Evolvability of new functions

From: pruest@pop.dplanet.ch
Date: Fri Nov 03 2000 - 11:42:51 EST

Tim Ikeda <tikeda@sprintmail.com>

Hi Tim,
(my new comments are those without > <)

David Campbell: >>>>> I would see the combination of parts from several
different genes followed by selection for a new function as a relatively
substantial innovation...<<<<<

Peter: >>>>I agree that this is a relatively substantial innovation.
But, nevertheless, I would consider the amount of novel information
gained to be relatively small. ("Information" has even more different
meanings than "micro-" and "macroevolution"!) I would justify this claim
as follows: After a single nucleotide mutation, the mutant and the
wild-type are subject to natural selection, whose "answer" to the
mutation is "yes" or "no" or something in-between, i.e. at most 1 bit of
information. The same consideration applies to any more complex
mutation, such as a new gene composed of shuffled exons: as far as
natural selection is concerned, the gain of information from the
environment is at most 1 bit. If this seems counter-intuitive, we must
ask whether this new construct was produced in a single step, such as an
unequal crossing-over. If yes, then it was a simple step, like a simple
mutation or deletion. If it required a series of coordinated steps, the
intermediates in this path probably were not under any selection, and
the probability of end product formation may have been extremely
Tim: >>> Hmm... Sounds like Lee Spetner...<<<
Peter: >>Never heard of Spetner...<<
Tim: > That's definitely a plus in my book. ;^)<
Peter: Hasn't it been requested that idiosyncratic abbreviations be

Tim: >>> There is a very serious difficulty, IMO (and others' - consult
earlier discussions in sci.bio.info-theory), in relating sequence and
structural information measurements with metrics derived from selection.
For example, ...<<<

Peter: >>I fully agree that a metric derived from selection cannot be
used for estimating sequence and structural information. But this is NOT
what I am doing. What I call functional or semantic information, given
by sequence / structure in a given environment, cannot be measured in
any way I know of. The closest we can get is what H.P.Yockey did
("Information theory and molecular biology" (Cambridge: Cambridge
Univ.Press, 1992), p.254) for the presumptive functional information
contained in a modern protein (family). But even this doesn't tell us
how this information arose. Presumably, the earliest structures
displaying this function were very much simpler. The only source for
functional information in biological systems we know of is the
environment acting in natural selection. Each event of fixation of a
genetic change of any type and size is at most a yes/no answer: at most
1 bit of information.<<
Tim: > This information metric is entirely dependent on the
environmental conditions in which the organism finds itself. And since
environmental conditions change, this metric will change as well. For
example, one may select for or against strains of bacteria carrying a
gene which imparts tetracycline resistance. On media with tetracycline,
the resistant strains are selected (an increase of one bit by your
metric). However, when spread on Bochner plates, these same strains
carrying tetracycline resistance alleles may be selected against -- but
in this case, the loss of the resistance allele (via deletion or point
mutation) must also be scored as a one bit increase which originates
from environmental sources of information.
So clearly selection alone, or interactions environment do not provide
terribly useful measures of biological information, particularly at the
sequence level as you've noted. While measures of fitness may provide
information about how some alleles become distributed across
populations, the models become largely uncomputable when more than a few
genes are considered.<

Peter: I agree. I said that an event of fixation due to selection yields
*at most* one bit of information, but possible nothing at all, depending
on circumstances.
Peter: >>But natural selection can only test a functional feature
already present to some minimal degree. If we consider the entire
historical developmental path of a functionality (e.g. an enzyme),
including all of the functional information contained in it, its
specific activity must have started sometime with a minimal amount of
activity just sufficient to make it selectable. And before that? This is
the interesting part of its history, because without selection, we can
estimate a probability of random emergence.<<

Tim: >Without selection, one can estimate such probabilities if one has
a good idea about the initial state of the system -- which requires
information about the makeup of the organism and the environment in
which it is found (& how these variables have changed over time). And
this is only viable if the gene or protein in question can be known to
have evolved in isolation. Include interactions with other components of
the cell or the environment and one has a difficult time predicting or
assigning probabilities to changes. I know of no such isolated systems
except possibly, those examined in vitro.<

Peter: As soon as a system or protein has any effect on its carrier, it
is under selection (by definition), and it is hardly possible to
estimate any probabilities - as you say. I also agree that it will be
difficult to find such isolated systems without selection. In this
sense, my most interesting case is hypothetical. But is an evolution of
an entire biosphere at all imaginable without (many) such cases?

