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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]