Genetics and Genesis

[gluadys]

I hate that!



The word I was looking for was adaptive, in other words positive and adaptive evolution are the same thing.

Well, that is an inference. We infer the existence of an adaptive advantage when an allele is affected by positive selection. We may not be able to pinpoint what the adaptive advantage is, but the existence of positive selection implies that there is one. Given that we cannot always establish what makes a given trait advantageous, it is hard to measure adaptation. What we can actually measure (as you note) is positive selection.

Did you catch that? It's a ratio. You are confusing the definition of evolution as the change of allele frequencies in populations over time.

The confusion is in your mind, not Deamiter's. The frequency of an allele in a population is also a ratio. And a change in that ratio is a measure of evolution. The KA/KS ratio is a different ratio. It is a ratio of synonymous to non-synonymous mutations. The two ratios are both related to evolution, but they measure it in different ways. The KA/KS ratio looks at specific changes in the genome. The change in allele frequency looks at the frequency at which those changes occur in a population. There is no conflict between them and there is no choice to be made between them. Each is a different measure of a different aspect of evolution, useful in its own way in helping us understand evolution.

Relaxed functional constraint is an unreasonable explanation since if mutations were allowed to accumulate with an effect that effect would be most often highly deleterious.

That is not quite right. Relaxed functional constraint is an unreasonable explanation in this case because there are deleterious consequences to some mutations of the ASPM gene, and relaxing the controls against them spreading into the general population would likely have negative consequences. However, for the ASPM gene to have a role in the evolution of the human brain, it is also necessary that some mutations do accumulate. The only way to permit the accumulation of the necessary mutations in a situation where functional constraint is not relaxed is through positive selection, and that is what is shown here.

One thing is crystal clear to me, the human brain is unique. Positive selection as an explanation is really nothing more then an assumption since the only other possibility has been rejected before actually looking at the evidence (a priori).

You can't have it both ways. You said earlier that positive selection can be measured, and in that you are correct. But since it is measured, it is not an assumption. How do you measure an assumption?

 

[Deamiter]

The word I was looking for was adaptive, in other words positive and adaptive evolution are the same thing. Positive selection is actually measured in genetics:
...
Did you catch that? It's a ratio. You are confusing the definition of evolution as the change of allele frequencies in populations over time.

Nope, I'm not confusing it. I figured you were looking for something specific, so I ran a quick google search to make sure I wasn't missing something -- the vast majority of hits (looking mainly at journal and .edu sites) say something like this and don't mention 'adaptive evolution.'

Bit of a moot point, but positive selection IS generally defined as an increase in helpful alleles in a population... which is also a possible definition of adaptation.

http://depts.washington.edu/jtlab/positiveSelection.html

Positive selection is the process by which new advantageous genetic variants sweep a population. Though positive selection, also known as Darwinian selection, is the main mechanism that Darwin envisioned as giving rise to evolution, specific molecular genetic examples are very difficult to detect. Pioneering work by Yang and Nielsen has provided a much more powerful methodology for detecting positive selection at the sequence level.

This comparison shows a significant excess of fixed nonsynonymous substitutions...It is interesting that there is no significant excess of nonsynonymous substitutions for either the chimpanzee or orangutan branches when the common polymorphisms and substitutions are compared

Interesting indeed, of course you've conspicuously left out that gorillas DO exhibit this evidence of positive selection -- in fact, it's been determined that the strong positive selection preceeded hominid brain expansion by millions of years!
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0020126

Here we have isolated large genomic clones containing the complete ASPM gene, including promoter regions and introns, from chimpanzee, gorilla, orangutan, and rhesus macaque by transformation-associated recombination cloning in yeast. We have sequenced these clones and show that whereas much of the sequence of ASPM is substantially conserved among primates, specific segments are subject to high Ka/Ks ratios (nonsynonymous/synonymous DNA changes) consistent with strong positive selection for evolutionary change. The ASPM gene sequence shows accelerated evolution in the African hominoid clade, and this precedes hominid brain expansion by several million years. Gorilla and human lineages show particularly accelerated evolution in the IQ domain of ASPM. Moreover, ASPM regions under positive selection in primates are also the most highly diverged regions between primates and nonprimate mammals. We report the first direct application of TAR cloning technology to the study of human evolution. Our data suggest that evolutionary selection of specific segments of the ASPM sequence strongly relates to differences in cerebral cortical size.

