Re: Evolution of Loss of Vitamin C Synthesis (was Hey Emma!)

[Guest guest]

Emma,

> I hate to point this out but we are about an inch away from

> having intelligent design in the average textbook as well.

Well I don't know what the situation is in the UK, but in the US the

only textbooks getting any mention of intelligent design is in the

Bible Belt HIGH SCHOOLS, and even there the school committees cannot

keep the intelligent design promoters on board long enough to keep

anything in the textbook (The ID promoters in Kansas recently got

booted off, for example). In the Bible Belt, it is highly

controversial and the political situation is very precarious. Outside

of the Bible Belt, it is a non-issue. In top-notch college textbooks

meant for biology majors, it is not even remotely an issue whatsoever.

> I am well

> aware of all the different forces involved in evolution and don't deny

> them,

To the extent your argument insists that there must be a competitive

advantage for an allele fixation to occur, you are for all practical

purposes denying them.

> but I'm sure not even the average school textbook declares that

> random mutation, bottlenecks or the founder effect are more powerful

> than Darwinian natural selection.

It is not an issue of " more powerful " or " less powerful. " In some

situations, one force will be dominant; in others, another. You can't

assess overall power, therefore, but only frequency of dominance. But

the frequency with which one force becomes dominant is completely

irrelevant to assessing which is acting in a particular scenario.

Instead, each case has to be judged on the merits of the evidence for

the particular scenario.

> > I'm not sure at what point in hominid/primate evolution it is posited

> > to have occurred, but the current mainstream opinion appears to be

> > that all live humans are descended ultimately from a single woman (and

> > I think a single man as well), which indicates a severe bottleneck

> > that would fixate any alleles that the surviving humans had regardless

> > of their benefit.

> I think we need to be careful about interpreting data as bottlenecks.

> If primordial Eve has some kids, and the rest of her tribe has some

> kids, primordial Eve's genes can become dominant through the whole

> gene pool over a matter of time due to natural selection, not just

> because a bottleneck occurs.

I have no idea what you are saying. If " Eve " and her partner don't

have the gene for vitamin C synthesis, none of her children do.

Period. If " Eve " and her partner were the only survivors of some

previous population in which the frequency of the null C synthesis

gene was low, the low frequency allele becomes fixated despite the low

frequency. There is no selective force shaping the frequency of the

allele because it is already fixated.

If you are questioning the mainstream conclusion that we all have one

common ancestral mother, I can't really debate the issue because I'm

not familiar with the evidence. Regardless, bottlenecks are possible

and the mainstream belief, based on genetic sequencing, is that one

occurred in human evolution.

> Yes *could* be, but statistically less likely than survival of the

> fittest.

Allele fixation of new mutations is not very common. It would be much

more common to reach some sort of equilibrium frequency in the

population I think. I would like to see some evidence that allele

fixations are statistically more likely to be due to natural selection

rather than random effects, as I doubt it has been studied enough to

not be highly controversial.

Besides that, statistical frequency can't be used to assess what is

most likely to have happened in a given scenario. The evidence of

that scenario would have to be taken itself.

> > But there is really no advantage to lacking the ability to create

> > vitamin C, because its synthesis should be able to be downregulated or

> > its gene silenced I would think.

> This is an offsetting scenario, you pay a price to give up one thing

> that is not very advantageous at the time in return for something else

> that is temporarily advantageous.

Yes, but what I'm saying is that most organisms seem to be capable of

silencing genes if necessary or regulating their expression. I think

this is an obstacle to your hypothesis, but not a refutation of it. I

think in order to back up the plausibility of your hypothesis -- that

there is a selective advantage to vitamin C loss mediated by increased

glucuronic acid synthesis -- you'd have to provide some evidence --

which is obtainable -- that animals with a loss of the vitamin C

synthesis gene actually do have higher glucuronic acid levels than

those that do not when under the same conditions.

Other obstacles for fixation, however, are explaining 1) why there

wouldn't be animals who had silenced their vitamin C gene who wouldn't

have an equal or greater selective advantage, or animals with a high

ability to regulate vitamin C synthesis that wouldn't have an even

greater selective advantage, such as to preclude the complete fixation

of the null vitamin C allele and 2) what environmental conditions

would change that would make the selective advantage for null vitamin

C allele so great as to actually fixate the allele.