Peter: >>Afterwards, normal darwinian evolution sets in, and I see no
way of estimating probabilities. There may be many other critical points
in the evolution of a new function, but this is certainly the first one
of them - and it is habitually ignored by evolutionary biologists.<<

Tim: >Because the answer cannot be determined at this time? I don't know
if the question is ignored or whether computational models are simply
not known.<

Peter: I suggested a (very rough) method to estimate an upper limit for
the amount of information reasonably attributable to random walk
processes, before selection should be able to set in: 2 specific amino
acid occupations (see below).
Tim: >>> 1) a single point mutation can allow a bacterium to survive on
one growth medium where it couldn't previously. What could that point
mutation have done? Is there only one bit of change involved?
2) It could have changed one amino acid to another in a protein. What is
the net change in the information content of the protein?
3) It could have erased a stop codon, permitting expression of a longer
protein. How many bits of information are in the longer sequence?
4) Or, the mutation could have wiped out a promoter, preventing the
expression of the protein. Is that information change positive or
negative with respect to the protein?
5) Or, the mutation could have generated a new splice site -- How much
information change in the resultant protein?
6) Or, the mutation could have replaced a proline with an aspartate,
taking the break out of an alpha-helix. What's the difference in
information content?
These cases are not readily quantifiable. The question is: With respect
to what is the information metric derived? Sure, the difference between
my having one or two hundred-dollar bills in my pocket may represent an
informational difference of one bit, by I can do a heck of a lot more
with two of those bills than I can with one.<<<
Peter: >>What is not quantifiable here is the amount of functional
information acquired by the system in its entire history. I was only
considering the last step of selection - which yields at most one bit of
additional information, no matter what type of change this last step
Tim: >Well, if selection can favor either the fixation of a new gene or
the deletion of a earlier one (e.g. the tetracycline example I give),
I'm not sure how the increase in information as defined by selection
coefficients maps to sequence variations, even at the last step in the
process. Thus, I don't see how this discussion could apply to protein
evolution. (Perhaps that wasn't the point anyway -- I've come to the
conversation a bit late I can definitely be dense).<

Peter: I agree that darwinian evolution under selection is not readily
quantifyable (cf. above).
Peter: >>The only reason I brought it up at all is because natural
selection is the only natural source of biological information we know
of. Of course, the probabilities of the different types of changes which
might have produced the new function may be very different, and are
usually not estimable. Even if this last step alone produced a new
function never before found in the biosphere, the functional properties
of the new protein are certainly a consequence of the sequence /
function properties of its precursor(s). I would not consider this to be
nothing, even if it didn't display any of the new function at all,
because it represents a very specific prerequisite for the new function:
you cannot splice together any two odd sequences and obtain a specific
function required at the moment.<<
Peter: >>>> But to assume that ALL functionalities emerged in such a
manner, without any non-selectable intermediates, is entirely
speculative. How do you know this is "the vast majority" of genes? You
yourself concede that the origin of "the first gene" is not dealt with.
There are an estimated 1000 different protein folds (each grouping a
series of protein families or superfamilies) in the biosphere,
considering the globular, water-soluble proteins only (Y.I.Wolf,
N.V.Grishin, E.V.Koonin, "Estimating the number of protein folds and
families from complete genome data", J.Mol.Biol. 299 (2000), 897-905).
Almost by definition, these 1000 folds are not related to each other by
exon shuffling and gene duplication.<<<<

Tim: >>>I think that may be hard to tell. For example, alpha-helices can
move and be rearranged by recombination and duplication. I think some
porins and other transmembrane proteins have likely arisen from events
such as these. <<<

