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What is functional genomics? What is comparative genomics? How does it relate to functional genomics?
Researching Human-Mouse Homologies
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Why is model organism research important? Why do we care what diseases mice get? How closely related are mice and humans? How many genes are the same? What are knockout mice? Why are mice used in this research? What genomes have been sequenced completely? What are the comparative genome sizes of humans and other organisms being studied? More Information
Understanding the function of genes and other parts of the Ethical, Legal, genome is known as functional genomics. The Human Social Issues Genome Project was just the first step in understanding Home Privacy Legislation humans at the molecular level. Though the project is Gene Testing complete, many questions still remain unanswered, Patenting including the function of most of the estimated 30,000 Forensics
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human genes. Researchers also don't know the role of single nucleotide polymorphisms (SNPs) --single DNA base changes within the genome-- or the role of noncoding regions and repeats in the genome.
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Why is model organism research important? Why do we care what diseases mice get?
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Functional genomics research is conducted using model organisms such as mice. Model organisms offer a costeffective way to follow the inheritance of genes (that are very similar to human genes) through many generations in a relatively short time. Some model organisms studied in the HGP were the bacterium Escherichia coli, yeast Saccharomyces cerevisiae, roundworm Caenorhabditis elegans, fruit fly Drosophila melanogaster, and laboratory
mouse. Additionally, HGP spinoffs have led to genetic analysis of other environmentally and industrially important organisms in the United States and abroad. For more information see HGN 11 (1-2) "Public, Private Sectors Join in Mouse Consortium", HGN 8 (1) "Third Branch of Life Confirmed", and HGN 7 (3-4) "Microbial Genomes Sequenced".
How closely related are mice and humans? How many genes are the same?
Answer provided by Lisa Stubbs of Lawrence Livermore National Laboratory, Livermore, California. Mice and humans (indeed, most or all mammals including dogs, cats, rabbits, monkeys, and apes) have roughly the same number of nucleotides in their genomes -- about 3 billion base pairs. This comparable DNA content implies that all mammals contain more or less the same number of genes, and indeed our work and the work of many others have provided evidence to confirm that notion. I know of only a few cases in which no mouse counterpart can be found for a particular human gene, and for the most part we see essentially a one-to-one correspondence between genes in the two species. The exceptions generally appear to be of a particular type --genes that arise when an existing sequence is duplicated. Gene duplication occurs frequently in complex genomes; sometimes the duplicated copies degenerate to the point where they no longer are capable of encoding a protein. However, many duplicated genes remain active and over time may change enough to perform a new function. Since gene duplication is an ongoing process, mice may have active duplicates that humans do not possess, and vice versa. These appear to make up a small percentage of the total genes. I believe the number of human genes without a clear mouse counterpart, and vice versa, won't be significantly larger than 1% of the total. Nevertheless, these novel genes may play an important role in determining species-specific traits and functions. However, the most significant differences between mice and humans are not in the number of genes each carries but in the structure of genes and the activities of their protein products. Gene for gene, we are very similar to mice. What really matters is that subtle changes accumulated in each of
the approximately 30,000 genes add together to make quite different organisms. Further, genes and proteins interact in complex ways that multiply the functions of each. In addition, a gene can produce more than one protein product through alternative splicing or post-translational modification; these events do not always occur in an identical way in the two species. A gene can produce more or less protein in different cells at various times in response to developmental or environmental cues, and many proteins can express disparate functions in various biological contexts. Thus, subtle distinctions are multiplied by the more than 30,000 estimated genes. The often-quoted statement that we share over 98% of our genes with apes (chimpanzees, gorillas, and orangutans) actually should be put another way. That is, there is more than 95% to 98% similarity between related genes in humans and apes in general. (Just as in the mouse, quite a few genes probably are not common to humans and apes, and these may influence uniquely human or ape traits.) Similarities between mouse and human genes range from about 70% to 90%, with an average of 85% similarity but a lot of variation from gene to gene (e.g., some mouse and human gene products are almost identical, while others are nearly unrecognizable as close relatives). Some nucleotide changes are neutral and do not yield a significantly altered protein. Others, but probably only a relatively small percentage, would introduce changes that could substantially alter what the protein does. Put these alterations in the context of known inherited human diseases: a single nucleotide change can lead to inheritance of sickle cell disease, cystic fibrosis, or breast cancer. A single nucleotide difference can alter protein function in such a way that it causes a terrible tissue malfunction. Single nucleotide changes have been linked to hereditary differences in height, brain development, facial structure, pigmentation, and many other striking morphological differences; due to single nucleotide changes, hands can develop structures that look like toes instead of fingers, and a mouse's tail can disappear completely. Single-nucleotide changes in the same genes but in different positions in the coding sequence might do nothing harmful at all. Evolutionary changes are the same as these sequence differences that are linked to person-toperson variation: many of the average 15% nucleotide
changes that distinguish humans and mouse genes are neutral; some lead to subtle changes, whereas others are associated with dramatic differences. Add them all together, and they can make quite an impact, as evidenced by the huge range of metabolic, morphological, and behavioral differences we see among organisms.
