Copy number variation may stem from replication misstep

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Copy number variation may stem from replication misstep

http://www.eurekalert.org/pub_releases/2007-12/bcom-cnv122607.php

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. 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 his former graduate student Dr. 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. 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.