I think you are in general underplaying the probable role of

randomness in allele fixation. If the population is relatively small,

it would not be very difficult for genetic drift to lead to random

fixation of the allele over time, if it has a reasonable degree of

prevalence. By contrast, if fixation was attributable to selective

advantage alone, the allele being fixated would have to offer complete

advantage, when in fact most alleles are usually comprimising x to

gain the benefity of y. I think in most cases where selective

pressure leads to fixation, it is for that reason probably going to

need the assistance of random chance and sampling error, while

fixation could also occur by the latter means alone. That is, barring

an environmental change that makes the mutation a clear necessary

survival advantage -- which no doubt has happened in the past, but I'm

not sure what such a fundamental change would be that would be able to

fixate such an equivocally (putatively) beneficial mutation as null

vitamin C synthesis.

> Enzymes tend on the whole to work on a zero-order basis, that is, they

> carry on production regardless, ignoring everything, and they're

> rate-limited by cofactors.

I would like to know on what basis you are formulating this view. If

this were true, organisms would probably simply fall apart. The

ability to regulate gene expression is fundamental to the ability to

maintain homeostasis. If enzymes carried on ignoring everything,

there would be no such thing as homeostasis whatsoever.

Vitamin C synthesis in mice is regulated by endproduct feedback

inhibition at the level of the enzyme that converts glucuronic acid to

vitamin C. So mice have the ability to downregulate this enzyme

itself in response to dietary vitamin C, which itself would increase

the amount of glucuornic acid, all things being equal:

==================

Effect of exogenous ascorbic acid intake on biosynthesis of ascorbic

acid in mice

Constance S. Tsao and May Young

Linus ing Institute of Science and Medecine 440 Page Mill Road,

Palo Alto, California 94306, USA

Received 11 August 1989. Available online 16 November 2002.

Abstract

The effect of exogenous ascorbic acid intake on biosynthesis of

ascorbic acid in mice has been studied. After the mice were on diets

containing added ascorbic acid for two months, the activities of

ascorbic acid synthesizing enzymes in the mouse liver homogenates were

measured using L-gulono-ã-lactone as a substrate. Exogenous ascorbic

acid intake (0.5, 1 or 5% in the diet) was able to increase the

concentration of ascorbic acid in the blood and to decrease the

activities of ascorbic acid synthesizing enzymes in mouse liver. The

results suggest that ascorbic acid synthesis was controlled by local

regulatory mechanism or by the concentration of ascorbic acid in the

hepatic portal blood. Ingestion of dietary erythorbic acid, a

stereoisomer of ascorbic acid, had no effect on the activities of

ascorbic acid synthesizing enzymes.

=============

Whether there is increased glucuronic acid or not probably depends on

the need for glucuronic acid. The whole pathway can be stimulated by

various xenobiotics:

===========

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Retrieve & dopt=Abstra\

ctPlus & list_uids=10606751 & query_hl=4 & itool=pubmed_docsum

(From full text)

Other studies demonstrated that ascorbate synthesis is stimulated by

the administration of a variety of xenobiotics including

3-methylcholanthrene (3-MC) [4, 5 and 6].Carcinogenic polycyclic

aromatic hydrocarbons, such as 3-MC, are archetypical inducers of the

genes belonging to the aromatic hydrocarbon-responsive gene battery

[7]. The upregulation of UDP-glucuronosyltransferase 1A6 (UGT1A6), a

member of this gene battery by Ah inducers [8], is accompanied by

increased urinary excretion of ascorbate [9]. Therefore, the

importance of UGT1A6 induction in 3-MC-stimulated ascorbate synthesis

has been suggested [10]. Horio et al. proposed that the first major

precursor for microsomal ascorbate synthesis, -glucuronic acid is

produced from UDP-glucuronic acid involving X(phenol)-â--glucuronide

formation catalysed by UGT1A6 and the subsequent hydrolysis of the

glucuronide by â-glucuronidase [10 and 11].

===========

> If the ascorbate gene is crunched, all the

> preceeding enzymes would carry on going, theoretically causing a

> build-up of glucuronic acid and other precursors.

