Biology Reference
In-Depth Information
millions of years of opportunity for divergence
[41,42]
.
Several studies have queried specific genetic interactions
between duplicate gene pairs in S. cerevisiae, providing
a direct measure of their functional redundancy. All of
these studies found extensive evidence for redundancy,
reporting that 25
protein complex
[43]
. These observations may be recon-
ciled by a simple model for how the functional redundancy
shared between duplicate genes should affect their genetic
interactions across the genome
[46]
(
Figure 6.4
). Immedi-
ately following a gene duplication event, all genetic inter-
actions should be masked owing to complete functional
redundancy of the duplicated genes, and only as the
duplicated genes begin to diverge will genetic interactions
begin to reappear. Thus, the observed genetic interaction
profiles of duplicate gene pairs are generally incomplete,
composed only of those interactions that reflect functions
unique to the diverged duplicated gene (as through sub-/
neo-functionalization), while interactions related to the
common function(s) of the paralog pair cannot be detected
in the absence of a single gene when one gene of the
duplicated pair remains intact and functional. Analysis of
the yeast genetic interaction map supported this hypothesis
and suggested that genetic interactions are useful for dis-
secting the functional divergence of duplicate genes
[46]
.
Additionally, we found that many duplicate pairs
exhibited a highly asymmetric pattern of functional diver-
gence where one gene retained or acquired a large number
of genetic interactions while the other exhibited relatively
few interactions
[46]
. Interestingly, the asymmetry in
number of genetic interactions for duplicated gene pairs
35% of paralogs exhibit negative genetic
interactions, which was between 10 and 20 times higher
than expected by chance
[28,43
e
45]
. The high rate of
negative genetic interaction observed among duplicates in
yeast, many of which have been maintained for ~100
million years, presents an evolutionary paradox: why
would functionally redundant copies of a gene be main-
tained with such high sequence similarity? Insight into this
question was gained by looking beyond individual inter-
actions connecting paralog pairs to examine broader
genome-wide interaction profiles associated with these
genes.
If duplicated genes share a high degree of redundancy, it
was reasoned that deletion of a single duplicated gene
should not yield many genetic interactions. However,
functionally redundant duplicates often exhibit genetic
interactions with other genes, suggesting that redundancy is
at best incomplete
[43]
. Moreover, they also shared fewer
interactions in common than other functionally related
gene pairs, such as two distinct members of the same
e
Common Ancestor
Immediately After Duplication
After Duplicate Divergence
Function 2
Function 3
Function 2
Function 3
Function 2
Function 3
Funtional
relationships
A
A'
A"
A'
A"
Function 1
Function 4
Function 1
Function 4
Function 1
Function 4
Function 5
Function 5
Function 5
X
Y
X
Y
X
Y
Genetic
interactions
A
A'
A"
A'
A"
W
V
W
V
W
V
Z
Z
Z
FIGURE 6.4
Role of genetic interactions in the characterization of duplicate gene pairs. A model for the buffering of genetic interactions by
partially redundant genes. Gene A has no redundant partner and its set of functional relationships is revealed through negative genetic interactions.
Immediately after duplication, genes A
0
and A
00
are fully redundant and their functional relationships are shared. Because each is capable of performing
their common functions without the other, the deletion of A
0
or A
00
has negligible effects and does not exhibit negative interactions with any other genes.
However, the simultaneous deletion of A
0
and A
00
reveals the original phenotype of their ancestor, and shows a negative genetic interaction. As A
0
and A
00
diverge, the redundancy becomes incomplete and unique deletion consequences emerge for each duplicate. Some of the negative genetic interactions
observed for the ancestor gene A are not observed following duplication and divergence; for example, despite the functional relationship between A
0
and
A
00
and Z, negative interactions are not observed with Z. A
00
has evolved a new relationship with Function 4. A
0
lacks this ability and we see a genetic
interaction between A
00
and V. Modified from
[46]
.
