From Genes to Genomes:- Genome Sequences Provide the Ultimate Genetic Libraries

The genome is the ultimate source of information about an organism, and there is no genome we are more interested in than our own. Less than 10 years after the development of practical DNA sequencing methods, serious discussions began about the prospects for sequencing the entire 3 billion base pairs of the human genome. The international Human Genome Project got underway with substantial funding in the late 1980s. The effort eventually included significant contributions from20 sequencing centers distributed among six nations: the United States, Great Britain, Japan, France, China, and Germany. General coordination was provided by the Office of Genome Research at the National Institutes of Health, led first by James Watson and after 1992 by Francis Collins. At the outset, the task of sequencing a 3X10⁹ bp genome seemed to be a titanic job, but it gradually yielded to advances in technology. The completed sequence of the human genome was published in April 2003, several years ahead of schedule.

This advance was the product of a carefully planned international effort spanning 14 years. Research teams first generated a detailed physical map of the human genome, with clones derived from each chromosome organized into a series of long contigs (Fig. 9–17). Each contig contained landmarks in the form of STSs at a distance of every 100,000 bp or less. The genome thus mapped could be divided up between the international sequencing centers, each center sequencing the mapped BAC or YAC clones corresponding to its particular segments of the genome. Because many of the

FIGURE 9–17 The Human Genome Project strategy. Clones isolated from a genomic library were ordered into a detailed physical map, then individual clones were sequenced by shotgun sequencing protocols. The strategy used by the commercial sequencing effort eliminated the step of creating the physical map and sequenced the entire genome by shotgun cloning.

clones were more than 100,000 bp long, and modern sequencing techniques can resolve only 600 to 750 bp of sequence at a time, each clone had to be sequenced in pieces. The sequencing strategy used a shotgun approach, in which researchers used powerful new auto mated sequencers to sequence random segments of a given clone, then assembled the sequence of the entire clone by computerized identification of overlaps. The number of clone pieces sequenced was determined statistically so that the entire length of the clone was sequenced four to six times on average. The sequenced DNA was then made available in a database covering the entire genome. Construction of the physical map was a time-consuming task, and its progress was followed in annual reports in major journals throughout the 1990s— by the end of which the map was largely in place. Completion of the entire sequencing project was initially projected for the year 2005, but circumstances and tech nology intervened to accelerate the process. A competing commercial effort to sequence the human genome was initiated by the newly established Celera Corporation in 1997. Led by J. Craig Venter, the Celera group made use of a different strategy called “whole genome shotgun sequencing,” which eliminates the step of assembling a physical map of the genome. Instead, teams sequenced DNA segments from through

out the genome at random. The sequenced segments were ordered by the computerized identification of sequence overlaps (with some reference to the public project’s detailed physical map). At the outset of the Human Genome Project, shotgun sequencing on this scale had been deemed impractical. However, advances in computer software and sequencing automation had made the approach feasible by 1997. The ensuing race between the private and public sequencing efforts substantially advanced the timeline for completion of the project. Publication of the draft human genome sequence in 2001 was followed by two years of follow-up work to eliminate nearly a thousand discontinuities and to provide high-quality sequence data that are contiguous throughout the genome.

FIGURE 9–18 Genomic sequencing timeline. Discussions in the mid 1980s led to initiation of the project in 1989. Preparatory work, in cluding extensive mapping to provide genome landmarks, occupied much of the 1990s. Separate projects were launched to sequence the genomes of other organisms important to research. The first sequencing efforts to be completed included many bacterial species (such as Haemophilus influenzae), yeast (S. cerevisiae), a nematode worm (C. elegans), the fruit fly (D. melanogaster), and a plant (A. thaliana). Completed sequences for mammalian genomes, including the human genome, began to emerge in 2000. Each genome project has a web site that serves as a central repository for the latest data.