Peter: >>Ok, I reduce my claim by adding "usually".<<

Peter: >>>>Each one of them had to originate somewhere at least once
during the past 3.8 billion years. Thus, it would be more realistic to
talk about "the first 1000 genes" whose emergence cannot be accounted
for at present. These are the cases I am considering when I talk about a
mutational random walk without intermediate selection until a minimal
selectable activity happens to be produced. These are cases I consider
macroevolutionary steps posing considerable informational problems
deserving careful attempts at estimating their probability and at
possibly finding more realistic evolutionary scenarios than merely
assuming that "it must have happened somehow" through selectable
You may call these the most elementary cases of Behe's "irreducibly
complex systems" - whose non-existence has not yet been made

Tim: >>>One thing about the "first 1000 folds" (I think fewer perhaps,
but nevermind), is that they seem to be common to all the major
divisions of life. I'm not sure how to peer behind the curtain of 2-3
billion years ago when the major divisions appear to have split.
However, one thing that comes to mind is that horizontal transfer may
have been a major factor in early life (which may account for the
relatedness between groups). With horizontal transfer, the pool is a
little bigger and testing may go somewhat faster.<<<

Peter: >>Wolf et al.'s estimate of 1000 different folds refers to the
entire biosphere; horizontal transfers are already taken into

Tim: >>>One other thing you've brought up previously was the suggestion
that the different protein families may represent local optima for
possible (or viable?) structures.<<<

Peter: >>I don't recall ... Was it the structural requirements for a
compact, stable fold, in addition to the functional requirements for
catalysis? This was an argument against assuming small peptides could
serve as viable proteins.<<

Tim: >Yes, that was what I recalled. And yes, small peptides may not
always serve as viable proteins in today's enviroment. Well heck, even
large polypeptides don't always serve as well in some catalyses: For
example, they've finally nailed the case for RNA serving as the
principle catalytic component for protein synthesis.<

Peter: Apparently those many ribosomal proteins are required to help
fold the rRNA into the specific conformation required and stabilize it
there, so it can perform the rather complex catalytic function of
protein synthesis (not just peptide bond formation). Several of them
send "tails" without secondary structure into specific crevices of the
massive RNA core to lock its parts into place.

Tim: >>>Those regions of "evolutionary stability" may be attactors for
structural convergence. I'm not sure what may represent the first steps
toward these stable regions, but is it possible that once these steps
begin, some convergence to a stable form would occur?<<<

Peter: >>What do you mean by "attractors for structural convergence"?
Chaotic attractors? Selection peaks of a fitness surface in parameter
space? I don't see the connection with the problem of finding the first
minimal activity for a given function. At those points, by definition,
the fitness surface is absolutely flat: nothing is selectable, we can
only have random walks. Once the selectable steps begin, of course,
normal darwinian evolution is possible. What do you mean by
"evolutionary stability" in this context?<<

Tim: >Yes, I am proposing the idea of "attractors" and fitness peaks in
this context. I agree that in isolation, and with a flat fitness
surfaces that random walks are what you get. But I don't think that
'flat fitness surfaces' necessarily remain flat forever -- The topology
will change with the local environment. While this could work against
evolutionary change (or directional change), I can see how it
continually 'jostles' the surface and can move sequences to peaks. Now
do these thousand or so 'folds' represent fitness peaks that sequences
will tend toward? And are these peaks inaccessible from the starting
sequences? That's tough to tell and I do not believe there is sufficient
information to perform a decent calculation.<

Peter: Yes, a changing environment corresponds to 'jostling' the fitness
surface. But jostling a flat surface will not drive the things on it
into just one direction, but randomly anywhere. And since the steps
still correspond to single mutations, whether or not the surface is
moving, you'll hardly need fewer mutations if it is.
David: >>>>>Obviously, examining every known gene sequence to determine
the relative frequency of egene duplication, exon shuffling, and the
like is not feasible. However, the general pattern that emerges as one
examines a gene, one finds related genes with different functions. If
there are 1000 truly novel genes, that is still a lot less than the
total number of genes in humans, for example. I did not mean to imply
that all functions evolved by duplication and modification of existing
genes, but rather that it was extremely common.<<<<<

