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Clues to a chromosome's past

Henikoff lab joins team that completes sequence of essential part of chromosome known as the centromere
An 1882 drawing of a dividing salamander cell shows chromosomes being pulled apart toward opposite poles at discrete points, known as centromeres.

A team of scientists, including center researchers, is the first to completely determine the sequence in a multicellular organism of a mysterious but essential part of the chromosome called the centromere.

These genetic elements — found in the chromosomes of all nucleated organisms — have long been thought to contain no genetic information, serving solely as anchors for the fibers that pull newly duplicated chromosomes apart during cell division. But in determining the DNA sequence of a rice centromere, the researchers made the surprising discovery that functional genes are present.

The researchers speculate that the rice centromere's unusual structure represents an intermediate stage in the evolution of a centromere, providing a glimpse into how these vital structures originated in all organisms, including humans. On a more practical level, knowledge of the centro-mere's sequence also will help scientists create artificial plant chromosomes engineered to contain useful genes, such as those for the synthesis of nutrients not normally present in certain crops.

The study was led by Dr. Jiming Jiang and colleagues at the University of Wisconsin. Dr. Steven Henikoff, investigator in the Basic Sciences Division and Dr. Paul Talbert, a research specialist in his laboratory, took part in the analysis, which is published in the February issue of Nature Genetics.

Structural platforms

As early as 1880, centromeres (from the Greek for centro, or middle, and mere, or part) caught the attention of cell biologists, who observed images of newly duplicated chromosomes separating as one cell becomes two. These classic pictures revealed spaghetti-like chromosomes being tugged apart at their midsections-or centromeres-during cell division.

Scientists now know that these focal points (not always located at the middle of chromosomes) serve as attachment sites for the fibers that pull chromosomes apart. Unlike a gene, which is a stretch of DNA that contains the code to make a protein, centromeres are typically composed of highly repeated, short sequences that do not encode proteins and that serve only as structural platforms to anchor proteins involved in chromosome segregation.

Because of their unusual structure, centromeres remain one of the few unsequenced portions of the human genome, Henikoff said.

"The highly repetitive DNA found in human and most other centromeres has made them technically very difficult to sequence," he said. "In rice, some centromeres contain very little of the repetitive DNA found in most organisms. It may be that in an evolutionary sense, this is a young centromere that has not yet acquired the features of a fully mature centromere. This may give us a glimpse into how human centromeres have evolved."

Henikoff said that what little is known about the origin of human centromeres comes from the study of neocentromeres, which serve as essential chromosome-partitioning sites on chromosomes that lack normal centromeres. Neocentromeres have been observed on the abnormal extra chromosomes in cells of individuals with birth defects.

"An extra chromosome can't be perpetuated without a centromere," he said. "So how do you get a new centromere? It has to come from some site on the chromosome."

Henikoff said that one human neocentromere has been sequenced, and its structure is unremarkable-it looks like an average stretch of DNA with active genes. Somehow, the DNA segment became co-opted for use as the chromosome segregation element during cell division.

Talbert said that scientists do not yet understand why a particular region of a chromosome might be selected as the site of a new centromere.

"Neocentromere formation is rare and unobservable, so we can only guess how it happens," he said. "We know that in some cases centromere-associated proteins go to other chromosomal locations besides centromeres. It may be that if a particular region by chance has enough centromere proteins at a time when a chromosome break occurs, separating it from the normal centromere, the region may be able to function as a neocentromere and perpetuate itself."

Scientists suspect that given enough time, neocentromeres would become overrun with repeated DNA and the sequences for active genes would be lost or pushed aside as the element becomes dedicated to its new role. The same process is thought to have occurred during the evolution of native human centromeres.

Centromeric repeats

Henikoff likened the process to a classic example of forest succession in which a young forest consisting of many species of trees and shrubs becomes dominated by a single species.

"When the climax situation is reached, trees that die are replaced by members of the dominant species," he said. "Centromeric repeats are the same way — once they become established, they continually replace themselves to the exclusion of other squences."

The researchers hypothesize that the rice centromere may represent an intermediate stage of evolution, somewhere between structures like human neo-centromeres and fully mature centromeres that consist of nothing but repetitive DNA.

"In rice, this intermediate form serves as its native centromere," Henikoff said. "Based on what we know about centromere structure in other organisms, finding active genes was very surprising."

Practical applications

The practical applications of the rice centromere sequence information could be far-reaching. Although researchers already have engineered crops that contain non-native genes, the use of plant artificial chromosomes could offer some advantage, Talbert said.

"To make 'golden rice,' the set of genes required to make vitamin A was introduced into rice with the aim of improving nutrition in areas like southeast Asia, where diets often lack sufficient vitamin A," he said. "Putting in whole sets of genes might be easier with artificial chromosomes than with currently available methods."

Other contributors to the study were Drs. Kiyotaka Nagaki and Zhukuan Cheng of the University of Wisconsin, and Drs. Robin Buell, Mary Kim, Shu Ouyang and Kristine Jones of The Institute for Genomic Research.

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