Werner Syndrome Essay Research Paper AbstractNowadays those — страница 2

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cancer or rare tumors. From this, it can be concluded that the Werner syndrome gene is not only an aging gene, but also a cancer gene. Schellenberg says he began looking for the Werner syndrome gene in 1992. At that point, Makoto Goto from Tokyo Metropolitan Otsuka Hospital and his colleagues had already shown that the gene is located on the short arm of chromosome 8 by genetic linkage studies-comparing the inheritance of the disease with that of markers at known locations on the chromosomes. To continue the hunt, scientists began by doing further genetic studies aimed at narrowing down the gene’s location. He then wanted to sequence DNA from the suspect region and scan the sequence to find likely genes. “My philosophy was to bring all the different gene identification

technologies to bear [on this problem],” he recalls. Other groups were also searching for the gene and a remarkable spirit of cooperation between competing groups aided the hunt. A team of American scientists and that of rival gene-hunter Tetsuro Miki of Osaka University Medical School shared tissue samples from affected families in order to improve each other’s chances of pinning down the gene’s location. Schellenberg credits the additional families and subjects with helping his team to narrow the search to a section of chromosome encompassing just a million bases-still a lot of DNA, but manageable for the detailed sequencing effort that followed. This began in early 1995, when Chang-En Yu and Junko Oshima from Schellenberg’s lab in Seattle teamed up with sequencing

expert Ying-Hui Fu from Darwin Molecular Corp., also in Seattle. Each time the researchers came across a gene in the DNA they were sequencing, they looked to see whether people with Werner syndrome, had mutations there. Finally, after sequencing 650,000 bases-possibly the most DNA ever sequenced in a gene hunt-and identifying four known genes and six new ones, whose sequences did not appear in the databases, the scientists found the one they were looking for. To date, Schellenberg’s group has found four different mutations disrupting this gene in Werner syndrome patients. Four mutations in Werner syndrome patients were detected in the gene corresponding to chromosome eight. Two mutations were nonsense mutations creating premature stop codons. Four Japanese Werner syndrome

patients, the offspring of first cousin marriages, and one Caucasian, from a second cousin marriage were homozygous for the mutation. The second mutation was found in one Japanese patient who is the offspring of a first cousin marriage and homozygous for the mutation. These mutations were not observed in 48 Caucasian or 96 Japanese control individuals. The third mutation, identified in a Syrian family, is a splice-junction mutation. This would result in the exclusion of the exons from the final mRNA. The exon is the DNA segment or segments of the gene that are transcribed and translated by the donor cell. The fourth mutation identified was similar to this exhibiting a missing exon and flanking genomic segments which results in a frame shift of codons. This Werner syndrome patient

is the offspring of a first cousin marriage and is homozygous for this mutation. As you can see from this evidence, the mode of inheritance appears to be from inbred marriages. Werner syndrome is a recessive disease, meaning symptoms will not occur unless both copies of the gene are mutated and present. A case study was conducted on twenty-one Japanese families. Of those, thirteen had marriages between the first cousins and two other families were suspected of the same. Eleven of the families consisted of a single generation, nine had two generations, and one had three generations. From these twenty-one families, seven of them had several offspring affected by Werner syndrome. In addition, from the sixty-three individuals that were studied, thirty-one of them were affected by the

syndrome. One of the 144 healthy people who served as controls also had one of these mutations, but in only one of the two copies of the gene. (Because Werner syndrome is a disease, symptoms do not develop unless both gene copies are mutated.) “We had started wondering where it was, but then it showed up and it was absolutely clear,” says molecular biologist David Galas of Darwin Corp. “I think it’s the first human gene that’s been identified by large-scale sequencing like this, but I think this [approach] is going to become more and more commonplace.” Meanwhile, Miki had also been closing in on the gene, but was still not there when Schellenberg let him know the search was over. The sequence of the Werner syndrome gene, which encodes a protein containing 1432 amino