What does the mouse genome draft tell us about evolution?
Alec MacAndrew
Click on the links below to explore various aspects of the mouse genome, its comparisons with the human genome and the consequences for evolutionary thinking:
Introduction
| The draft mouse genome was published on 6th December 2002 , Waterstone et al, Nature 420, 520 - 562
Note that this is a 43 page paper (Nature averages 2 -3 pages per paper) with around 200 authors and 330 references. This is all new to science and the volume of material is more than a very fat text book if one includes the references . The detail is published not in a single paper, but in about six related papers occupying more than half of the super fat 6th December issue of Nature. |
Scientists think that the mouse genome will be even important
than the human genome to medicine and human welfare. That seems bizarre: why
is that? The reason is that, because of the relatively 'recent' divergence
of the mouse and human lineages from our common ancestor (about 75
million years ago), an astonishing 99% of mouse genes turn out to have
analogues in humans. Not only that, but great tracts of code are syntenic -
that means the genes appear in the same order in the two genomes.
Since we can experiment on
the mouse genome (we obviously cannot do that with people), the mouse will
be a hugely valuable model to understand the function and operation of the
genetic machinery in people. We already have incredibly precise tools to
modify the mouse genome including the ability to delete or duplicate
extensive tracts of code, the ability to knockout or knock-in single genes and even the
ability to make single base substitutions.
The astonishingly close
homology that has been revealed in the code between mouse and human genome
extends to functionality. Many homologous genes have identical functions in
the two species, anatomy, physiology and metabolism are similar and genetic
disease pathology can be very similar. So the fact that we can study the
mouse empirically, means that we can identify the functions of genes in
people and both understand human disease pathology and create ways to treat
it.
One example, given in the accompanying News and Views article
in the same edition of Nature, is that the same genetic defect causes
cystic fibrosis in humans and a similar disease in the mouse, except
that in the mouse it does not lead to the most debilitating aspect of
human cystic fibrosis which is lung disease. By understanding how the
mouse avoids contracting lung disease in the presence of this genetic
lesion, we could well find a way to prevent the development of lung
disease in human cystic fibrosis sufferers.
Another interesting
finding is a surprising level of conservation in certain tracts of
non-coding sequence (so-called junk DNA). It seems that some of this material
does have some (probably regulatory) functionality and that there is more of
this than we thought. (Not all of course is conserved - there is still a
huge amount of junk that can be regarded as genetic fossils).
Click
on the links below to explore various aspects of the mouse genome, its
comparisons with the human genome and the consequences for evolutionary thinking:
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Synteny occurs when similar genetic code occurs in the genomes of two species in the same order |
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Sequence repeats are the result of insertions of genetic material by retroviruses etc |
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Concentrating on the sequences coding for proteins |
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Concentrating on the proteins themselves |
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The basic mechanism of evolution are mutation and selection - what do the mouse and human sequences tell us? |
Evidence for the Theory of Evolution
The findings of the draft mouse genome are astonishingly powerful evidence for common ancestry, mutation and selection: in short for the Theory of Evolution. There is a list with links below for the key points within the paper which can only be explained by evolution. It is just not possible to explain what we see in the two genomes if they have only been in existence for 6500 years unless we invoke deliberate deceit on God's part:
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The syntenic blocks have been re-arranged
by chromosomal events over time - 
The distribution of size of the syntenic
blocks is consistent with a random mechanism for chromosomal rearrangements
- 
It is possible to recognise the difference
between repeat sequences that were added to the genomes before
divergence of mouse and man lineages and those added after divergence -
The measured mutation rate since divergence
of mouse and man is ample to explain the divergence of the
species - 
The rate of insertions of repeat sequences
as a function of time can be measured for both man and mouse - 
Repeat sequences are tolerated
in the same regions in mouse and man and in both cases insertion
of repeat sequences is not tolerated in functionally critical regions
such as the homeobox clusters - 
Two sorts of pseudogene exist in eukaryotes
- processed and unprocessed - we know how they arise and it has
taken millions of years for the pseudogenes we see in mouse and
man to arise - 
Pseudogenes can be identified by the
ratio of synonymous to non-synonymous mutations occurring over millions
of years and by the fact they do not generally have a homologous
gene in the same syntenic position in the other genome - 
99% of mouse genes have homologues
in humans and 96% are in the same syntenic location - 
The fact that mouse and human are
relatively closely related allows us to study orthologous genes
- genes which have arisen and diverged from a common ancestor -
12,845 orthologous gene pairs were
found between man and mouse (homologous genes in the same syntenic
location) - 
The 
Within genes, regions containing known
domains have a lower 
The percentage of cases in mouse where
the mouse gene matches the most common human allele at sites which
have Single Nucleotide Polymorphisms is very close to the percentage
of amino acid identity across the two genomes: very strong evidence
for common ancestry - 
Expansion into gene families has occurred
in cases where the family has important functionality specific to
a lineage - 
The 
The percentage nucleotide alignment
across the whole of the mouse and human genomes (about 40%) is compatible
with what is known about the rate of DNA deletion in the two lineages
since divergence - 
The rate of substitutions in ancestral
repeat sequences in non-coding DNA is the same as the rate
of substitution at four fold degenerate sites in functional regions -
very strong evidence for mutation and selection over a long time
- 
The detail of which parts of the genome
are more highly conserved between the two species aligns well with
functionality - 
Introns are conserved no more than
background non-functional DNA and so do not appear to have functionality
in their code - 
Gene structures - number of exons
and coding length in exons - is strongly conserved across mouse
and human genomes - very strong evidence for common ancestry - 
The difference in mutation rate (obtained
by comparing mouse and human genomes) between X-chromosomes and
autosomes can be explained by what we know about differences in
mutation rate in male and female meiosis and relies on common ancestry
and mutation over millions of years -