Possibly. It depends on a lot of regulatory interactions (which you

for some reason I don't understand are claiming do not exist).

Presumably the vitamin C plays some role in the same system (it is

mediated by AhR, and vitamin C and other antioxidants protect against

toxicity mediated by AhR stimulators like dioxin), so the advantage

isn't particularly obvious unless there is a plenty of dietary vitamin

C to compensate, even in which case the vitamin C can be suppressed by

feedback inhibition, which would seem to have the same effect. The

competitive advantage does not seem clear to me at all, especially

with regard to increased glucoronic acid, which should happen even

without loss of function.

Perhaps, at best, there might be some energy-saving benefit to not

having to use the feedback inhibition, but even this seems quite a

stretch to me. If you want to posit that competitive advantage is

responsible for fixation, it has to be a pretty big comeptitive

advantage.

> So maybe the crunched vitamin C gene was just " accidentally " fixed in

> spite of all the environmental pressures against that happening.

There aren't ANY environmental pressures against it happening if

dietary vitamin C is abundant. These pressures exist if and only if

dietary vitamin C is limited. They exist also even in the face of

increased glucuronic acid (assuming this would even be a significant

result of loss of C synthesis), unless dietary vitamin C is abundant.

> I thought it was fairly neat to point out there's an offset advantage to

> survival in not having it rather than down to a mere accident. Which

> is the most powerful explanation in evolutionary terms? I'm presenting

> a natural selection argument. ing is presenting a founder effect.

I do think it's a cool idea. Maybe I'm reacting more strongly to it

because you are using the fallacious argument that ing's

hypothesis is faulty because it doesn't stipulate a clear competitive

advantage.

I think at best, the putative advantage of increased glucuronic acid

would at best be a partial contributor to the loss of function

allele's prevalence, but I don't think it is apparent that there is

necessarily an advantage in this sense at all. I think this could be

settled by some experimentation, but I can't really see it having such

a selective adantage as for it to independently fixate the loss of

function allele.

> That was my point. My problem with ing's theory is that it only

> tells half the story, being based on a rather half-hearted theory of

> evolution. Surely the idea that we gave up vitamin C for a small

> advantage is a more compelling argument than we gave up vitamin C for

> NO advantage?

Not really.

> > No it doesn't -- it requires acknowledging the observed phenomenon of

> > random selection (e.g. genetic drift) and allele fixation occuring

> > through that mechanism.

> And this outweighs Darwininan natural selection?

Neither of them " outweigh " the other.

> > They don't compete at all because I stipulated that they became

> > isolated.

> So basically what you are saying is that one or two homozygous

> individuals went off and became isolated somehow and just happened to

> be the one or two individuals who would evolve into human beings. I'm

> not denying that random genes can become fixed, but like I say, what

> are the odds?

Probably considerably better than a very small (possible but not

substantiated) advantage leading to fixation over a very large

population solely on its competitive merit. And in any case it would

not have to be two pre-humans that just happened to develop into

humanity. The bottleneck could have happened after most of much of

human evolution had occurred, and it wouldn't have to be two people

(I'm not up on hominid evolution though so I'm not sure what the

current thoughts on this are).

Chris

--

The Truth About Cholesterol

Find Out What Your Doctor Isn't Telling You:

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[Guest guest]

On 10/26/06, Emma Davies <emma@...> wrote:

> > To the extent your argument insists that there must be a competitive

> > advantage for an allele fixation to occur, you are for all practical

> > purposes denying them.

> I don't really deal in absolutes, I prefer to deal in

> likelihoods. As I have already stated, what are the chances?

The chances of genetic drift leading to an allele fixation in a small

population are pretty decent. In a large population, they are pretty

poor. Not knowing exactly when the mutation came up, there's no way

to quantify the chances.

> I'm saying that we do not have to be directly descended from one Eve

> due to a bottleneck, rather, Eve's genes can become dominant

> throughout the whole gene pool due to natural selection. Bottlenecks

> aren't the only ways to produce Eves.

I still don't understand. Are you questioning the mainstream

conclusion that there was such a bottleneck involved in human

evolution? My vague understanding is that this comes from gene

sequencing, not explanations of what " had to " have happened.

