ABSTRACTS:
TITLE: YEAST GENOME SEQUENCE FERMENTS NEW RESEARCH
AUTHOR: NIGEL WILLIAMS
JOURNAL: SCIENCE, Vol. 272, 26 APRIL 1996
ABSTRACT: Seven years ago a number of labs banded together to sequence a single chromosome of the brewer's yeast - saccharomyces cerevisiae. 12 million base sequences later, scientists have completely sequenced the entire genome of this primitive eukaryote. This achievement represents a milepost in our understanding of the genetic coding of life processes. This is the first eukaryote (nucleated cells) ever completely sequenced. The yeast genome is more than six times larger than the first complete bacterial sequences, reported last YEAR.
The 16 genes making up yeast's genome contain many genes found in higher organisms, including man. This has generated excitement because understanding the manner in which yeast's genes control biochemical processes will lead to similar understandings as to higher organisms. The yeast genome may hold the key to unlock the secret of everything from evolution to human disease.
The next step in the project will be the functional analysis of the newly discovered genes. There is a high degree of redundancy in the genome. Several genes may have homologous sequences and possibly the same function. We don't know why that happens. There are also a large number of genes (30%) whose sequence gives no clue to their function. That number is shrinking, however, as other studies bring correlate knowledge from studies of other organisms to the yeast project. Recently, a supercomputer was devised which performed 19 billion sequence comparisons between genes from other organisms and yeast genes. As a result, only about 12% of yeast genes show no resemblance to any other gene.
Knowledge of the yeast genome will give researchers a major tool in understanding biochemical pathways, not just in yeast, but in other forms of life. A major research goal will be to identify patterns of gene regulation. Evolution can be studied by comparing genes in brewer's yeast with those of fission yeast - Schizosaccharomyces pombe - two species that separated 500 to 1,000 million years ago.
The new genes are exciting interest in medical circles. Among 51 cloned human genes associated with disease, 13 show similarities with yeast genes and 12 more show some weaker similarities. By studying these genes in yeast, scientists may learn how these genes function in human and thereby gain an understanding of a disease process.
KEY WORDS/PHRASES:
BACTERIAL SEQUENCES
BIOCHEMICAL PATHWAYS
DISEASE
EUKARYOTE
EVOLUTION
FUNCTIONAL ANALYSIS
HOMOLOGOUS SEQUENCES
YEAST GENOME
TITLE: PROTEIN MATCHMAKER MAY LEAD NEW GENE THERAPY TO THE ALTAR
AUTHOR: MICHAEL BALTER
JOURNAL: SCIENCE, VOL. 273, 12 JULY 1996
ABSTRACT: It has long been known that a bacterial enzyme, rapamycin, has the ability to inhibit growth in neighboring organisms. However, recent scrutiny of this protein reveals a rather surprising ability. Rapamycin apparently plays the role of a molecular marriage broker, merging together two proteins that would not normally be joined, into a complex called a heterodimer. Rapamycin does this by neatly fitting into binding sites on each protein. This complex actively interferes with the proliferation of the immune system's T lymphocytes.
Taking advantage of the enzyme's ability, researcher's linked together portions of two proteins, FKBP12 and FRAP and joined this complex to other proteins capable of performing such tasks as turning genes on or off. Experiments show that rapamycin's interference with the cell cycle involves interfering with an enzyme required for protein synthesis, known as p70 ribosomal protein S6 kinase. Under normal conditions, the protein FRAP turns the kinase on, but when it is bound to a FKBP-rapamycin complex, the gene switch is turned off. The binding site on FRAP may be associated with a regulatory domain, (an area of DNA associated with gene regulation). By jamming the regulatory domain on FRAP, rapamycin may switch off the protein's activation of the kinase.
The area causing the most excitement is the discovery that rapamycin-protein complexes can be designed to control expression of other human genes. Scientist recently genetically engineered two sections of a DNA transcription factor (a DNA binding site and an activation protein) and attached the binding segment to FKBP12 and the activation protein to FRAP. They then inserted these complexes into a line of human cells, along with an inactivated version of the human growth hormone gene. When these cells were transplanted into mice, researchers were able to bring the two complexes together, and turn on production of human growth hormone in the mice. By varying the concentration of rapamycin, scientists were able to vary the amount of growth hormone produced in the blood of the mice. This experiment demonstrated a degree of gene control previously unknown. With such "tools" in hand, researchers can move more aggressively to redesign genes, including control genes capable of activating other genes, or deactivating undesired (e.g. mutated) genes.
KEY WORDS/PHRASES
ACTIVATION PROTEIN
BINDING SITE
DNA TRANSCRIPTION FACTOR
HETERODIMER
RAPAMYCIN
REGULATORY DOMAIN
TITLE: DIVIDE AND CONFER: HOW WORM EMBRYO CELLS SPECIALIZE
AUTHOR: WADE ROUSH
JOURNAL: SCIENCE, VOL.272, 28 JUNE 1996
ABSTRACT: How does an embryonic cell "know" how to assign its offspring the task of becoming specialized cell types? Breakthrough research in the fruit fly - Drosophila melanogaster - has begun to answer this question. Now, additional insights are emerging from another popular animal subject, the worm Caenorhabditis elegans, an animal whose genome has been completely mapped.
Researchers recently described the identification of a protein that plays an important, if not vital role, in the initial stages of the worm's embryonic development. As the initial one-celled zygote undergoes mitosis to create two daughter cells, control genes become active. These genes direct the development of additional generations of daughter cells. At the earliest stage of development, within the single-celled embryo, certain materials (P granules and developmental factors) shift to one side of the cell, ensuring that the two resulting daughter cells (the smaller one called P1 and the larger, AB) will be different from each other.
The job of transporting those growth factors is accomplished by the protein myosin. Myosin is a muscle protein that can "slide" along a network of cellular microfilaments (the cell's cytoskeleton) , dragging other materials with it. PAR proteins, which are involved in cytoskeleton development, bind to myosin. As soon as the daughter cells divide, the embryo begins to use other mechanisms to control further differentiation. This mechanism involves sensitivity to chemical signals emitted by neighboring cells. The "signals" are sent by one of P1's daughter cells, called P2. P2 interacts with the daughter cells of AB, called ABa and Abp. Although ABa and ABp seem to be identical, they give rise to different sets of tissues. It appears that ABp receives the signal to differentiate from P2. When P2 cells were removed from their normal position next to ABp, ABp and ABa descendants develop identically.
Researchers are now studying how the P2 cell sends its signal, and what that signal might be. A likely suspect is a cell surface protein called APX-1. It also seems that P2's sister cells receive signals from P2.
KEY WORDS/PHRASES
CHEMICAL SIGNALS
CELLULAR MICROFILAMENTS
CYTOSKELETON
MYOSIN
P GRANULES
DEVELOPMENTAL FACTORS