# HISTORY
23 Mar 2016: Updated by: TOUCHUP-v1.15
14 Mar 2016: Updated by: TOUCHUP-v1.12

# molecular_function
20120921: node_PTN000002250 has function methylenetetrahydrofolate dehydrogenase (NADP+) activity (GO:0004488) 
20120921: node_PTN000002250 has function methenyltetrahydrofolate cyclohydrolase activity (GO:0004477) 
20120921: Eukaryota_PTN000002254 has function methylenetetrahydrofolate dehydrogenase (NAD+) activity (GO:0004487) 
20120921: Opisthokonta_PTN000002266 has function formate-tetrahydrofolate ligase activity (GO:0004329) 
20120921: Bilateria_PTN000002329 has function methylenetetrahydrofolate dehydrogenase (NAD+) activity (GO:0004487) 
20120921: Bilateria_PTN000002329 has LOST/MODIFIED function formate-tetrahydrofolate ligase activity (GO:0004329) 
20120921: Amniota_PTN000002274 has LOST/MODIFIED function methylenetetrahydrofolate dehydrogenase (NADP+) activity (GO:0004488) 
20120921: Amniota_PTN000002274 has LOST/MODIFIED function methenyltetrahydrofolate cyclohydrolase activity (GO:0004477) 
20120921: Eukaryota_PTN000002254 has LOST/MODIFIED function methylenetetrahydrofolate dehydrogenase (NADP+) activity (GO:0004488) 
20120921: Eukaryota_PTN000002254 has LOST/MODIFIED function methenyltetrahydrofolate cyclohydrolase activity (GO:0004477) 

# cellular_component
20120921: node_PTN000002250 is found in cytosol (GO:0005829) 
20120921: Saccharomycetaceae_PTN000002392 is found in mitochondrion (GO:0005739) 
20120921: Bilateria_PTN000002329 is found in mitochondrion (GO:0005739) 
20120921: Amniota_PTN000002274 is found in mitochondrion (GO:0005739) 
20120921: Bilateria_PTN000002329 is NOT found in cytosol (GO:0005829) 
20120921: Saccharomycetaceae_PTN000002392 is NOT found in cytosol (GO:0005829) 
20120921: Amniota_PTN000002274 is NOT found in cytosol (GO:0005829) 

# biological_process
20120921: node_PTN000002250 participates in one-carbon metabolic process (GO:0006730) 

# WARNINGS - THE FOLLOWING HAVE BEEN REMOVED FOR THE REASONS NOTED

# NOTES
Tree:
- The tree is based on the MTD/MCH domain only (note that it's one domain that generally has two MFs).  Many members also have an FTS domain, that can be explained by a gain of this domain at the base of the opisthokonts in the ancestor of the MTHFD1 (human) gene.
- Root is spurious, due to two outliers that have only a single domain (FTS) that is not found in most family members.  Do not annotate root.
MF:
- Annotate the root of the folD (E. coli) clade at LUCA with MCH activity and MTD (NADP) activity based on widespread annotations, including the E. coli gene.
- Annotate the base of the MTD1 (yeast) clade with MTD (NAD).  This is a monofunctional MTD that is specific for NAD (Swiss-Prot), so annotate loss of MTD (NADP) and MCH.
- Annotate the gain of FTS function when the FTS domain is gained.
- Annotate the loss of FTS function in the Nmdmc (D. mel) clade, due to the loss of the FTS domain.
- Annotate the loss of MCH/MTD function in the Nmdmc (D. mel) clade, due to loss of this domain.  Annotate gain of NAD specificity in this clade, but not loss of NADP due to an NADP annotation for the human enzyme.
- f-Met-tRNA synthesis function is not correct for yeast MIS1, suggest removal (should be annotated to downstream gene FMT1 instead)
- f-tetrahydrofolate dehyd function is not correct for mouse Mthfd1 (should be annotated to Aldh1l1 instead), suggest removal
CC:
- annotate root of each major clade with cytosol
- annotate loss of cytosol and gain of mitochondrion in MTHFD1L (human) clade, Nmdmc (D. mel) clade, and MIS1 (yeast) clade.
- nucleus annotation to ADE3 (yeast) is an outlier, so do not annotate
BP:
- annotate one carbon metabolism to root of main clade
- do not annotate other folate biosynthesis-related terms, as this pathway, while it does create folate every time a methyl/formyl group is removed, folate is used as a shuttle and is not synthesized by this route.
- do not annotate purine biosynthesis terms, as purine biosyn pathway is distinct and downstream (purine biosynthesis uses formate obtained via the one carbon pathway)
- do not annotate formate metabolic process. In theory it would be OK, but it sounds like a grouping term: one-carbon pathway should probably be a child of this term
- do not annotate oxidation-reduction process.  Again this is a grouping term and even worse, it only describes a molecular function.
- do not annotate determination of adult lifespan as it is more properly a phenotype and not a process.
- do not annotate transcription regulation, as it is an outlier and it is not clear when it evolved
- also suggest removal of mouse Mthfd1 annotations to oxidation-reduction process and histidine catabolic process due to same problem as MF above
PDT 2012-09-21

# REFERENCE
Annotation inferences using phylogenetic trees
The goal of the GO Reference Genome Project, described in PMID 19578431, is to provide accurate, complete and consistent GO annotations for all genes in twelve model organism genomes. To this end, GO curators are annotating evolutionary trees from the PANTHER database with GO terms describing molecular function, biological process and cellular component. GO terms based on experimental data from the scientific literature are used to annotate ancestral genes in the phylogenetic tree by sequence similarity (ISS), and unannotated descendants of these ancestral genes are inferred to have inherited these same GO annotations by descent. The annotations are done using a tool called PAINT (Phylogenetic Annotation and INference Tool).