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.
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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