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Researching
Human-Mouse
Homologies |
Quick Links to questions and answers on this page:
What is functional genomics?
Understanding the function of genes and other parts of the genome is
known as functional genomics. The Human Genome Project was just the first
step in understanding humans at the molecular level. Though the project is complete, many questions still remain unanswered,
including the function of most of the estimated 30,000 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.
What is comparative genomics?
How does it relate to functional genomics?
Comparative genomics is the analysis and comparison of genomes from
different species. The purpose is to gain a better understanding of how
species have evolved and to determine the function of genes and noncoding
regions of the genome. Researchers have learned a great deal about the
function of human genes by examining their counterparts in simpler model
organisms such as the mouse. Genome researchers look at many different
features when comparing genomes: sequence similarity, gene location, the
length and number of coding regions (called exons) within genes, the amount
of noncoding DNA in each genome, and highly conserved regions maintained
in organisms as simple as bacteria and as complex as humans.
Comparative genomics involves the use of computer programs that can line
up multiple genomes and look for regions of similarity among them. Some
of these sequence-similarity tools are accessible to the public over the
Internet. One of the most widely used is BLAST,
which is available from the National Center for Biotechnology Information.
BLAST is a set of programs designed to perform similarity searches on
all available sequence data. For instructions on how to use BLAST, see
the tutorial Sequence
similarity searching using NCBI BLAST available through Gene
Gateway, an online guide for learning about genes, proteins, and genetic
disorders.
Why is model organism research
important? Why do we care what diseases mice get?
Functional genomics research is conducted using 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 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 25,000 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-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?
In addition to the human genome, the genomes of about 800 organisms have been sequenced in recent years. These include the mouse Mus musculus,
the fruitfly Drosophila melanogaster, the worm Caenorhabditis
elegans, the bacterium Escherichia coli, the yeast Saccharomyces
cerevisiae, the plant Arabidopsis thaliana, and many microbes.
Other resources for information on sequenced genomes:
- DOE Joint Genome Institute -- Human, plant, animal, and microbial sequencing.
- 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.
- 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 |
estimated size
(base pairs) |
estimated
gene number |
average gene density |
chromosome
number |
Homo sapiens
(human) |
3.2 billion |
~25,000 |
1 gene per 100,000 bases |
46 |
Mus musculus
(mouse) |
2.6 billion |
~25,000 |
1 gene per 100,000 bases |
40 |
Drosophila melanogaster
(fruit fly) |
137 million |
13,000 |
1 gene per 9,000 bases |
8 |
Arabidopsis thaliana
(plant) |
100 million |
25,000 |
1 gene per 4000 bases |
10 |
Caenorhabditis elegans
(roundworm) |
97 million |
19,000 |
1 gene per 5000 bases |
12 |
Saccharomyces cerevisiae
(yeast) |
12.1 million |
6000 |
1 gene per 2000 bases |
32 |
Escherichia coli
(bacteria) |
4.6 million |
3200 |
1 gene per 1400 bases |
1 |
H. influenzae
(bacteria) |
1.8 million |
1700 |
1 gene per 1000 bases |
1 |
*Information extracted from genome
publication papers below. |
Genome size does not correlate with evolutionary status, nor is the number
of genes proportionate with genome size.
Genome Publication Papers
Human
International Human Genome Sequencing Consortium. Initial sequencing
and analysis of the human genome. Nature 409: 860-921. (15 February 2001)
[ Full
Text]
Rat
Rat Genome Sequencing Project Consortium. Genome Sequence of the Brown Norway Rat Yields Insights into Mammalian Evolution. Nature 428: 493-521. (1 April 2004)
[Full Text
Mouse
Mouse Genome Sequencing Consortium. Initial sequencing and comparative
analysis of the mouse genome. Nature 420:
520 -562. (5 December 2002)
[Full
Text]
Fruit Fly
M. D. Adams, et al. The genome sequence of Drosophila melanogaster.
Science (24 March 2000) 287: 2185-95.
Arabidopsis - First Plant Sequenced
The Arabidopsis Genome Initiative. Analysis of the genome sequence of
the flowering plant Arabidopsis thaliana. Nature 408:
796-815. (14 December 2000)
Roundworm - First Mutlicellular Eukaryote Sequenced
The C. elegans Sequencing Consortium.Genome sequence of the
nematode C. elegans: A platform for investigating biology. Science (11 December 1998) 282: 2012-8.
Yeast
A. Goffeau, et al. Life with 6000 genes. Science (25 October
1996) 274: 546, 563-7.
Bacteria - E. coli
F. R. Blattner, et al. The complete genome sequence of Escherichia coli K-12. Science 277: 1453-1474. (5 September 1997)
Bacteria - H. influenzae - First Free-living Organism
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.
NCBI Entrez Genomes
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.
More Information
Related Web Sites
Articles
Other Resources
- Genomics:
The Human Genome and Beyond - 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
and black fur. Requires free Shockwave plug-in.
- 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.
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