Some Diseases Caused by Changes in Genome

Although a defective gene might be the cause of some diseases, researchers are finding that some disorders result from abnormalities in the genome.

"The idea of a single gene being responsible for a particular disease, such as sickle-cell anemia, enabled scientists to discover how mutations in a gene can alter DNA," says Dr. James Lupski, professor of molecular and human genetics and pediatrics at Baylor College of Medicine.

"Advances of the Human Genome Project and completion of the total genome sequences for yeast and many species of bacteria have enabled us to understand some genetic diseases at the genomic level," he says.

The genome is the complete set of genetic instructions encoded on DNA that determines an organism's structure and function. The human genome consists of 3 billion chemical building blocks that form 100,000 genes.

Sometimes portions of the genome get rearranged. A segment of DNA might lack a gene or fragments of genes, or it might contain duplicate copies of a gene because of these rearrangements. Dr. Lupski says such structural changes have been linked to "genomic disorders."

For example, the red-green pigment gene on the X chromosome is repeated tandemly, or side by side. If a portion of the structure is deleted, colorblindness can occur. Hypertension has been associated with a rearrangement due to tandem repeats of genes also.

The blood disorder hemophilia can be due to a rearrangement that is caused by an inverted repeat in which one copy of a repeated gene is arranged within another gene.

Dr. Lupski compares the human genome to a 46-volume encyclopedia, with each chromosome representing a volume. Genes on the chromosomes represent a page or paragraph. "Traditionally, when we searched for a gene mutation that caused a disease, we looked for a missing word or sentence or a misspelled word," he says. "For genomic disorders, we need to be on the lookout for bunches of pages missing, because the whole genome or portions of the genome are altered."

Rather than concentrate on DNA sequence analysis that might reveal a small piece of a gene is missing, researchers now have the tools available to analyze the structure of large portions of the genome and see the "bigger picture," Dr. Lupski says.

"As the structure of the human genome is completed this summer and we analyze the sequence of DNA at greater depth, we might be able to predict which portions of the genome are more susceptible to rearrangements that can lead to genomic disorders," he says. "This should also lead to a more rapid understanding of the genetic basis of certain disease traits."

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©2006 Texas Medical Center

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