involves a
number of steps. The gene is first transcribed in what can be
termed a “primary” RNA transcript that carries the coding of the
exons and the introns. (RNA, like DNA, is a class of chemical
compounds known as nucleic acids.) Next comes a splicing
operation, in which the introns are spliced out of the primary
transcript, leaving the exons lined up in an “exonic” RNA known
as “messenger RNA” (mRNA). With the exons, each coding for
a segment, or building block of a protein, the mRNA can pass on
the complete formula to a ribosome, which then handles the
manufacture of the protein in the cell. What happens to all the
introns? They form “intronic” RNA and, not coding for proteins,
get broken down and recycled.

That’s the traditional view and it works pretty well for bacteria.
A few bacterial genes code for RNAs that perform regulatory
jobs but, except for them and the mRNAs, the other RNAs are
consigned to the recycling bin. But how can something as
complicated as us can be constructed with a paltry 25 or 30
thousand genes? Mattick likens the process to the building of a
house.

To build a house, what needs to be specified? You need two
things: (1) a list of materials and (2) an architectural plan to tell
you how to put the bricks, boards, screws, nails, etc. together.
Those 3 billion base pairs in our DNA somehow contain both the
materials list and the blueprints for putting the materials
together! If the protein-coding genes specify the materials, the
proteins, what contains the blueprint for putting the proteins
together?

If the blueprint isn’t in the protein-coding genes, it must be in the
non-coding DNA, right? Let’s follow up on that idea. If the
blueprint is in the non-coding, so-called junk DNA, what does
that say to us? Let’s go back to our single-celled bacterium. It
shouldn’t take much “junk” DNA to make a blueprint for its
construction. On the other hand, without being conceited, it
should take a lot more “junk” to lay out the construction plans
for you and me.

So, let’s compare the amounts of “non-coding for protein” DNA
in our genome with that in the genomes of single-celled bacteria
and other so-called “prokaryotes”, organisms whose cells have
no nucleus. Our human genome is almost all non-coding DNA,
over 98 percent. In contrast, only about 5 to 30 percent of the
DNA is non-coding in the genomes of bacteria and other
prokaryotes. Bringing in other organisms, there is a smooth
increase in the percentage of non-coding “junk” DNA as you go
up in complexity of the organism from the prokaryotes to
humans. This correlation of the amount of “junk” DNA with the
complexity of the organism is good evidence that, far from being
junk, this non-coding DNA is critical in the production and
assembly of proteins to form a complex organism.

What is today’s view of gene expression? The first transcript
and splicing are the same as in the traditional view, resulting in
the formation of “exonic” and “intronic” RNA. As in the
traditional view, a portion of the exonic RNA becomes
messenger RNA and a portion of the intronic RNA gets recycled.
But not all of the exonic and intronic RNA share these fates.
Some of each are processed into so-called “microRNAs”. The
importance and identities of these microRNAs and their
functions are only recently beginning to become clear.

Some microRNAs are thought to go back to the DNA and to
perform regulatory functions. For example, a microRNA might
tag a certain part of the DNA by attaching to it or causing
another chemical group of some sort to be attached. This tagging
might turn off the gene or it might affect the transcribing and
splicing process, causing the gene to express a different form of
protein. This expression of more than one type of protein from a
single gene has been observed and is known as alternative
splicing.

So far, hundreds of microRNAs have been found in plants,
animals and fungi. They have been shown to participate in
controlling timing of various processes such as the number of
cells formed, the programmed death of cells (apoptosis) and the
maintenance of stem cells.

When the human genome was first decoded, it was stressed that
future progress would depend on finding all the proteins coded
by the genes and what these proteins do in the body. Now we
find that proteins are only part of the answer. Most of our DNA
no longer seems to be “junk”, but gives rise to those microRNAs.
It’s said that one person’s junk is another person’s treasure. Our
genome is loaded with treasures and we may need the scientific
equivalent of the Antiques Road Show to determine their full
worth.

Allen F. Bortrum



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-09/29/2004-      
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Dr. Bortrum

09/29/2004

Junk It Ain't

Every so often, I get an urge to try to understand genes and
DNA. That urge struck last in March of 2003 (see columns of
3/20 and 3/27/2003 in the archives). The death of Francis Crick,
an article by John S. Mattick in the October issue of Scientific
American and a visit to the Department of Energy’s Human
Genome Project Web site stirred me to try once again.

Sixty years ago, Oswald Avery, Collin MacLeod and Maclyn
McCarthy published work in which they took some stuff from a
smooth-surfaced bacterium and put it into a rough-surfaced
bacterium. The result was a smooth surface. The stuff was
DNA. In 1953, Crick and James Watson proposed that DNA’s
structure was a double helix. That and the knowledge that the
four chemical bases adenine, cytosine, guanine and thymine (A,
C, G and T) form A-T and C-G bonds, the “base pairs” that are
the rungs between the two DNA ribbons in the helix ladder,
revealed the basic coding of life and how it propagates.

The next step was decoding the genome, the complete set of
DNA in an organism. The single-cell bacterium has the smallest
genome, about 600 thousand base pairs. Our human genome has
about 3 billion base pairs. The recent decoding of the human
genome is a tremendous achievement but, by itself, it’s like
having a dictionary of 3 billion letters all strung out without any
punctuation, spacing or grouping of the letters into words. Genes
are like words in that they are groupings of the A, C, G, T bases
with special meanings - they code for the proteins used in
constructing our bodies and in enzymes and the like that carry
out bodily functions.