Peter: >>>>If each selected mutational step adds 1 bit of information
from the environment to a genome, the biosphere can collect quite a lot
of information from the environment. But how about the "truly novel

Tim: >>>The counter you're making seems to be that in instances where it
is clear that a modified sequence gives rise to a function which it
didn't possess before, that these aren't truly novel genes but an
un-novel mixing of old ones.<<<

Peter: >>Not quite. What I call a truly novel gene is one whose function
has never before existed in the entire biosphere, no matter what led to
the last step which originated the first minimal amount of the new

Tim: >As mentioned in another reply, that's an impossible criterion to
meet because one would have to have information that's simly not
available. We can't completely survey the current biosphere let alone
conditions in the past.<

Peter: You're right, it is hypothetical.

Peter: >>If it is a mixing of old genes, the new gene may display a
combination of the old functions (whose novelty is a matter of
definition, but these cases need not concern us here), or possibly (but
very unlikely) something entirely new, while the old functions no longer
exist (perhaps due to clipping). For a reasonable discussion of such a
possibility, we should have actual examples where this happened.<<

Tim: >Such as the crystallins or anti-freeze proteins? Or the nylon
digesting enzyme discovered in a bacterium?<

Peter: I suspect that, the physico-chemical requirements for crystallin
or antifreeze function may be rather minimal. In fact, antifreeze
proteins with the characteristic ala-ala-thr repeats seem to have been
derived from unrelated proteins in different species (M. Rouhi,
Chem.Eng.News (Apr.21, 1997), 10). I have read about the nylon-degrading
bacterium, but I can't find the reference, for the moment. I don't
recall it as being very relevant for the evolution of a novel
functionality (for a long time I have paid particular attention to this
Peter: >>Maybe I should distinguish between (1) the emergence of one of
Wolf et al.'s 1000 folds and (2) a novel function whose initial
emergence required 2 or more changes (mutations, shufflings, ...) going
through non-selectable intermediates. I just assumed that cases of (2)
are most likely to be found among (1). But this doesn't imply that each
(1) must be a (2), or that each (2) leads to a new (1).<<
Tim: >OK.<
Tim: >>>I wonder what "truly novel genes" one would expect to find from
duplication, recombination, mutation and deletion of _previously
existing_ sequences? To what does "novelty" apply: the new function, the
new arrangement of DNA sequences, or the _ultimate_ original origin of
the sequences from which the components of the new function were

Peter: >>Novelty applies to the biological function having never existed
before in the entire biosphere. There might be many different ways in
which novelty may emerge, but the easiest conceivable way (IMO) is a
sequence of point mutations in a gene duplicate (possibly in a
pseudogene state) leading to a minimal combination of specific amino
acid occupations defining a new active site in the protein product.<<
Tim: >Such as transaldolases and transketolases? Or the many different
dehydrogenases? I think the hemoglobin and myoglobin families present
interesting varieties. Yes, they bind oxygen (and NO -- which is another
interesting diversion...), but their physiological properties can be
very different.
One additional mechanism with the potential of increasing diversity is
recombination (which could also involve duplication). This could
'encourage' the co-evolution of different parts of protein after a
fusion welds new parts together.<

Peter: I get the impression we aren't using the term "novelty" in the
same way. You list cases of variety within protein families, providing
different functionalities, and recombination, which usually relies on
modules (exons) with preexisting functions to be successful in a new
application. In these cases, step-by-step microevolution with viable
intermediates may be reasonably assumed. But I claim novelty formed
through multi-step non-selected intermediates is difficult to explain.
Peter: >>In order to bypass, for the moment, difficulties with the
definition of the amount of functional information, we'd better not
begin with cases where some previous function is incorporated into the
new one.<<
Tim: >>>Because it's clear that new functions can and do arise from
biochemical mechanisms which we have observed.<<