> If " Eve " and her partner don't

> > have the gene for vitamin C synthesis, none of her children do.

> > Period.

> I wasn't taking about vitamin C, I was talking about interpretation of

> data.

You can substitute any other allele. If the bottleneck occurred, no

natural selection is necessary for fixation.

And yes, I acknowledge that fixation can occur without bottlenecking

(both randomly and non-randomly). However, it's pretty unlikely to

occur, I would think, in a population unless either a) the advantage

of a mutation becomes complete due to a fundamental change in the

environment or the population is small. If the population is very

small, you could get the very helpful assistance of sampling error in

conjunction with natural selection, if the latter is only sufficient

to make the allele pretty prevalent but not absolutely essential.

Without the help of random sampling error, the mutation is probably

going to have to become absolutely essential somehow and not just

advantageous for fixation to occur.

In your example below, someone might have an advantage of higher

glucuronic acid production if they come into contact with some high

load of something particularly toxic, but that's only enough selective

pressure, it seems, to give a prevalence to the mutation roughly in

proportion to the frequency of such an occurrence. Certainly such an

occurrence wouldn't have been the norm prior to the mutation or the

species would have been wiped out. So either a) something in the

environment changed to make it the norm and thus make the mutation

essential or the population was relatively small and the selective

advantage was facilitated by random sampling error in leading to the

fixation.

> Well until I hire a lab and carry out the necessary experiments, it is

> still a perfectly plausible hypothesis. I don't know why everyone had

> to jump all over it and rubbish it when it's no more or less valid

> than ing's theory. Presumably because I am not the vaunted

> ing.

I'm sorry for jumping on the idea so quickly rather than acknowledging

it as a pretty cool idea -- which it is. I think the reason I jumped

on it is because you were (and are) arguing for it based on the idea

that a moderate or small selective advantage is superior to genetic

drift as an explanation of fixation, which I think is entirely

fallacious. I think it's very possible for genetic drift to yield

fixation in a small population and 100% impossible for a small

selective advantage to in and of itself lead to fixation.

Had you presented your idea as an additional point of selective

advantage that could have contributed to the prevalence of the allele

prior to fixation I would have found your argument much less

objectionable and welcomed the idea more. I think it would be really

interesting to discuss, in that context.

> There are in fact several other plausible hypotheses in

> published papers pertaining to possible natural selection advantages.

> I happen to think they're all more plausible than " we just

> accidentally lost the gene. "

There may well have been multiple forces operating, including numerous

different selective advantages, random chance, and the whole deal.

What is implausible, however, is a small or moderate selective

advantage leading to fixation without the assistance of sampling

error.

Sampling error by itself can produce fixation, or the essentiality of

a mutation can produce fixation, but small or moderate advantage can

never lead to fixation, as a rule, without sampling error. If the

mutation is not essential, there will always be the persistence of the

original genotype (unless wiped out by sampling error) and therefore

no fixation.

> This was an overemphasis to get the point across, but according to the

> book I have on the subject, many enzymes operate on a zero order

> basis.

What book?

> If you produce a maximum rate of 20 grams of glucuronic acid and 10

> grams of that is normally converted to ascorbic acid, but you lose

> your vitamin C enzyme, but you get five grams of ascorbic acid from

> your diet, which is enough to get by, you are left with fifteen grams

> instead of ten grams of glucuronic acid to play with to detoxify the

> nasty poisons you ate that morning in some leaves when mother ape took

> her eye off you for a minute. That could sway whether you survive

> undamaged or not. Your companion who also ate the leaves, was stressed

> by the experience and therefore produced more of her own ascorbic acid

> in response to demand, leaving the body to divide its efforts between

> ascorbic acid and glucuronic acid production, resulting in less

> glucuronic acid available to remove the toxins, and she got liver

> damage, or died.

What environmental change would have occurred to make the eating of

poisonous leaves so common that the mutation would become fixated? If

no environmental change occurred producing this, but selective

pressure was sufficient to lead to fixation (i.e. selective pressure

was total and the original allele produced certain inability to pass

on genes) why didn't the species just die out in the first place?

Chris

--

The Truth About Cholesterol

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