Being such complex animals, it was expected that our genome
would contain lots of genes; estimates ranged from 80 to 140
thousand genes. It’s been a shock to find only about 25 or 30
thousand genes, give or take a few thousand. Why is it so
shocking? Our bodies are composed of trillions, maybe a
hundred trillion cells. The body of C. elegans, a much-studied
tiny nematode worm, has less than a thousand cells. Its genome
has 19 thousand genes. We have billions of times the number of
cells but don’t even have twice the number of genes. How can
we possibly be so much more complex than a microscopic worm
with so few additional genes?

Mattick’s Scientific American article, titled “The Hidden Genetic
Code of Complex Organisms”, makes it clear that genes are not
the only important “words” in the DNA string of 3 billion
“letters”. Mattick, former director of the Australian Genome
Research Facility, points out that the prevailing view has been
one based primarily on studies of single-cell bacteria. In this
“traditional” view, genes code for proteins. The proteins play
not only their roles in the organism’s structure and functioning
but also regulate when and how genes are “expressed”, that is,
when the gene is activated to initiate the process of forming a
protein.

Let’s see what a gene looks like. You might think that a gene is
just a …CTTAGCGGG… sequence in DNA lined up in the code
for a given protein. Not so, at least in more complicated
organisms. A gene is composed of “exons”, stretches of DNA
that code for segments of the protein, not the whole protein.
These exons are separated by “introns”, stretches of DNA that do
not code for proteins. The size of a gene varies greatly,
averaging around 3,000 bases, but one particular human gene
weighs in at more than 2 million bases!

The “traditional” view of the expression of a gene involves a
number of steps. The gene is first transcribed in what can be
termed a “primary” RNA transcript that carries the coding of the
exons and the introns. (RNA, like DNA, is a class of chemical
compounds known as nucleic acids.) Next comes a splicing
operation, in which the introns are spliced out of the primary
transcript, leaving the exons lined up in an “exonic” RNA known
as “messenger RNA” (mRNA). With the exons, each coding for
a segment, or building block of a protein, the mRNA can pass on
the complete formula to a ribosome, which then handles the
manufacture of the protein in the cell. What happens to all the
introns? They form “intronic” RNA and, not coding for proteins,
get broken down and recycled.

That’s the traditional view and it works pretty well for bacteria.
A few bacterial genes code for RNAs that perform regulatory
jobs but, except for them and the mRNAs, the other RNAs are
consigned to the recycling bin. But how can something as
complicated as us can be constructed with a paltry 25 or 30
thousand genes? Mattick likens the process to the building of a
house.

To build a house, what needs to be specified? You need two
things: (1) a list of materials and (2) an architectural plan to tell
you how to put the bricks, boards, screws, nails, etc. together.
Those 3 billion base pairs in our DNA somehow contain both the
materials list and the blueprints for putting the materials
together! If the protein-coding genes specify the materials, the
proteins, what contains the blueprint for putting the proteins
together?

If the blueprint isn’t in the protein-coding genes, it must be in the
non-coding DNA, right? Let’s follow up on that idea. If the
blueprint is in the non-coding, so-called junk DNA, what does
that say to us? Let’s go back to our single-celled bacterium. It
shouldn’t take much “junk” DNA to make a blueprint for its
construction. On the other hand, without being conceited, it
should take a lot more “junk” to lay out the construction plans
for you and me.

So, let’s compare the amounts of “non-coding for protein” DNA
in our genome with that in the genomes of single-celled bacteria
and other so-called “prokaryotes”, organisms whose cells have
no nucleus. Our human genome is almost all non-coding DNA,
over 98 percent. In contrast, only about 5 to 30 percent of the
DNA is non-coding in the genomes of bacteria and other
prokaryotes. Bringing in other organisms, there is a smooth
increase in the percentage of non-coding “junk” DNA as you go
up in complexity of the organism from the prokaryotes to
humans. This correlation of the amount of “junk” DNA with the
complexity of the organism is good evidence that, far from being
junk, this non-coding DNA is critical in the production and
assembly of proteins to form a complex organism.

What is today’s view of gene expression? The first transcript
and splicing are the same as in the traditional view, resulting in
the formation of “exonic” and “intronic” RNA. As in the
traditional view, a portion of the exonic RNA becomes
messenger RNA and a portion of the intronic RNA gets recycled.
But not all of the exonic and intronic RNA share these fates.
Some of each are processed into so-called “microRNAs”. The
importance and identities of these microRNAs and their
functions are only recently beginning to become clear.

Some microRNAs are thought to go back to the DNA and to
perform regulatory functions. For example, a microRNA might
tag a certain part of the DNA by attaching to it or causing
another chemical group of some sort to be attached. This tagging
might turn off the gene or it might affect the transcribing and
splicing process, causing the gene to express a different form of
protein. This expression of more than one type of protein from a
single gene has been observed and is known as alternative
splicing.

So far, hundreds of microRNAs have been found in plants,
animals and fungi. They have been shown to participate in
controlling timing of various processes such as the number of
cells formed, the programmed death of cells (apoptosis) and the
maintenance of stem cells.

When the human genome was first decoded, it was stressed that
future progress would depend on finding all the proteins coded
by the genes and what these proteins do in the body. Now we
find that proteins are only part of the answer. Most of our DNA
no longer seems to be “junk”, but gives rise to those microRNAs.
It’s said that one person’s junk is another person’s treasure. Our
genome is loaded with treasures and we may need the scientific
equivalent of the Antiques Road Show to determine their full
worth.

Allen F. Bortrum