Archive for December, 2007
Green tea may protect brain cells against Parkinson’s - Xinhua
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Green tea may help prevent advanced prostate cancer - Toronto Star
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Copy number variation may stem from replication misstep
HOUSTON -- (December 28, 2007) -- Genome rearrangements, resulting in variations in the numbers of copies of genes, occur when the cellular process that copies DNA during cell division stalls and then switches to a different genetic "template," said researchers at Baylor College of Medicine in Houston in a report that appears today in the journal Cell.
The new mechanism is called replication "Fork Stalling and Template Switching," said Dr. James R. Lupski, Cullen professor of molecular and human genetics and vice chair of the department at BCM. He is also professor of pediatrics. It not only represents a new way in which the genome generates DNA copy number variation, but it also demonstrates that copy number variation can occur at a different time point in the life of a cell. DNA replication takes place as the cell is dividing and becoming two.
Copy number variation involves structural changes in the human genome that result in the deletion or extra copies of genes (or parts of them). Often, this process is associated with disease, and also with evolution of the genome itself.
DNA (deoxyribonucleic acid) exists as two complementary strands that remain together because of the attraction between nucleotides. A or adenosine is always attracted to T (thymidine). C or cytosine is always attracted to G or guanine.
When a cell divides, it must reproduce its DNA so that each cell that results from the division has the same genetic code. That means it must replicate its DNA. During this process, an enzyme called a helicase separates the two strands, breaking the hydrogen bonds between the A – T and G – C base pairs holding the strands together. The two separating strands become the replication fork. On one strand, an enzyme called DNA polymerase reads the genetic material in the strand as a template and makes a strand (leading strand) of complementary DNA to pair to it. Again, the code is A to T and C to G. This process is continuous. On the other strand that comprises the fork, the complementary strand (lagging strand) is made in short, separated segments by a process that involves RNA and a series of enzymes.
Until the 1990s, researchers studying reasons for genetic mutations or changes looked at molecular "typos" in this process, tiny changes in the As, Ts, Cs or Gs called single nucleotide polymorphisms (SNPs). These SNPs changed the message of the gene. However, in the early 1990s, Lupski was one of the pioneers to elucidate a new mechanism in which the structure of the DNA itself was grossly duplicated or deleted, which changed numbers of copies of a gene that occurred in this genetic material. This "copy number variation" wrote a new chapter in the understanding of genetic variation.
Lupski and former graduate student Dr. Jennifer Lee (now a postdoctoral fellow at BCM) found in their experiments that this process stalls when there is a problem with the DNA. In that case, the process switches to a different template, copying another similar but significantly different stretch of DNA, before it switches back to the appropriate area. Dr. Claudia M. B. Carvalho, also of BCM, took part in this research.
Previously, Lupski and colleagues had identified two different ways in which recombinations of genetic material resulted in copy number variation. However, when Lee was studying an inherited disease called Pelizaeus-Merzbacher disease, she found changes in the genome that the previous theories about DNA recombination did not explain.
Structural changes in the genome in people with the disease, a neurodevelopmental disorder, vary from person to person. In some places, genetic material that was duplicated was similar to that nearby but it was thrust into the middle of another duplication of material. The question was how they got there, Lee said.
The fork stalling, template switching mechanism explained the oddities, said Lupski.
"It stalls and rather than restart at the position where it is, it switches to a different template," said Lupski. Usually this occurs in an area of the genome where there are many repeats of the nucleotides that form an unusual structure. This can actually aid in the template switching, he said.
"One could envision that it could happen anywhere in the genome and would be a way to make copy number changes in any gene you want," he said. It might even play a role in evolution, allowing organisms to change. Some of the changes might make it easier for that organism to live in particular environment or survive in a stressed situation.
Funding for this research came from the Charcot Marie Tooth Association, the National Institute of Child Health and Development and the Baylor College of Medicine Mental Retardation and Developmental Disabilities Research Center.
Green tea may protect brain cells against Parkinson’s - Xinhua
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Similarities between genetic diseases create hope for treatment
HOUSTON -- (December 27, 2007) -- Two rare neurodegenerative diseases -- Huntington's disease and spinocerebellar ataxia 1 – share genetic modifiers in the cellular pathways that cause nerve cell damage, a fact that may make studying them and developing treatments more attractive to biotech companies, said a Baylor College of Medicine researcher.
A report on the research led by Dr. Juan Botas, associate professor of molecular and human genetics at BCM, appears in the current issue of the journal Human Molecular Genetics.
"We found commonalities in the diseases," he said. "These diseases are not like Alzheimer's disease or Parkinson's, which affect many patients. Often these rarer diseases get less attention in the media or from pharmaceutical companies, but they are no less devastating."
Symptoms of both these diseases show up in adulthood. They are both polyglutamine disorders. Expansion of DNA repeats encoding glutamine within the genes for each disease – ataxin-1 for the ataxia and huntingtin for Huntington's – spell disaster for how the protein is used by the cell. While studies indicate that the repeats interfere with the proper folding of the proteins encoded by the genes, other research indicates that other factors specific to each disease are involved.
When Botas and his colleagues compared the two diseases in models in Drosophila, or fruit flies, they found that some genes that modify the neuronal toxicity of ataxin-1 and huntingtin function similarly in both insect models of the diseases. In contrast, others have opposite effects, suppressing toxicity in one case and enhancing it in another.
Some of the genes that they found affect RNA (ribonucleic acid) metabolism, or its production, modulating the toxic effect of the proteins ataxin and huntingtin on nerve cells.
The genes that have opposite effects on the neuronal toxicity of ataxin-1 and huntingtin might help identify differences in how the two proteins affect nerve cells negatively, he said.
The modifier genes ameliorating the neuronal toxicity of both ataxin-1 and huntingtin, and their corresponding cellular pathways, might point to targets for drugs in both diseases, said Botas.
Others who took part in this research include Joana Branco, Ismael Al-Ramahi, Lubna Ukani, Alma M. Perez, Pedro Fernandez-Funez and Diego Rincón-Lima, all of BCM. Funding for this work came from the National Institutes of Health and the Portuguese Foundation for Science and Technology.
This paper is available at http://hmg.oxfordjournals.org/cgi/reprint/ddm315v1