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Genome Biol Evol
2012 Jan 01;49:883-99. doi: 10.1093/gbe/evs061.
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Repeated evolution of identical domain architecture in metazoan netrin domain-containing proteins.
Leclère L
,
Rentzsch F
.
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The majority of proteins in eukaryotes are composed of multiple domains, and the number and order of these domains is an important determinant of protein function. Although multidomain proteins with a particular domain architecture were initially considered to have a common evolutionary origin, recent comparative studies of protein families or whole genomes have reported that a minority of multidomain proteins could have appeared multiple times independently. Here, we test this scenario in detail for the signaling molecules netrin and secreted frizzled-related proteins (sFRPs), two groups of netrin domain-containing proteins with essential roles in animal development. Our primary phylogenetic analyses suggest that the particular domain architectures of each of these proteins were present in the eumetazoan ancestor and evolved a second time independently within the metazoan lineage from laminin and frizzled proteins, respectively. Using an array of phylogenetic methods, statistical tests, and character sorting analyses, we show that the polyphyly of netrin and sFRP is well supported and cannot be explained by classical phylogenetic reconstruction artifacts. Despite their independent origins, the two groups of netrins and of sFRPs have the same protein interaction partners (Deleted in Colorectal Cancer/neogenin and Unc5 for netrins and Wnts for sFRPs) and similar developmental functions. Thus, these cases of convergent evolution emphasize the importance of domain architecture for protein function by uncoupling shared domain architecture from shared evolutionary history. Therefore, we propose the terms merology to describe the repeated evolution of proteins with similar domain architecture and discuss the potential of merologous proteins to help understanding protein evolution.
Fig. 1.—. Phylogenetic analyses of the
complete amino acid domain datasets support polyphyly of netrins and sFRPs.
(A) Netrin domain maximum likelihood (ML) analysis under a WAG
+ Γ(8) + I model (111 aa, 101
sequences, − ln L 21377.15); (B)
LamininNT-3EGF supra-domain ML analysis under a model WAG +
Γ(8) + I (363 aa, 99 sequences,
−ln L 50081.22); (C) Frizzled-CRD domain ML
analysis under a model LG + Γ(8) +
I (112 aa, 87 sequences, −ln L 10857.68).
For deep branches, nonparametric bootstrap values BP (ML)—500
replicates—are indicated on the left (A) or above the
branches (B and C), and Bayesian posterior
probability (PP) are indicated on the right or below the branches. Asterisks
indicate branches with maximum support for both BP (ML) and PP. A dash indicates
branches with BP (ML) < 50% and PP < 70%. (B)
Values in parenthesis correspond to BP (ML) and PP values from analyses without
Amphimedon and Monosiga sequences. For other
branches, black dot indicates PP ≥ 90%, yellow dot indicates PP ≥
95% and BP (ML) ≥ 90%. The scale bar indicates the estimated
number of substitution per site. Consistent grouping of netrin and sFRP subfamilies
in individual domain phylogenies are highlighted in red and green, respectively.
(A–C) Domain composition of proteins are sketched next to
each subgroup and are oriented N- to C-terminal from top to bottom in
A and from left to right in B and
C. Size of netrin and sFRP protein sketches are double that for
the other proteins. The two first letters of gene names in B and
C correspond to the first letters of genus and species names (see
Materials and Methods).
Fig. 3.—. Netrin,
LamininNT-EGF, and frizzled-CRD domains display a significant level of substitution
saturation. Estimation of the substitution saturation of the domains netrin
(A), LamininNT-EGF (B), and frizzled-CRD
(C) at the amino acid level (complete datasets) as a ratio
between inferred (x axis) and observed (y axis)
differences for each pair of sequences. Inferred number of substitutions between
pairs of sequences were determined using parsimony on the best ML trees. White
squares and grey diamonds represent netrin-1/2/3/5-netrin-4 and sFRP-1/2/5-sFRP-3/4
pairwise comparison, respectively. Data points on the straight line X = Y
correspond to completely unsaturated comparisons.
