Download icholas` DNA: Unraveling the mystery

icholas’
DNA:
Unraveling
the mystery
Chemical
bases
Thymine
Guanine
Adenine
Cytosine
DNA is
composed
of a pair of
chemical
chains
twisted into
a double
helix shape.
Each chain
is made
from
chemical
bases.
Time was running out for Nicholas Volker,
a young boy from Monona with a
devastating intestinal disease.
A group of doctors and researchers at
Children’s Hospital of Wisconsin and the
Medical College of Wisconsin spent
months searching individual genes
without success for an explanation for
a condition never seen before.
They decided to search all of his genes.
It's one of the first times in history that a
patient has had his genes sequenced for
diagnosis. But, with the latest DNA
sequencing technologies at hand,
researchers set out to explore Nicholas’
genetic code.
1
Extraordinary problem required extraordinary methods
The researchers started with two key assumptions: The mutation must disrupt an
important process and must not have been identified before. They also began by
searching the medical literature for any genes associated with any of Nicholas’
key symptoms. This gave them a preliminary list of more than 2,000 suspects.
Sequencing process
A. Getting DNA from Nicholas’ blood
m A research technician used detergents
and a centrifuge to break apart
Nicholas’ blood sample and isolatee
the white blood cells, the portion that
hat
contains DNA.
m The technician broke open the white
blood cells and removed proteins, fats and
sugars until all that remained was DNA.
B. Zooming in on the exons
m Scientists decided to examine Nicholas’
exons, the part of each gene that contains
the recipe for making proteins
m Scientists loaded Nicholas’ DNA onto a
special chip that attracts only his exons.
C. Putting machine to work
m The exons were attached to tiny beads
and spread over a sequencing plate
the size of a Post-it note. The plate was
then loaded into the sequencing machine.
m One by one the machine sent the four
chemical bases over the plate containing
Nicholas’ exons.
m A light flashed whenever a base
encountered its match in Nicholas’ exons.
Each base will
G
C connect only with
its complement
A
T
(adenine with
G thymine and
C
A
T guanine with
cytosine)
m A camera recorded the pattern of
flashes and a computer translated the
photos into Nicholas’ sequence.
D. Finding the answer
D
m Nicholas’ sequence contained 16,124
4
variations – sections in which his pattern
ern of
bases differed from the norm.
m Medical College researchers used a new
software tool they created to weed
out variations that could not have
triggered Nicholas’ disease.
m They homed in on eight suspects and
examined them in detail by searching
medical literature and gene functions.
m They discovered a newly published
paper linking the XIAP gene to
inflammatory bowel disease, which shares
some symptoms with Nicholas’ illness.
m An immune system specialist conducted
two tests to confirm that Nicholas’
mutation had disrupted the function of an
important protein.
Photos: GARY PORTER/
[email protected]
diagnosis. But, with the latest DNA
sequencing technologies at hand,
researchers set out to explore Nicholas’
genetic code.
2
mutation had disrupted the function of an
important protein.
Photos: GARY PORTER/
[email protected]
What researchers found deep within Nicholas’ DNA
Nucleus
The blueprint: How the
body stores its protein plans
Each cell’s nucleus
contains 46
chromosomes.
Twenty-three are
inherited from the
mother, 23 from the
father. Together,
they hold the body’s
DNA blueprint.
Pairs of DNA
strands are
intertwined into
shapes called a
double helix. They
are then coiled into
the well-known “X”
shapes associated
with chromosomes.
In the course of a
lifetime, the body‘s
DNA continually
produces proteins.
These proteins
initiate nearly every
process each cell
needs to carry out
its purpose.
Ribosomes
Cytoplasm
White blood cell
Chromosome
(Coiled DNA
strands)
Exon
(Segment that codes for
a particular protein)
T
T
A
On Nicholas’ X chromosome, the gene XIAP
contains a single mistake in the sequence.
Nicholas’ has thymine-adenine-thymine in a part of the sequence that should read thymine-guanine-thymine.
Copy and deliver: How the
blueprint is made into molds
Inside the nucleus,
RNA polymerase
and transcription
factors form a
transcription
molecule. Racing
along, the molecule
unzips the DNA
template (the gene it
needs to copy).
Chemical bases are
assembled in
complementary
order to the strand
being read. The
resulting ribbon
called mRNA
ventures outside the
nucleus and into the
cytoplasm.
The factory: How the
molds produce proteins
When the mRNA
reaches the cytoplasm,
ribosome will form
around it. As the mRNA
ratchets through the
ribosome, its chemical
bases are read in
codons, or sets of three.
2. If a match is made,
the amino acids are
released, 3. A protein
chain is formed.
If a mutation exists,
it gets translated as
well. Some mutations
don’t produce
noticeable effects. But If
1. The ribosome
a key gene has even one
receives proteinbuilding amino acids in base out of place,
ribosomes will generate
sets of three from
the wrong protein.
transfer molecules.
Transcription molecule
moves along the DNA
template
Messenger
RNA (mRNA))
TAT
Nucleotides
For Nicholas, that slight change in sequence (TAT instead of TGT) means that his blueprint
will call for the amino acid tyrosine instead of cysteine in a key position of the genome.
In Nicholas’ case, the single misplaced amino acid is now one of 497 that make up a key protein
that is supposed to keep his immune system from attacking his intestine in response to
bacteria. His immune system is at war with his intestine.
Amino acids
Protein chain
Ribosome
Transfer
molecules
Release
3
Match
1
2
Messenger RNA
Codon
with an answer, doctors must
Coming Sunday: Armed
decide how to treat Nicholas’ condition.
Source: Children’s Hospital of Wisconsin; Medical College of Wisconsin; DNA: The Secret of Life
LOU SALDIVAR/[email protected]