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#21 MSH6 family
ORTHOLOGY
I have run a BLAST in UniProt, for the human protein to check the orthologs.
Good hits to human seq:
human - P52701
mouse - P54276, checked against MOD seq
fly - Q9VUM0, checked against MOD seq
Dicty - Q55GU9, checked against MOD seq
S. pombe - O74502, checked against MOD seq
S. cerevisiae - Q03834, checked against MOD seq
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Checked additional species listed in the GO comparison graph
http://www.geneontology.org/images/RefGenomeGraphs/2956.html
Zebrafish - Q803S7, confirmed from MOD
Worm - Q9N3T8, confirmed from MOD
A. thaliana - O04716, in MOD this is OBSOLETE, see http://www.arabidopsis.org/servlets/TairObject?accession=gene:3713809
E.coli - P23909, confirmed from MOD
However, this is mutS, a paralog of MSH6, not an ortholog
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Have looked at the PPOD cluster to find remaining species
http://ppod.princeton.edu/cgi-bin/ppod.cgi/GO0/ORTHOMCL1834
Rat is a predicted protein, RGD:1310689, which is withdrawn in the MOD
There is no chicken gene in this cluster. A search on Entrez Gene results in a model Ref Seq, XP_419359.2 (GeneID: 421291). BLAST of this model seq in UniProt returns no chicken proteins.
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So planning to look at annotations across the following 8 species only:
human - P52701
mouse - P54276
fly - Q9VUM0
Dicty - Q55GU9
S. pombe - O74502
S. cerevisiae - Q03834
Zebrafish - Q803S7
Worm - Q9N3T8
Only one species annotated to each of the following terms:
MutLalpha complex binding
Oxidised purine DNA binding
Chromatin binding
Dinucleotide insertion or deletion binding
Single thymine insertion binding
Single guanine insertion binding
ADP binding
Magnesium ion binding
Purine specific mismatch base pair DNA N-glycosylase activity
Nuclear chromatin
Cytosol
Determination of adult life span
Response to UV
DNA damage response, signal transduction resulting in induction of apoptosis
induction of apoptosis by intracellular signals
base excision repair
negative regulation of DNA recombination
isotype switching
somatic recombination of immunoglobulin gene segments
somatic hypermutation of immunoglobulin genes
Abstracts reviewed to confirm each of these terms to be maintained:
MutLalpha complex binding – human confirmed
Oxidised purine DNA binding – human confirmed
Chromatin binding – mouse confirmed
Dinucleotide insertion or deletion binding – human confirmed
Single thymine insertion binding – human confirmed
Single guanine insertion binding – human confirmed
ADP binding – human confirmed
Magnesium ion binding – only in human, see further comments.
Purine specific mismatch base pair DNA N-glycosylase activity – human confirmed
Nuclear chromatin – mouse confirmed
Cytosol – only in Pombe, see further comments.
Determination of adult life span – only in mouse, see further comments.
Response to UV - only in mouse, see further comments.
DNA damage response, signal transduction resulting in induction of apoptosis – mouse confirmed
induction of apoptosis by intracellular signals – mouse confirmed
base excision repair – only in human, see further comments
negative regulation of DNA recombination – mouse confirmed
isotype switching – mouse confirmed
somatic recombination of immunoglobulin gene segments – mouse confirmed
somatic hypermutation of immunoglobulin genes – mouse confirmed
5 annotations removed or need rechecking:
1. Magnesium ion binding – only in human from PMID:16403449.
Rereading the paper, I no longer agree that this is a correct annotation, so have removed it from the human gene.
2. Cytosol – only in Pombe from PMID:16823372.
Not sure that this is correct as all other species have nuclear location for this protein, please could Pombe curators check if they are still happy with this. I don’t recommend that this annotation is transferred by ISS to any of the other species.
3. Determination of adult life span – only in mouse from PMID: 9390556 and PMID: 10545954.
I think this is a secondary effect, as not all mice with this gene mutation developed cancer. Mutated alleles of MSH6 result in tumours, thereby decreasing life expectancy, whereas I would expect genes annoted to this term to more directly be involved in determination of life span. Therefore I do not think this term should be transferred by ISS to any of the other species, and suggest that mouse curators check if they are still happy with this annotation.
