Scientists disclose chromosome's knock-off parts

For some chromosomes, a brief lapse in creativity can encourage a lifetime of imitation. A team of scientists has announced the full DNA sequence and analysis of human chromosome 15, exposing its frequent reuse of second-hand parts. Published in the March 30 issue of Nature, these findings shed light on the structural basis of chromosome evolution and could guide researchers in resolving the gaps that remain in the sequence of the human genome.

From the outside, chromosome 15 has the air of novelty. It is one of five "acrocentric" chromosomes in the human genome, which means its centromere is shifted off-center, lying close to one edge. This displacement gives the chromosome a distinct lopsided shape and creates two arms with drastically different lengths. Like those of its crooked cousins, the short arm of chromosome 15 consists mainly of repetitive sequences and has not yet been entirely decoded.

But the contents of its long arm, particularly an unusually high percentage of segmental duplications, cast the chromosome in an entirely different light. Segmental duplications are essentially genetic carbon copies, which recur throughout the genome, either on the same or different chromosomes. Related copies have highly similar DNA sequences, reflecting their common origin. These duplications are of interest, in part, because they can contribute to genetic instability, making the areas that contain them prone to DNA rearrangements. Such rearrangements, which include the removal or abnormal shuffling of genetic information, can underlie human disease. In fact, two human syndromes, Prader-Willi and Angelman, result from the abnormal restructuring instigated by a cluster of segmental duplications on chromosome 15.

In their analysis of the chromosome, Broad scientists noticed two distinct collections of segmental duplications perched at either end of the chromosome's long arm. Notably, these are separated by a long stretch of DNA that is largely free of such copied sequences. While this configuration might suggest independent origins, the researchers found that most of the segmental duplications, or "duplicons," fall into a single related group, indicating shared ancestry.

"Using the tools of comparative genomics, we have reconstructed the natural history of human chromosome 15, which explains its remarkably duplicated structure," said Mike Zody, lead author of the Nature paper and chief technologist in the Broad's Genome Biology Program. "This work is a significant step forward in understanding the frequency and distribution of segmental duplications in humans and other primates, and provides a physical framework for understanding how duplication affects gene and genome evolution."

Although the vast majority of the duplication family appears only on chromosome 15, its roots seem to lie elsewhere. The researchers identified a core sequence element, a small piece of DNA that is conserved among the related duplicons on chromosome 15, which helped them locate a handful of additional copies in the human genome. To identify which one was the original, they looked for versions of the core element in the dog and mouse genomes, where they found a single copy equivalent to the one on chromosome 2 in humans. This suggests that, in humans, the two clusters of segmental duplications first arose from a sequence on chromosome 2 that was later copied to chromosome 15.

Although these results clarify their initial beginnings, they do not explain how the duplicons became so markedly divided. To address this question, the scientists surveyed the genetic terrain surrounding, but not including, the duplications in humans, as well as in other animals. Surprisingly, they discovered that the two regions originally were neighbors. Sometime later, likely during the evolution of early primates, a break occurred between adjacent duplicons that enabled the chromosome to flip itself, end over end. The data also suggest that the duplications themselves may have had a hand in initiating the maneuver, which somersaulted them to opposite ends of the chromosome.

More generally, segmental duplications pose a logistical challenge in the proper alignment of DNA sequences, due to their inherent repetitiveness. Indeed, the researchers note that many of the gaps that remain in the sequence of chromosome 15 are positioned near segmental duplications. Most of these gaps also coincide with known sites of DNA copy number polymorphisms, a form of structural variability in the human genome. Thus, a more detailed characterization of segmental duplications — both on chromosome 15 and elsewhere in the genome — may help to resolve sequencing gaps and, in addition, could contribute to our understanding of human genetic diversity.