yeast Saccharomyces cerevisiae, the plant Arabidopsis thaliana, and several microbes. For a complete listing see A Quick Guide to Sequenced Genomes from the Genome News Network. Other resources for information on sequenced genomes:
GOLD -- Genomes Online Database provides comprehensive access to information regarding complete and ongoing genome projects around the world. Comprehensive Microbial Resource -- A tool that allows the researcher to access all of the bacterial genome sequences completed to date. From The Institute for Genomic Research (TIGR). Entrez Genome -- A resource from the National Center for Biotechnology Information (NCBI) for accessing information about completed and in-progress genomes.
What are the comparative genome sizes of humans and other organisms being studied?
organism
estimate averag chromosom estimate d e gene e d size gene density number number 2900 million bases 2,750 million bases 2500 million bases 180 million bases 125 million bases ~30,000 1 gene per 100,000 bases 1 gene per 100,000 bases 46
Homo sapiens (human) Rattus norvegicus (rat) Mus musculus (mouse) Drosophila melanogaster (fruit fly) Arabidopsis thaliana (plant)
~30,000
42
1 gene per ~30,000 100,000 bases 13,600 1 gene per 9,000 bases 1 gene per 4000 bases 1 gene per 5000 bases 1 gene per 2000 bases 1 gene per 1400 bases 1 gene per 1000 bases
40
25,500
10
Caenorhabdit 97 million is elegans bases (roundworm) Saccharomyc 12 million es cerevisiae bases (yeast) Escherichia coli (bacteria) H. influenzae (bacteria) 4.7 million bases 1.8 million bases
19,100
12
6300
32
3200
1700
to be Sequenced R. D. Fleischmann, et al. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science. (28 July 1995) 269: 496-512.
Browse the genomes of model organisms with MapViewer and other genome resources from the National Center for Biotechnology Information (NCBI). For a step-by-step tutorial on how to use NCBI MapViwer to view the human genome see Finding a gene on a chromosome map.
Homo sapiens Genome View (human) Mus musculus Genome View (mouse) Drosophila melanogaster Genome View (fruit fly) Arabidopsis thaliana Genome View (plant) Caenorhabditis elegans Genome View (roundworm) Saccharomyces cerevisiae Genome View (baker's yeast)
More Information
Related Web Sites
Functional and Comparative Genomics Research - More technical information Of mice and men (36k GIF) on HGP involvement with comparative and functional genomics. Virtual Library of Genetics - Links to genetic and genomic information organized by organism. Microbial Genome Program - U.S. Department of Energy program to study the genetic material of microbes that may be useful in helping DOE fulfill its missions. DOE Joint Genome Institute - Consortium of U.S. Department of Energy researchers developing and exploiting new technologies as a means for discovering and characterizing the basic principles and relationships underlying living systems.
A Quick Guide to Sequenced Genomes - Illustrated index of organisms that have had their genomes sequenced. From the Genome News Network. Model Organisms for Biomedical Research Information on model organisms from the National Institutes of Health. Mouse Genome Resources - Gateway to mouse resources in and beyond National Center for Biotechnology Information (NCBI) resources. Functional Genomics - Gateway to functional genomics sources from Science. Ecce homology: A primer on comparative genomics From Modern Drug Discovery, a publication of the American Chemical Society.
Articles
Comparative Genomics: The Mouse That Roared Article from the December 5, 2002, issue of Nature. Why You Can Read This And Why the Chimp Can't-from USA Today (April 14, 2002). Functional Genomics Articles from Human Genome News Functional Genomics: Technological Challenges and Opportunities - Article from the Physiological Genomics (July 15, 1999). Of Mice, Monitors, and Medicine - Article from the ORNL Review (1999). Mysteries of Life: From Molecules to Mice - Article from the ORNL Review (1999). The Mighty Mouse - Narrative from To Know Ourselves (1996).
Other Resources
Genomics: The Human Genome and Beyond - Poster available from the DOE Joint Genome Institute. Interactive Mouse Genetics from Explore Learning - Learn about mouse genetics and the statistics behind the inheritance of red eyes
Graphic - Using Mice to Understand Human Gene Function. From the HGP Image Gallery. Graphic - Mouse-human homology. Graphic - Researcher and mouse. Discovering Genomics, Proteomics, and Bioinformatics by A.M. Campbell and L.J. Heyer. Cold Spring Harbor Laboratory Press (2003), 252 pp. Send the url of this page to a friend
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