ABSTRACTS:
"Hacking the Genome."
Erickson, D. Scientific American, Vol. 266, No. 4, April 1992, p. 128.
Abstract: The human genome, the collection of genetic information contained in human DNA is an immense document. Although it is written in only four letters - G, C , A, T (the initials for the nucleic acid bases guanine, cytosine, adenine and thymine), it consists of 50,000 - 100,000 genes including more than three billion nucleotides, yet fits comfortably within the nuclei of each of your bodies cells. The vast effort known as The Human Genome Project has partially deciphered about 5,000 of these genes so far but the rest will follow within nine years.
The vast amount of information that flows from this effort will be lose much of its value unless it can be processed and readily accessed by other researchers. The term "informatics" describes the function of doing just that, i.e. developing the systems to handle, process and make accessible the mountain of data from the Human Genome Project and related research efforts. It also includes the construction of genetic maps. At this time the U.S. Dept. of Energy provides significant funding to three national genome centers: Lawrence Livormore, Lawrence Berkeley and Los Alamos. The NIH supports seven academic centers at universities. Each center has primary responsibility for a major piece of the project, e.g. mapping a single chromosome or group of chromosomes.
The project's near term goal is to create genetic and physical maps of each chromosome. Genetic maps will show the approximate positions of genes that code for different traits. Markers will punctuate the map to provide reference points for researchers, enabling them to track specific genes through family trees. Physical maps show collections of DNA fragments from each chromosome, each of which can be cloned (made to reproduce itself), then restitched together. Eventually the pieces and their overlaps will be used to build a third kind of map - showing the specific sequences of the bases G, C, A, T. This is the ultimate goal of the Genome Project.
As if this mountain of data was not enough, the Project also includes the mapping of the genomes of experimental organisms such as Escherichia coli, yeast, fruit flies, mice and worms. Techniques learned on these animals assist workers on the human genome effort. Also, the striking similarity of genes in different species opens new avenues of research; e.g. the ubx group of genes determines the body plan of the fruit fly. A closely related group of genes controls the organization of human and mouse nervous systems during embryonic development.
Because of differing needs, various types of data bases are evolving. Some data bases are general, taking all information provided, verified or not. Others are quite specific, e.g. chromosome 21, or only data about zinc finger genes. Still another may specialize in the genetics of nematode worms.
A major informatics debate concerns the question of standardization of data, that is, finding the single most useful a economic method. Other issues relate to the manner in which questions are addressed to the data bases, for example, should a fixed description language be developed or should commercially available query language be employed?
"NIH Takes a New Tack on Gene Mapping."
Roberts, Leslie. SCIENCE, Vol.258, 12/4/92, p. 1573
Abstract: For the past several years the Human Genome Project (the goal of which is to map every gene possible on a given set of human chromosomes, collectively known as a Genome) has progressed in a piecemeal fashion. One research group working on a small part of one chromosome, another group working on another piece or another chromosome, etc. This chromosome by chromosome, bit by bit, approach has not gotten the project through one-third of the material in the human chromosomes. A new cloning technique that processes 'mega-clones' would enable scientists to unravel huge chunks of several chromosomes at once. Although this new technique may make things easier and, thus, move the Genome Project along toward completion, it will not replace the need for carefully examining every one of the billions of base pairs that constitute the entire human genome.
"NIH/CEPH Collaborative Mapping Group A Comprehensive Genetic Linkage Map of the Human Genome." Foote, S. et al. SCIENCE, Vol.258, 10/2/92, p. 67.
Abstract: A genetic linkage map (sort of a draft of some major guideposts along the way toward a complete description) of the human genome is presented in this article. Maps such as this have helped researchers locate and evaluate the genes responsible for diseases such as cystic fibrosis (a lung disorder,) neurofibromatosis (a nerve disorder) and fragile X-linked mental retardation. However, for other diseases, those that are caused by more than one gene, linkage maps do not provide enough information to solve the riddle of the locations of the genetic causes of these diseases. As studies progress, the details on genetic linkage maps improve. Specific aspects of this map are explained as are some of the laboratory methods employed for its construction. Along with the linkage maps for each chromosome is a brief summary of the loci and genes present and those markers currently under study. The references for this article include a listing of the research teams and centers working on each chromosome.
"The Human Y Chromosome: Overlapping DNA Clones Spanning the Euchromatic Region."
Mandel, Jean-Louis Monaco, Anthony P. Nelson, David L. Schlessinger, David and Willard,SCIENCE, Volume 258, 10/2/92, p. 60.
Abstract: The human Y chromosome is one of the smallest of the human chromosomes (the average size for a Y chromosome is about 60 million base pairs.) The human Y chromosomeis divided into two clearly marked regions; the heterochromatic ('different color') and the euchromatic ('good color'.) The heterochromatic region seems quite variable in size and markings from individual to individual. But the euchromatic region appears to be the same for all males. Thus, it seems that the euchromatic region is a likely candidate with which to begin mapping all of the genes found in the human genome.
The major laboratory technique for analyzing portions of this chromosome employs yeast artificial chromosomes (YAC) vectors. These are small portions of yeast DNA that may be used to help amplify and reference larger portions of human chromosomal DNA. This technique may shorten the time required for mapping the entire human genome. The completeness and utility of the resulting physical chromosome map, described herein is discussed.
"Huntington Genome Analysis and the Human X Chromosome,"
SCIENCE, Vol. 258, 10/2/92, p.103.
Abstract: The DNA of the human X chromosome contains about 160 million base pairs of nucleotides. Over 26 genes representing inherited diseases have been identified and cloned (copied for study) using yeast artificial chromosome (YAC) techniques. The use of YACs helps researchers to break up the huge X chromosome DNA molecule (It is after all only one molecule that makes up any one chromosome.) and then literally splice its pieces back together for study. The use of the polyerase chain reaction (PCR) allows tiny fragments of DNA to be multiplied into workable quantities of DNA. Progress of the mapping of the X chromosome is discussed and several sex-linked genetic disorders are located on the presented map. By comparing similar regions of the X chromosome from such different species as mouse and human, regions responsible for some sex-linked genetic disorders, we can evaluate evolutionary changes through any mutated differences in the base pair sequences.
"Genome Shortcut Leads to Problems."
Anderson, Christopher, SCIENCE, Vol.259, 3/19/93, p.1684.
Abstract: With the development of a system capable of cloning long stretches of human DNA, gene mappers' dreams appeared to have come true - but it has also brought a few nightmares.
An aggressive approach toward mapping the human genome using megaYACs (yeast artifical chromosome that holds on to extremely large chunks of human DNA for amplification and analysis has brought with it some problems. It seems that the process of breaking up large human DNA into manageable pieces tagged with YAC leads to a lot of erroneous reassembly of tiny DNA fragments that contaminate the process. Some researchers report that as much as 80% of their sample DNA under examination is contaminated. Such a large amount of contamination makes their analysis results unreliable. This creates difficult problems for researchers who rely upon the accuracy of early maps to explore and unravel further mysteries of the human genome and develop newer maps. The extra unwanted pieces of DNA that are spliced into their samples while using mega-YAC techniques may lead scientists down many dead-ends along the road to the complete sequencing of the human genome.