Jan. 5, 2004 Berkeley - For all its importance in sexual reproduction, the process of creating eggs and sperm, called meiosis, is still poorly understood. How the chromosomes in germ cells pair off, trade a few genes and split to give each gamete half a normal complement of genes is so complicated that researchers have had a hard time making sense of the mechanisms involved.
A team of biologists at the University of California, Berkeley, has now found a key gene involved in the first step in the process. The gene, isolated from corn, allows chromosomes floating around in the cell's nucleus to recognize and pair with their homologs in preparation for the later steps that lead to cell division. If this crucial first step fails, the whole chain of events breaks down and cells fail to produce eggs or sperm.
Meiosis in corn has many similarities to the process in yeast, fruit flies, mice and humans, making this finding an important step in understanding meiosis in many organisms.
"Understanding chromosome pairing in plants will eventually lead to understanding the same process in humans, which will help in elucidating the causes of infertility and genetic diseases that result from abnormalities of meiosis, such as Down Syndrome," said principal author Wojtek P. Pawlowski, a postdoctoral fellow at UC Berkeley. "It's clear that this gene plays a crucial role in the process, though we still don't understand what it does or how pairing happens."
Pawlowski and W. Zacheus Cande, a professor of molecular and cell biology and of plant biology at UC Berkeley, with colleagues from the University of North Dakota and Pioneer Hi-Bred International, Inc., a DuPont subsidiary and the world's leading developer and supplier of advanced plant genetics, reported their findings in the Jan. 2 issue of Science.
The goal of meiosis is to produce gametes - sperm or egg cells - with half the normal number of chromosomes, so that they can fuse with a gamete of the opposite sex to produce a fertilized cell with a complete set of chromosomes. In maize a complete set is 10 pairs of chromosomes, one member (or homolog) of each pair from the father and one from the mother. Humans have 23 pairs of chromosomes, but the process is very similar, Pawlowski said.
In animals, specialized cells called germ cells are the only ones that can undergo meiosis to produce eggs or sperm, though in corn, or maize, many cells are capable of meiosis. The process common to most organisms starts after the cell's chromosomes duplicate as if the cell were ready to divide into two identical daughter cells, a process called mitosis. In meiosis, however, these duplicated chromosomes don't split apart, but instead seek out and pair with their homologs, creating a structure consisting of four DNA double helices aligned side-by-side.
"Each cell of most living organisms, including humans and plants, contains two nearly identical sets of chromosomes, one set from the father and one from the mother," Pawlowski explained. "During meiosis, each chromosome from one parent must find its equivalent, or homolog, that comes from the other parent and must physically pair with it. The purpose of this behavior is to facilitate sorting of chromosomes into gametes so that only one chromosome from each pair is transmitted to a gamete."
After pairing, protein machines move in to zip them together. Finally, in a process called recombination, genes get shuffled as the paired chromosomes break at a random spot along their arms and switch pieces. Recombination is the critical process that mixes genes from the father and mother to create genetic variation in offspring.
"The process of meiotic recombination involves a purposeful generation and repair of breaks in the DNA by the cellular machinery," Pawlowski said.
After pairing, zipping (called synapsis) and recombination, the chromosome pairs are pulled apart, then the duplicated chromosomes are separated, and the cell splits into four gametes, each with only half the standard number of chromosomes.
The UC Berkeley researchers found a corn mutant that prevented the duplicated chromosomes from finding and pairing with their homologs. In the mutant, called phs1 (poor homologous synapsis 1), chromosomes paired up with the wrong partner and were zipped together. The gene phs1 appears to prevent the attachment of the protein machinery that causes recombination, because after zipping the process basically stops.
"Although we do not know yet how the phs1 gene accomplishes all its functions, it is clear that it possesses the ability to sense homology between two DNA molecules," Pawlowski said. "This DNA recognition ability is the key to the process of chromosome pairing that has been eluding scientists for more than two decades."
In a Perspectives piece in the same issue of Science, Enrique Martinez-Perez of Stanford University and Graham Moore of the John Innes Center in the United Kingdom, noted that "the function of phs1 lies at the core of coordination between these two events (pairing and synapsis). The phs1 gene can now be used to identify new components of this coordinating mechanism.""
Though several dozen mutations are known to screw up meiosis in corn, all either prevent chromosome pairing altogether or else lead to pairs that easily break apart.
Other genes are known to be involved specifically in recombination, while still others appear to be critical to synapsis. The gene phs1, however, appears to coordinate the three steps.
"Ongoing research on the molecular function of the phs1 gene will lead to understanding the molecular mechanisms by which chromosomes identify each other and pair during meiosis," Pawlowski said. He plans to continue his study of chromosome pairing and how homologous chromosomes actually recognize one another. This apparently requires about 600 breaks along all 10 chromosomes that, after the homologous chromosomes hook up, are repaired.
The work also has implications for corn breeding.
"In plants, in addition to its scientific importance, this research also has the potential to lead to developing methods for exchanging genes, or gene targeting," he said. "Gene targeting could be used for precise exchange of a plant gene with its modified version and will be enormously useful in agricultural biotechnology."
Coauthors of the paper include Inna Golubovskaya, a maize geneticist and visiting scientist in UC Berkeley's Department of Plant and Microbial Biology, who discovered the phs1 mutant in a North Dakota corn field; Robert Meeley of Pioneer Hi-Bred, who used reverse genetics technologies to identify additional phs1 mutants; Ljudmilla Timofejeva, a visiting scientist at UC Berkeley; and William Sheridan of the University of North Dakota.
The work was supported by the National Institutes of Health and the Torrey Mesa Research Institute-Syngenta Research and Technology.
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