col1a1a / col1a1b

Warnings (3)

col1a1a / col1a1b

Back to pairs

Bottom line: DOSAGE, with a minor expression partition. The duplicate did become a
distinct subunit of the same complex: col1a1b encodes the teleost alpha3(I) chain,
which is built into type I collagen alongside alpha1(I) (col1a1a) and alpha2(I). But
no evidence shows that alpha3(I) adds a property that alpha1(I) lacks. The two
chains are co-expressed almost everywhere and occur at about equal amounts in adult
bone, skin and scales. Genetically they behave as partly interchangeable doses of
one "alpha1-like" chain: either single heterozygote is normal, but the double
heterozygote has fragile bones. The split is asymmetric. col1a1a is dose-limiting
(its null is lethal) and alone supplies the fin-fold actinotrichia, while col1a1b
is dispensable (its null is viable), evolves faster, and has been lost in several
teleost lineages. The expression and genetic facts are established. That alpha3(I)
is a quantitatively supplementary chain, and not a functional innovation, is an
inference from the absence of any copy-specific phenotype or property.

col1a1a col1a1b
UniProt Q6U1J5 (1447 aa; RefSeq NP_954684) Q6PEI9 (1449 aa; RefSeq NP_958886)
Chain alpha1(I) alpha3(I) (teleost-specific; synonym col1a3)
Human ortholog COL1A1 (literature; the PANTHER table lists COL3A1, see section 1) COL1A1 (literature; the PANTHER table lists COL3A1)
Review genes/DANRE/col1a1a genes/DANRE/col1a1b

1. Evidence the pair comes from the TGD

PANTHER (row in panther_tgd_pairs.tsv): call TGD_tree, duplication branch
Neopterygii|Teleostei, pair class 1:1, family PTHR24023 (COLLAGEN ALPHA). There is
1 gar co-ortholog, shared by both copies, and there are 2 medaka co-orthologs, with no
parallel medaka duplication. This is the strongest PANTHER call: one gar gene, and the
duplication placed after the gar split and before the zebrafish–medaka split. The
table's human_orthologs column gives COL3A1 for both copies, not COL1A1. We read
this as a quirk of PANTHER's orthology assignment within the large fibrillar collagen
family: both the literature phylogeny and the synteny place the pair with COL1A1
(below). It has no bearing on the TGD call.

Literature.

What is established: alpha3(I) is an alpha1(I) paralog, and the PANTHER tree places
the duplication on the teleost stem with a single gar gene. Not established: no
double-conserved-synteny (gar bridge) analysis has been published for this locus. The
sturgeon report has not been resolved at the sequence level. Sturgeons have their own
polyploidy, so a sturgeon "alpha3" could be an independent duplicate; that is our
inference, not a published test.

2. Protein-level comparison

Does each copy keep the ancestral molecular function? Yes. Both are structural type
I collagen chains built into the same trimer, and dominant glycine substitutions in
either gene damage bone collagen
[PMID:30082390 "The functional similarity between α1(I) and α3(I) is further illustrated by the fact that glycine substitutions in both genes can cause severe skeletal phenotypes, arguing for a dominant-negative effect on type I bone collagen and thus incorporation of a substantial amount of both α1(I) and α3(I) into the type I collagen triple helix."].
The protein-level change is in how alpha3(I) takes part in the complex: it has
changed assembly signals and fills one of the two "alpha1" positions. It does not do
a different kind of thing.

3. Expression

Shared vs copy-specific. Almost everything is shared. col1a1a has one extra domain
(fin fold and actinotrichia). col1a1b has no domain of its own; its only distinctive
feature is a quantitative bias toward skin and scales at the protein level. Whether
the fin-fold domain was ancestral and lost by col1a1b (a partition) cannot be told
without a non-teleost reference. Actinotrichia are a fish fin structure, so this is
plausible but untested.

4. Experimental evidence of function

All germline data come from one study that crossed the two paralogs
[PMID:30082390 "We systematically analyzed skeletal phenotypes in a large set of zebrafish models carrying different mutations in the zebrafish type I collagen-encoding genes col1a1a, col1a1b, and col1a2 (Table 1)."].
The null alleles are ENU nonsense alleles from the Zebrafish Mutation Project
[PMID:30082390 "The col1a1asa1748, col1a1bsa12931, col1a2sa17981, bmp1asa2416, and plod2sa1768 mutant zebrafish were generated by the zebrafish mutation project"],
i.e. PTC/NMD-type alleles. Each removes its chain from bone collagen
[PMID:30082390 "Two zebrafish knockout mutants with a premature stop-codon mutation in either col1a1a or col1a1b show absence of α1(I) and α3(I), respectively, in the vertebral bone"]
[PMID:30082390 "Accordingly, in col1a1b−/− mutants, no tryptic peptides of α3(I) could be detected, confirming decay of mutant col1a1b mRNA transcripts."].

col1a1a

col1a1b

Both copies together

Not done: there is no cross-rescue or allele swap, no RNA-less allele, and no test
of transcriptional adaptation (for example, col1a1a up in col1a1b PTC mutants). The
normal single heterozygotes could partly reflect upregulation of the paralog. There
are no data on skin or scale collagen in the col1a1b null, although that is where
alpha3(I) is relatively enriched.

5. Fate classification

DOSAGE, with a minor expression partition (col1a1a-only fin fold). No evidence of
protein-level innovation.

What would change the call:
- If collagen lacking alpha3(I) (col1a1b-/- skin or scales) showed a measurable change
in stability, cross-linking or fibril structure, the protein-level call would move
toward innovation (a specialized skin/scale chain).
- If a col1a1a CDS knocked into col1a1b fully restored col1a1b-/- skin and bone, pure
dosage would be confirmed.
- If col1a1a were upregulated in col1a1b PTC mutants, the apparent dispensability of
alpha3(I) would be partly an artefact of transcriptional adaptation.

6. GO annotation consistency across the pair

From annotation-comparison.md:

7. Open questions

References