Peter: >>Are there known cases which fit my definition of novelty?<<

Tim: >None meeting the requirement that the functionality could not have
every existed anywhere or anytime previously. But the anti-freeze
proteins are one of the easiest examples to see if we open the field to
functions which didn't exist previously in a particular lineage.
Were I to look for more ancient examples, I might examine the members of
a particular family of folds to see if they all have the same catalytic
activity. In particular, I would want to focus on those families where
the catalytic activities can be found entirely contained within a
subunit, and at 'half-sites' where the catalytic groups are shared at
interfaces between subunits or at different locations in the subunits.
The idea behind this approach is that one might be more likely to see
evidence of other functions arising on different sites of the proteins.
Also, I might look at families that have metal-binding complexes at the
centers of their structural motifs. In some cases the metal complex
serves a catalytic function, in others a primarily structural function,
and in other cases they serve as sensors for oxidation states.<

Peter: On the antifreeze proteins, see above. There are folds comprising
proteins having different functions, such as the TIM barrel (e.g. L.A.
Mirny & E.I. Shakhnovich, J.Mol.Biol. 291 (1999), 177), but these seem
to be composed of a structural module incorporating different
modifications yielding different specificities (sometimes a compact
active site is composed of amino acids widely separated in the
sequence). These and other cases you mention are interesting to
investigate darwinian evolution of functional modifications. It would
still be very difficult to find cases of modules or functional sites
requiring multi-step mutational paths with at least one wholly
functionless intermediate. I can't prove that such cases exist, but when
you consider the biosphere as a whole, during its entire existence, it
would be very surprising if they were not plentiful.
Tim: >>>Given that sequences do tend to fall into families (with
vertical and sometimes horizontal linkages) in which many members can
exhibit different functions, this suggests (to me, at least), that much
of the variation seen can be understood by descent with modification
rather than by "spontaneous insertion".<<<

Peter: >>This is the reason why I concentrate on folds (i.e. sequences
without any recognizable homology), rather than families. What do you
mean by "spontaneous insertion"?<<
Tim: >E.g.: Close encouters of the third kind; Or God did it. Or
from Mars.<

Peter: I agree that much of the divergence between proteins can probably
be accounted for by simple darwinian mechanisms. But to conclude that
these account for ALL of it appears to be far-fetched. It is a step of
faith without sufficient evidence. We have hardly scratched the surface
as far as detailed evolutionary paths are concerned. By far the largest
part of the picture still consists of "just-so stories".
Peter: >>>>Their minimally active form must have arisen by truly
random-walk mutagenesis. Of which type of information - step-by-step
selected or random-walk generated - is there more in the biosphere? I
think we don't know. But what I am getting at is the challenge of the
random-walk type. Even if this concerns only a few percent of all
existing genes, it poses a big problem, as darwinian evolution cannot be
invoked. Don't you think so?<<<<

Tim: >>>This is certainly an interesting problem. It's also related to
what "minimal" activity is, which is a relative question. Is the fitness
topology absolutely flat between peaks in most areas or not? This is
very difficult to determine. No studies of possible mutational variation
can be exhaustive and we're kidding ourselves if going through a few
thousand or a few million variations of an existing sequence will tell
us what we need to know about the possible activity of the ur-protein,
especially if may not be certain of the original function and context of
the original sequence. <<<

Peter: >>I agree, and I never intended to approach the problem in this
way. I define "minimal" activity by an absolutely flat fitness topology
some distance away from where the fitness starts to go up (cf. the above
definition of "novelty"). Of course we don't know any ur-protein
sequence. At best we might approach a last-common-ancestor sequence. But
the minimal protein for a given function presumably is still much

Tim: >Or very 'complex'. It depends on where the function initially
arose. The function may be less efficient but it could reside on a huge
protein which is doing something else in the cell.<

Peter: All that counts for a new function is the specific amino acid (or
a.a. group) requirements that contribute to the (structure and)
function. Whatever else is "hanging on" doesn't contribute to the
complexity of this function.

