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| Researching
Human-Mouse Homologies |
- What is functional genomics?
- 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?
- What genomes have been sequenced completely?
- What are the comparative genome sizes of humans and other organisms being studied?
- More Information
What is functional genomics?
Understanding the function of genes and other parts of the genome is known as functional genomics. The Human Genome Project is just the first step in understanding humans at the molecular level. When the sequencing phase of the project is complete, many questions will remain unanswered, including the function of most of the estimated 100,000 human genes. [ NOTE: this was still the estimate in late September 2000 only 8 months before the "draft bombshell in April 20001! ..... WB] Researchers also don't know the role of single nucleotide polymorphisms (SNPs) --single amino acid base changes within the genome-- or the role of noncoding regions and repeats in the genome.Why is model organism research important? Why do we care what diseases mice get?
Functional genomics research is conducted through model organisms such as mice. Model organisms offer a cost-effective 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 being studied in the HGP are:- the bacterium Escherichia coli
- yeast Saccharomyces cerevisae
- roundworm Caenorhabditis elegans
- fruit fly Drosophila melanogaster
- laboratory mouse
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. We won't know for certain until both genomes are completely sequenced, but 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 approximate 100,000 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 100,000 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 related genes in humans and mouse 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-to-person 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.
What are knockout mice?
How will they help us determine human gene function? Knockout mice are transgenic mice whose genetic code has been altered by the insertion of foreign genetic material into their DNA. Using this technology, researchers target specific genes --causing them to be expressed or inactivated. These mice are then bred --creating a population of offspring with the trait.When researchers isolate human genes with unknown functions, they can create knockout mice with these genes and observe the results. Instead of creating merely the mouse equivalent of the human gene, researchers are able to reproduce and express actual human genes and their corresponding proteins in mice. Subsequent offspring will inherit not only the instructions coded by their original mouse genome, but also the traits coded for by the inserted human DNA. This helps researchers understand health and disease by observing how genes work in cells.
Knockout mice have many benefits. They not only allow researchers to determine gene function and understand diseases at the molecular level, but they also aid scientists in testing new drugs and devising novel therapies.
Why are mice used in this research?
Mice are genetically very similar to humans. They also reproduce rapidly, have short life spans, are inexpensive and easy to handle, and can be genetically manipulated at the molecular level.What genomes have been sequenced completely?
Numerous genomes have been completed including the fruitfly Drosophila melanogaster, the worm Caenorhabditis elegans, the bacterium Escherichia coli, the yeast Saccharomyces cerevisiae, and several microbes. The sequence of the first plant genome to be sequenced, Arabidopsis thaliana, is expected to be completed in 2000.See the following sites for listings
What are the comparative genome sizes of humans and other organisms being studied?
| Estimated sizes are the following: | |
|---|---|
| Human | 3000 million bases (~100,000 genes) |
| Mouse | 3000 million bases (50,000 to 100,000 genes) |
| Drosophila (fruit fly) | 165 million bases (15,000 to 25,000 genes) |
| Nematode (roundworm) | 100 million bases (11,800 to 13,800 genes) |
| Yeast (fungus) | 14 million bases (8355 to 8947 genes) |
| E. coli (bacteria) | 4.67 million bases (3237 genes) |
| H. influenzae (bacteria) | 1.8 million bases |
| M. genitalium (bacteria) | 0.58 million bases |
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More Information
- The Mighty Mouse, narrative from To Know Ourselves
- Graphic depicting the Mouse-Human Homolog
- Graphic showing researcher and the mouse
- More technical Functional and Comparative Genomics research website
- Human Genome News Functional Genomics articles
- DOE Microbial Genome Program
- Virtual Library of Genetics (links organized by organism)
- NIH Model Organisms for Biomedical Research
- Functional genomics: technological challenges and opportunities --an article from Physiological Genomics
- Of Mice, Molecules, and Men --an article from the ORNL Review
- Mysteries of Life: From Molecules to Mice --an article from the ORNL Review
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