Variety In The Splice Of Life: Chromosome Breaks Are Surprisingly Complex

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Variety In The Splice Of Life: Chromosome Breaks Are Surprisingly

Complex

http://www.medicalnewstoday.com/articles/120674.php

When chromosomes break, trouble usually ensues; chromosome

abnormalities are the single biggest cause of birth defects in

humans. But a new study of translocations, in which two chromosomes

swap segments of DNA, shows that the chromosomes can splice the

pieces together in a variety of ways with no ill effects. The study

sheds light on how and where chromosome breaks occur in

translocations, and how translocated segments of DNA are joined to

their new chromosome.

Marzena Gajecka, research assistant professor at Washington State

University Spokane and lead author on the study, said the most

significant finding was how variable the sequences around the break

points and in the junctions were, in people who had no translocation-

related symptoms.

" We assumed that phenotypically normal individuals would have

balanced translocations, " she said. In a balanced translocation, DNA

segments are swapped between chromosomes but no sequences are lost

from or added to the chromosomes involved in the swap. Such

translocations are referred to as " balanced " because, although the

genome has been rearranged, all the necessary coding sequences are

still present in the right number of copies.

In unbalanced translocations, one or both of the chromosomes involved

ends up with a stretch of DNA that doesn't have a matching segment on

another chromosome. Unbalanced translocations cause observable

problems in the people who carry them. Discovering that many

individuals with a balanced translocation actually have short

sequences that don't match anything else in the genome was a surprise.

The research team included Gajecka, three other scientists from WSU

Spokane and colleagues at Mount Sinai Hospital in Toronto, Stanford

University and the University of Southern California. Their

paper, " Unexpected complexity at breakpoint junctions in

phenotypically normal individuals and mechanisms involved in

generating balanced translocations t(1;22)(p36;q13) " will appear in

the October issue of the journal Genome Research; the abstract can be

read online at

http://genome.cshlp.org/cgi/content/abstract/gr.077453.108v1?papetoc.

The researchers started with DNA from 143 children who were missing

part of chromosome 1 and had symptoms including mental retardation

and developmental delay. In four of the children the chromosome

abnormality was traced to a parent who was phenotypically normal that

is, who had normal development and behavior but who carried a

translocation in which a segment of chromosome 1 and a segment of

chromosome 22 had switched places.

Translocations are fairly common about one in 500 people have one and

as long as they don't disrupt needed genes or involve extra or

missing segments of DNA, the people who carry them show no signs of

an abnormality.

However, problems may arise when a person with a balanced

translocation has children. Our cells have two copies of every

chromosome. A translocation involves one copy from each of two pairs

of chromosomes; the other copy of each pair remains normal. As long

as the copies that swapped stretches of DNA end up in the same egg or

sperm cell, the child will be fine. He or she has all the necessary

DNA, it is just rearranged. But if the chromosomes involved in an

exchange get distributed into different cells during the production

of eggs or sperm, the child could end up with extra or missing

segments.

" If kids are unlucky, they get just one chromosome with a

translocated segment, " said Gajecka. " It would look like a deletion. "

That's what happened with the children at the beginning of this

study, who had inherited the copy of chromosome 1 that carried a

chunk of chromosome 22, but did not get the corresponding copy of 22

that had the swapped segment from chromosome 1. As a result, the

children were missing a segment of chromosome 1. Their symptoms

stemmed from that.

Gajecka said the team uses specialized molecular techniques to obtain

detailed DNA sequences of the chromosome break points. The techniques

revealed that many translocations that were previously thought to be

balanced are, in fact, " cryptic imbalances " whose small size makes

them impossible to detect by the standard methods for identifying

chromosome abnormalities. The differences between the affected

chromosomes were also found to be highly variable, involving

duplications, deletions and the addition of short new segments.

" We were not aware of this high complexity at the break points, " said

Gajecka. " If you use regular techniques you can't see it. If you go

really deep and get the sequence data, you find it. "

Gajecka said that finding so much variation around the break points

suggests that the breaks occurred randomly, rather than at points on

the chromosome that were particularly vulnerable to breakage. That

has implications for understanding how breaks happen and what causes

them. The finding also suggests that the splicing of a swapped

segment onto a broken chromosome is accomplished by a process known

as nonhomologous end-joining (NHEJ), which allows two strands of DNA

that do not have matching sequences to be joined end-to-end. That has

implications for understanding how cells repair major damage to their

DNA.

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Pullman, WA 99164-1040

United States

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