The Human Genome Project marks the culmination of twentieth-century biology and promises a vastly changed scientific landscape for the new century. The human genome is only part of the story, as the genomes of many other species are also being (or have been) sequenced, including the yeasts Saccharomyces cerevisiae (completed in 1996) and Schizosaccharomyces pombe (2002), the nematode Caenorhabditis elegans (1998), the fruit fly Drosophila melanogaster (2000), the plant Arabidopsis thaliana (2000), the mouse Mus musculus(2002), zebrafish, and dozens of bacterial and archaebacterial species (Fig. 9–18). Most of the early efforts have been focused on species commonly used in laboratories. However, genome sequencing is destined to branch out to many other species as experience grows and technology improves. Broad efforts to map genes, attempts to identify new proteins and disease genes, and many other initiatives are currently under way. The result is a database with the potential not only to fuel rapid advances in biology but to change the way that humans think about themselves. Early insights provided by the human genome sequence range from the intriguing to the profound. We are not as complicated as we thought. Decades-old estimates that humans possessed about 100,000 genes within the approximately 3.2X10⁹ bp in the human genome have been sup planted by the discovery that we have only 30,000 to 35,000 genes. This is perhaps three times more genes than a fruit fly (with 13,000) and twice as many as a nematode worm (18,000). Although humans evolved relatively recently, the human genome is very old. Of 1,278 protein families identified in one early screen, only 94 were unique to vertebrates. However, while we share many protein domain types with plants, worms, and flies, we use these domains in more complex arrangements. Alternative modes of gene expression (Chapter 26) allow the production of more than one protein from a single gene—a process that humans and other vertebrates engage in more than do bacteria, worms, or any other forms of life. This allows for greater complexity in the proteins generated from our gene complement. We now know that only 1.1% to 1.4% of our DNA actually encodes proteins (Fig. 9–19). More than 50% of our genome consists of short, repeated sequences, the vast majority of which—about 45% of our genome in all—come from transposons, short movable DNA sequences that are molecular parasites (Chapter 25). Many of the transposons have been there a long time, now altered so that they can no longer move to new genomic locations. Others are still actively moving at low frequencies, helping to make the genome an ever dynamic and evolving entity. At least a few transposons have been co-opted by their host and appear to serve useful cellular functions.

What does all this information tell us about how much one human differs from another? Within the hu man population are millions of single-base differences, called single nucleotide polymorphisms, or SNPs (pronounced “snips”). Each human differs from the next

FIGURE 9–19 Snapshot of the human genome. The chart shows the proportions of our genome made up of various types of sequences.

by about 1 bp in every 1,000 bp. From these small genetic differences arises the human variety we are all aware of—differences in hair color, eyesight, allergies to medication, foot size, and even (to some unknown degree) behavior. Some of the SNPs are linked to particular human populations and can provide important information about human migrations that occurred thousands of years ago and about our more distant evolutionary past. As spectacular as this advance is, the sequencing of the human genome is easy compared with what comes next—the effort to understand all the information in each genome. The genome sequences being added monthly to international databases are roadmaps, parts of which are written in a language we do not yet understand. However, they have great utility in catalyzing the discovery of new proteins and processes affecting every aspect of biochemistry, as will become apparent in chapters to come.

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مواضيع ذات صلة

Storage Lipids: - Triacylglycerols Are Fatty Acid Esters of Glycerol

Storage Lipids:- Fatty Acids Are Hydrocarbon Derivatives

Genome Alterations and New Products of Biotechnology: -Recombinant DNA Technology Yields New Products and Challenges

Genome Alterations and New Products of Biotechnology:- New Technologies Promise to Expedite the Discovery of New Pharmaceuticals

Genome Alterations and New Products of Biotechnology: -Manipulation of Animal Cell Genomes Provides Information on Chromosome Structure and Gene Expression

Genome Alterations and New Products of Biotechnology:- A Bacterial Plant Parasite Aids Cloning in Plants

From Genomes to Proteomes:- Detection of Protein-Protein Interactions Helps to Define Cellular and Molecular Function

From Genomes to Proteomes:- Cellular Expression Patterns Can Reveal the Cellular Function of a Gene

From Genomes to Proteomes:- Sequence or Structural Relationships Provide Information on Protein Function

From Genes to Genomes:- The Polymerase Chain Reaction Amplifies Specific DNA Sequences

From Genes to Genomes:- DNA Libraries Provide Specialized Catalogs of Genetic Information

DNA Cloning: The Basics:- Alterations in Cloned Genes Produce Modified Proteins