4. Response to UV - only in mouse from PMID: 14632208
I think this annotation could be included as part of the larger discussion of ‘response to’ terms (http://wiki.geneontology.org/index.php/Annotation_consistency:_%27Response_to%27_terms). In this case I do not recommend ISS transfer of this term to other species, as I think the experimental evidence shows up-regulation of mouse MSH6 protein in response to damaged DNA, and this occurs irrespective of how the damage was caused.
5. base excision repair – only in human from PMID: 8942985
Rereading the paper, I think that this gene is actually acting too far upstream of this process to be annotated to this term, so I have replaced it with the parent term GO:0006281 DNA repair for the human gene.
Terms to transfer by ISS
1. Four-way junction DNA binding
Currently in: Human; Yeast
Transfer to: Mouse; Zfish; Fly; Worm; Dicty; Pombe
2. Damaged DNA binding
Currently in: Human; Mouse
Transfer to: Zfish; Fly;Worm; Dicty; Yeast; Pombe
3. Mismatched DNA binding
Currently in: Human; Mouse; Zfish; Dicty; Yeast; Pombe
Transfer to: Fly; Worm
4. ATP binding
Currently in: Human; Dicty; Yeast; Pombe
Transfer to: Mouse; Zfish; Fly; Worm
5. ATPase activity
Currently in: Human; Dicty; Yeast
Transfer to: Mouse; Zfish; Fly; Worm; Pombe
6. Mismatch repair complex
Currently in: Human; Mouse; Dicty; Yeast
Transfer to: Zfish; Fly; Worm; Pombe
7. mismatch repair
Currently in: Human; Mouse; Fly; Worm; Dicty; Yeast; Pombe
Transfer to: Zfish
8. Induction of apoptosis by intracellular signals
Currently in: Mouse
Transfer to: Human; Zfish; Fly; Worm; Dicty; Yeast; Pombe
These terms may not be applicable to all species, so I recommend trying to find experimental evidence for these terms in each species rather than transfer by ISS
1. Maintenance of DNA repeat elements
Currently in: Worm; Pombe
Look for evidence in: Human; Mouse; Zfish; Fly; Dicty; Yeast
2. Purine specific mismatch base pair DNA N-glycosylase activity
Currently in: Human
Look for evidence in: Mouse; Zfish; Fly; Worm; Dicty; Yeast; Pombe
3. Meiotic mismatch repair
Currently in: Fly; Yeast
Look for evidence in: Human; Mouse; Zfish; Worm; Dicty; Pombe
4. negative regulation of DNA recombination
Currently in: Mouse
Look for evidence in: Human; Zfish; Fly; Worm; Dicty; Yeast; Pombe
5. isotype switching
Currently in: Mouse
Look for evidence in: Human; Zfish; Fly; Worm; Dicty; Yeast; Pombe
6. somatic recombination of immunoglobulin gene segments
Currently in: Mouse
Look for evidence in: Human; Zfish; Fly; Worm; Dicty; Yeast; Pombe
7. somatic hypermutation of immunoglobulin genes
Currently in: Mouse
Look for evidence in: Human; Zfish; Fly; Worm; Dicty; Yeast; Pombe
Annotations added and QC complete for human MSH6
1. Induction of apoptosis by intracellular signals
Transferred by ISS from mouse
2. Maintenance of DNA repeat elements
Negative evidence for this in human MSH6, see PMID: 16388310
3. Meiotic mismatch repair
Evidence for this process in pombe, rat, mouse, fly and yeats, but not in human. Transferred by ISS to human from Yeast
4. negative regulation of DNA recombination
human evidence from PMID: 17715146
5. isotype switching
no human evidence, transferred by ISS from mouse
6. somatic recombination of immunoglobulin gene segments
no human evidence, transferred by ISS from mouse
7. somatic hypermutation of immunoglobulin genes
no human evidence, transferred by ISS from mouse