Fig.
4.—. Distribution of the polyphyly versus monophyly signal for
netrins and sFRPs. Differences in log likelihood per-site (Δpsln
L) between unconstrained and constrained maximum likelihood
analyses of (A) LamininNT-EGF supra-domain, with netrin-1/2/3/5
+ netrin-4 + netrin-G constrained as monophyletic; (B)
LamininNT-EGF and netrin domains, with netrin-1/2/3/5 + netrin-4 constrained as
monophyletic; (C) frizzled-CRD and netrin domain, with sFRP-1/2/5
+ sFRP-3/4 constrained as monophyletic. The x axes correspond
to the alignment columns along the complete amino acid matrices and the
y axes correspond to the Δpsln L between
unconstrained and constrained ML analyses. The sites with positive
y axis values have a higher likelihood for the unconstrained
topology in which netrin or sFRP is polyphyletic, whereas the sites with negative
y axis values have a higher likelihood for the constrained
topology in which netrin or sFRP is monophyletic.
Fig. 5.—. Polyphylies of
netrins and sFRPs are supported by slow-evolving sites and are not caused by
heterotachy in the ML analyses of the LamininNT-EGF (A,
B, E, F, I,
and J) and frizzled-CRD (C, D,
G, H, K, and
L) amino acid datasets. (A and C)
Proportion of sites for each rate category, corresponding to the calculated number
of steps in seven monophyletic groups using parsimony. For displaying purpose, each
category contains two merged sequential values. (B and
D) Cumulated difference in log likelihood per-site between
unconstrained and constrained (B: netrin-1-4 monophyletic;
D: sFRP-1/2/5-3/4 monophyletic) ML analysis for all sites within
each rate category. (E and G)
“Evolution” of the ML bootstrap support values (100 replicates) as
fast-evolving sites are progressively removed from the original dataset;
(E) 90% of bootstrap support is figured by a dotted line;
(G) the “evolution” of BP-ML support value for sFRP
monophyly is also indicated as slow-evolving sites are progressively removed from
the original dataset. (F and H) Estimation of the
mutational saturation as a ratio between inferred (x axis) and
observed differences (y axis) for each pair of sequences in the
LamininNT-EGF (F) and frizzled-CRD (H) datasets
containing, respectively, the 30% and 50% slowest evolving sites. Data
points on the straight line X = Y correspond to completely unsaturated
comparisons. Data coming from the analyses of the 30% slowest evolving sites
of the LamininNT-EGF dataset (in A, B,
E, and F) and of the 50% slowest evolving
sites of the frizzled-CRD dataset (in C, D,
G, and H) are shaded. (I and
K) Histogram of the absolute difference of steps per site
calculated between the netrin-1-laminin-γ and netrin-4-laminin-β clades
for the LamininNT-EGF dataset (I) and between the
frizzled-5/8-frizzled-1/2/7-3/6-sFRP-3/4 and frizzled-4-frizzled-9/10-sFRP-1/2/5
clades for the frizzled-CRD dataset (K). (J and
L) Cumulated difference in log likelihood per-site between
unconstrained and constrained (netrin-1-4 monohyletic in J;
sFRP-1/2/5-3/4 monophyletic in L) ML analysis for all sites within
each “Δsteps per site” category. Data coming from the analyses of
the 70% nonheterotachous sites of the LamininNT-EGF dataset
(I and J) and of the 84% nonheterotachous
sites of the frizzled-CRD dataset (K and L) are
shaded.
Fig.
6.—. Evolutionary scenario for the origin and evolution of
netrins and sFRPs. Schematic representation of expansion of (A)
netrins and (B) sFRP within one evolutionary lineage by both
convergent domain shuffling and gene duplication. Note that diversification of
laminin and frizzled proteins in vertebrates and origin and diversification of
laminin-α, β/γ-like and netrin-G have been
omitted.
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