Peter: >>It is much more hypothetical, too. But we may estimate the
probability of emergence for a given number of specific amino acid
occupations. According to my model estimate, this number cannot be
higher than 2 (my post of 22 Sep 2000). We could then compare this
number with the known invariances found in protein families, and
possibly folds, certainly much higher than 2.<<

Tim: >That is a post-hoc determination of a probability for a particular
model of a pathway. It's not a bad first approximation considering that
uncertainty of the route. But how can we determine whether your pathway
is correct and reflects the initial conditions and steps along the way?<

Peter: The estimate is independent of any particular initial conditions
or details of the pathway leading to the first minimally active
sequence, just estimating an average probability.
David: >>>>>The example of a pseudogene reactivated, discussed in other
posts, would be a case of passing through unselected "random"
intermediates before arriving at a useful function.<<<<<

Peter: >>>>Yes, and this is exactly one of the interesting cases. Do you
know of any case where such a path via unselected intermediates has been
documented in a real biological system, not just stated as a general
hypothesis? I am eager to find such cases!<<<<

Tim: >>>Hmm... I recall a series of papers by Daniel Dykhuizen (and Dan
Hartl) in the late-'80s & early '90s about natural variation in genes of
the lactose operon in bacteria (I think E. coli but possibly S.
typhimurium). Using metabolic modelling and competition experiments in
chemostats they showed that although natural variations the lac permease
and b-galactosidase sequences were often effectively neutral with
respect to growth on lactose, there were real diffences to be found
during growth on other carbohydrates. In modelling the pathway, these
relationships correlated with the measured activities of the enzyme
variants. So, in the absence of these alternate carbon sources (some of
which you wouldn't expect the bacterium to see often), the lac system
could tolerate variation with little effect on the net metabolic flux.
Thus under "normal" conditions some intermediates appeared to have
escaped selection... at least until conditions changed (different growth
environments) when suddenly those variants which arose from previously
unselected intermediates became fixed via selection.<<<

Peter: >>I haven't searched for this paper.<<

Tim: >Dykhuizen also has a chapter in Methods in Enzymology. I think the
title was "Evolution in chemostats".<

Peter: As you describe it, Dykhuizen's system appears to deal with a set
of variant lac permeases and b-galactosidases which are all basically
active not only with the usual substrate lactose, but also with some
less usual alternative galactosides. Under normal conditions (lactose
medium), the set is optimized for lactose. In the alternative
galactosides, the set is not optimized, but allows their use. It looks
to me like a system of allozyme genes flexible enough to permit survival
under a variety of conditions. The alternative variants need not be
previously unselected intermediates, but "spare tools" for rare
emergencies kept in the toolbox. They haven't escaped selection, because
the emergencies do sometimes occur.
Peter: >>But I happen to have a copy of B.G.Hall & H.S.Malik,
"Determining the evolutionary potential of a gene", Mol.Biol.Evol. 15
(1998), 1055. They analyzed a cryptic E.coli beta-galactosidase ebgA
("evolved b-galactosidase"). In the absence of the normal (paralogous)
lacZ b-galactosidase, ebgA can be used, and after 2 specific mutations
it works as efficiently as lacZ. Why does it exist? 25 years earier,
ebgA had been thought to represent a newly evolved function. Now, a
phylogenetic tree of 14 b-galactosidases indicates that the separation
between ebgA and lacZ must have occurred more than 2.2 billion years
ago. Apparently, an occasional use for ebgA ensured its persistence
during this time. The same may be true of Dykhuizen & Hartl's cryptic
enzymes. Such cases, therefore, don't provide clear evidence for
evolution of a new function by a random
mutational walk.<<

Tim: >Dykhuizen wasn't working with cryptic sequences. These are fully
expressed. The point I wanted to make was that even with proteins which
are subject to selection and can even be considered to be optimized for
a particular condition, there can still be (and often are), variations
carried which are neutral under those conditions but not in others.
Basically I'd like to point out the importance of the local environment
in determining the fitness landscape at any particular moment. For
growth on lactose, the utilization pathway was optimized and relatively
insensitive to the variations in proteins examined (a flat landscape
with no siginificant differences in activity). However, for growth on
alternate carbohydrates, strains carrying the same variations were no
longer on a flat landscape: The combinations could be differentiated.
Under these alternate conditions, a new trajectory is found.<

