Human osteoarthritis is a progressive disease of the joints characterized by degradation of the cartilage, a major component of which is aggrecan. Several groups of researchers have recently identified ADAMST5 as the primary enzyme responsible for the degradation of aggrecan and the resulting loss of cartilage in mice.
Adult mice lacking the active portion of the ADAMST5 gene (knockout mice) were found to have no gross abnormalities and 17 tissue types as well as blood and serum were examined and found to be normal. Knockout mice underwent surgery to simulate joint injury. A significant reduction in cartilage destruction was observed in these mice compared to wild-type mice.
Again (see the previous article), ADAMST5 appears to confer no benefit and actually exacerbate injury and yet has been conserved in the mouse genome.
Ref: Nature 31-Mar-2005 Pg 644
Tuesday, April 19, 2005
Why Do Mice Cells Have Cyclophilin D?
Several groups of researchers investigating the mechanisms of cell death have reported a puzzling result. Mice lacking the gene for Cyclophilin D appear to develop normally and additionally to be more resistant to cell necrosis.
Cells die in two ways. Apotosis is a controlled process in which the cell's contents are broken down before the cell membrane ruptures thereby avoiding inflammatory damage to nearby tissue. Necrosis is an uncontrolled process which occurs in response to injury such as lack of oxygen and causes further injury to nearby tissue.
When blood supply to a tissue is disrupted (ischaemia), cells begin to die by necrosis. If a long time elapses before blood flow is restored (reperfusion), additional cells undergo necrosis causing even further damage to the tissue. The recent research establishes that Cyclophilin D mediates the process of necrosis after reperfusion.
The puzzling finding is that mice lacking Cyclophilin D develop normally but also appear to be protected from reperfusion injury following ischaemia. Why would a gene that appears to confer no benefit and actually exacerbate injury be conserved in the mouse genome?
Ref: Nature 31-Mar-2005 Pg 658
Cells die in two ways. Apotosis is a controlled process in which the cell's contents are broken down before the cell membrane ruptures thereby avoiding inflammatory damage to nearby tissue. Necrosis is an uncontrolled process which occurs in response to injury such as lack of oxygen and causes further injury to nearby tissue.
When blood supply to a tissue is disrupted (ischaemia), cells begin to die by necrosis. If a long time elapses before blood flow is restored (reperfusion), additional cells undergo necrosis causing even further damage to the tissue. The recent research establishes that Cyclophilin D mediates the process of necrosis after reperfusion.
The puzzling finding is that mice lacking Cyclophilin D develop normally but also appear to be protected from reperfusion injury following ischaemia. Why would a gene that appears to confer no benefit and actually exacerbate injury be conserved in the mouse genome?
Ref: Nature 31-Mar-2005 Pg 658
Can Plants "Evolve Backwards"?
Researchers at Purdue may have discovered a revolutionary new ability of organisms to correct their DNA. Using a mutant variety of the plant Arabidopsis, they found plant offspring that had apparently corrected various mutations in their DNA.
The rate at which the corrected mutations occurred ruled out chance as the explanation. The possibility that the correction came from another similar DNA segment acting as a template was also considered and ruled out. The researchers scanned the entire genome for similar sequences without result. Also, the fact that the correction was to a single nucleotide and no flanking DNA was different from the wild-type gene makes it unlikely that a similar but not identical sequence was used as the basis for the correction.
The authors speculate that the correction mechanism is based on a cache of ancestral sequences in RNA carried in the gamete. If true this would be a powerful new evolutionary mechanism that could help to explain how organisms can evolve at observed rates. The authors further speculate that the phenomenon may be related to some type of stress-recognition system.
Assuming that gametes carry a cache of ancestral RNA templates, when an organism detects that is undergoing stress, the new mechanism may use the cached templates to "evolve backwards" by correcting recently mutated genes thereby passing to offspring the ancestral DNA sequence.
Because it is generally thought that the vast majority of DNA mutations are detrimental, such a mechanism would allow a mutation to be "tested" in one generation and corrected in the next generation if it were determined to cause stress to the organism. So the evolving organism could avoid some detrimental mutations becoming fixed in the genome. And thus the overall rate of beneficial mutation in a population would increase.
Ref: Nature 24-Mar-2005 Pg 505
The rate at which the corrected mutations occurred ruled out chance as the explanation. The possibility that the correction came from another similar DNA segment acting as a template was also considered and ruled out. The researchers scanned the entire genome for similar sequences without result. Also, the fact that the correction was to a single nucleotide and no flanking DNA was different from the wild-type gene makes it unlikely that a similar but not identical sequence was used as the basis for the correction.
The authors speculate that the correction mechanism is based on a cache of ancestral sequences in RNA carried in the gamete. If true this would be a powerful new evolutionary mechanism that could help to explain how organisms can evolve at observed rates. The authors further speculate that the phenomenon may be related to some type of stress-recognition system.
Assuming that gametes carry a cache of ancestral RNA templates, when an organism detects that is undergoing stress, the new mechanism may use the cached templates to "evolve backwards" by correcting recently mutated genes thereby passing to offspring the ancestral DNA sequence.
Because it is generally thought that the vast majority of DNA mutations are detrimental, such a mechanism would allow a mutation to be "tested" in one generation and corrected in the next generation if it were determined to cause stress to the organism. So the evolving organism could avoid some detrimental mutations becoming fixed in the genome. And thus the overall rate of beneficial mutation in a population would increase.
Ref: Nature 24-Mar-2005 Pg 505
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