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Cutting away DNA the mitochondrial way.

Cutting away DNA the mitochondrial way

When British researchers last year showed that a deletion of DNA within the mitochondria of cells caused a series of related muscle ailments, they revealed a new type of disease-causing genetic defect. Now a team at Emory University in Atlanta suggests it has unraveled the basic mechanism causing the loss of mitochondrial DNA.

"We think we understand how the deletions occur, that the deletions are a direct result of the normal replication process and that the deletion process can occur anytime during [fetal] development," team leader Douglas C. Wallace reported last week at the annual Short Course in Medical and Experimental Mammalian Genetics in Bar Harbor, Maine. "This is a very interesting class of mutation. They are spontaneous mutations; they are not inherited."

Mitochondria serve as power plants inside cells, producing adenosine triphosphate, the key fuel used by cells. A human cell contains 300 to 600 mitochondria, each harboring four to 10 double-stranded circular bits of DNA that hold a few dozen genes. These genes are distinct, and replicate separately, from those packed on the rod-like chromosomes inside the cell nucleus.

Mitochondrial genes reside on two concentric circles of dna called the heavy and light strands. During DNA replication, these strands separate, and each becomes a template upon which a new, identical strand is made. Wallace and his colleagues have identified a series of direct repeats - short segments of DNA with identical sequences of the nucleotides that make up DNA. They propose that during replication of a DNA strand, one repeat can mistakenly join to an identical repeat site further along the strand, creating a loop that breaks off.

"Our model is that during this period when a single-strand region is bowed out, you could have base pairing between this upstream repeat and this downstream repeat to give you [a loop]," Wallace explains. The shortened DNA piece then serves as a template for DNA replication, and all subsequent copies of the strand will lack any sequences lost when the loop broke off.

The process is vaguely analogous to a loop in a river that gets eliminated when the river eats through the land within the loop, shortening the river's course. In mitochondrial DNA, however, the lost loop contains information vital to cell functioning. Because the rate of DNa replication is proportional to its length, the mitochondrion produces the shorter, defective DNA faster. Thus an increasing percentage of mutan mitochondrial DNA gets passed on to descendants of the original defective cell. Eventually, the percentage becomes so gret that the cell canno function properly.

"What's amazing is that depending on when [in fetal development] a deletion occurs, different organ systems are involved," Wallace says. "If you have the deletion very, very early, then all cells will have the deletion and all cells will be affected. But if the mutation occurs very, very late, just at the end of development, then just the cells to be derived from that [mutated cell] will have the deletion."

Several groups have found that the same mitochondrial DNA deletion can cause a variety of ailments, depending on the fetal stage at which the mutation occurs. Wallace's group recently discovered that a specific deletion can cause a wide range of eye problems, from optthalmoplegia (a loss of eye movement in the socket) to Kearns-Sayres syndrome, which includes ophthalmoplegia, night blindness, uncoordinated gait, deafness and abnormal heart rhythm.
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Author:Young, P.
Publication:Science News
Date:Aug 5, 1989
Words:565
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