Peter: Yes, a fitness landscape may be flat for one kind of environment,
while having a slope for another kind. In such a case, a change of
medium may initiate selection of a previously unselected function. But,
in this sense, wasn't the "new" function already present in a way, i.e.
the protein's sequence and structure was specific for splitting a
disaccharide different from lactose?
Tim: >>>There is another interesting case related to the "most
elementary cases of Behe's 'irreducibly complex systems'". This is a
little off the main topic of protein origins, but I think an elementary
case can be found in the evolution of streptomycin resistance. It's been
known that some mutations which give rise to streptomycin resistance can
reduce the growth rates of the bacteria relative to "wild-type" strains
on media without the antibiotic. So it was thought that if the selective
pressure of streptomycin resistance was removed the resistant strains
would eventually become less common in the environment. But studies
showed that these resistant strains persisted, even though they had not
encountered streptomycin in a long while. It turned out that these
strains had acquired a second mutation which suppressed the problems of
carrying streptomycin resistance. When either of these mutations were
carried in separate strains (strains with either the streptomycin
resistance gene or the suppressor gene), growth was slower, compared to
strains without both mutant genes. When both were present the strains
grew as well as those lacking both genes. This represents an
"elementary" IC system: a strain lacking one of the two mutations could
not compete against the wild-type in normal growth -- both mutations
were necessary. Interestingly, this system arose in much the way that
one would expect an IC system to evolve: indirectly, through steps of
selection under conditions that were not the same as where the system
finally emerged.<<<

Peter: >>If I remember correctly, streptomycin resistance occurs by a
ribosomal mutation.<<

Tim: >Yes, it often occurs there but can arise elsewhere. In this case,
I'm fairly sure it was a ribosomal mutation.<

Peter: >>It is to be expected that, in the absence of the antibiotic,
the mutant would be worse off than the wild-type; and it would not be
surprising if in the presence of the antibiotic, the mutant would be
under some selective pressure to get another mutation elsewhere that
would mitigate the damage done by the first one, without eliminating the
protection from streptomycin.<<

Tim: >Yes, exactly. In the presence of the antibiotic the resistant
bacteria still have each other to compete against. If a suppressor can
arise to restore faster growth, then that mutation will come to
predominate the culture. Many cases of this sort of adaptability were
documented a long time ago in the microbial fields.<

Peter: >>If this should turn out to be the case, it would not constitute
an IC system, as each mutation can be selected by itself and the
intermediate is viable.<<

Tim: >ICness, as I understand it from reading Behe's book, has nothing
directly to say about the route by which a system arose but how the
system responds the removal of one of its components. It's from this
criterion that Behe tries to make a general case about the evolvability
of such systems. If we take strains carrying the two mutations and
restore either one of the mutant genes with the original, wild-type
form, then the resultant strains cannot compete against the wild-type
strain carrying no mutations. The doubly-mutant system is IC in the
sense that the removal or alteration of a single component leads to a
loss of functionality.<

Peter: The IC definition implies lethality of removing a component, not
just some loss of functionality. The conclusion to lack of evolvability
implies this. The double mutants you discuss therefore do not represent
Tim: >You are correct that the intermediate steps can be viable -- But
that depends on the pathway. In the absence of streptomycin, the changes
of getting those two complementary mutations in the same bacterium at
the same time are very small. That's because a step-by-step random walk
under those conditions is more likely to require steps with drops in
relative fitness. However, under different conditions, such as prolonged
growth in the presence of streptomycin, it's almost a certain outcome.
Thus the probability of an evolutionary route is not simply a function
of the starting and final sequence but also of the local conditions and
the history of the system. These must be taken into consideration in any
calculation. The only trouble is, how do we get that information?<

Peter: As long as we have some relative fitness, there is selection and
therefore NOT the step-by-step random walk I was considering.
Peter Ruest

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