 

[mark kennedy]

Well, that is an inference. We infer the existence of an adaptive advantage when an allele is affected by positive selection. We may not be able to pinpoint what the adaptive advantage is, but the existence of positive selection implies that there is one. Given that we cannot always establish what makes a given trait advantageous, it is hard to measure adaptation. What we can actually measure (as you note) is positive selection.

When are you finally going to realize these research papers are nothing more then comparisons. We are talking about ratios that are over one when converted to a decimal.

The confusion is in your mind, not Deamiter's. The frequency of an allele in a population is also a ratio. And a change in that ratio is a measure of evolution. The KA/KS ratio is a different ratio. It is a ratio of synonymous to non-synonymous mutations. The two ratios are both related to evolution, but they measure it in different ways. The KA/KS ratio looks at specific changes in the genome. The change in allele frequency looks at the frequency at which those changes occur in a population. There is no conflict between them and there is no choice to be made between them. Each is a different measure of a different aspect of evolution, useful in its own way in helping us understand evolution.

I don't think Deamiter is confused, I think he spliced the definition for evolution in some place it doesn't belong. You on the other hand don't seem all that interested in the classic measure of positive selection. You are certainly not responding to detailed descriptions of it or facts concerning it. I think maybe your confused.

That is not quite right. Relaxed functional constraint is an unreasonable explanation in this case because there are deleterious consequences to some mutations of the ASPM gene, and relaxing the controls against them spreading into the general population would likely have negative consequences. However, for the ASPM gene to have a role in the evolution of the human brain, it is also necessary that some mutations do accumulate. The only way to permit the accumulation of the necessary mutations in a situation where functional constraint is not relaxed is through positive selection, and that is what is shown here.

I thought that is what I said, relaxed functional constraint is not viable due to the energetic costs. We have been through this a number of times and you don't seem to realize what my interest in all of this is.

You can't have it both ways. You said earlier that positive selection can be measured, and in that you are correct. But since it is measured, it is not an assumption. How do you measure an assumption?

It is a comparison gluadys, it is a ratio and you just said the same thing to me like you understood that and I didn't. They are calling it positive selection because that is the only explanation for how the differences got there given the assumption of a common ancestor. Relaxed functional contraint would allow too many deleterious effects and selective sweeps restrict the gene flow. All you are left with at that point is positive/adaptive evolution.

Pay attention this time:

"The human brain, particularly the cerebral cortex, has undergone a dramatic increase in its volume during the course of primate evolution, but the underlying molecular mechanisms that caused this expansion are not known." (Accelerated Evolution of the ASPM Gene Controlling Brain Size Begins Prior to Human Brain Expansion, PloS 2004)​

That is from the first line of the introduction, do you really think that just contradicting Creationists is the same thing as science? Where is the demonstrated or directly observed mechanism because the researchers are virtually unanimous in saying they don't have a clue.

 

[mark kennedy]

Nope, I'm not confusing it. I figured you were looking for something specific, so I ran a quick google search to make sure I wasn't missing something -- the vast majority of hits (looking mainly at journal and .edu sites) say something like this and don't mention 'adaptive evolution.'

Ok, the measure of positive/adaptive evolution is when the Ka/Ks ratio is over 1 when converted to a decimal. It is not required for an adaptation but a solid indicator that one has, or must have occurred. I'm glad you picked the discussion that you did it emphasizes a couple of things that bear repeating:

Because they cause mutant phenotypes, these mutations are well known to functional geneticists, since they account for nearly all of the mutant strains and human diseases that are much studied throughout biology and human health.

Positive selection

Though advantageous mutations are of great interest, they are difficult to detect and analyze because of the fact that neutral and deleterious mutations predominate them in frequency. Two major classes of methods are currently in use to detect positive selection: population methods, based on analyzing the nature and frequency of allele diversity within a species, and codon analysis methods, based on comparing patterns of synonymous and nonsynonymous changes in protein coding sequences. Unfortunately, a nearly complete lack of population sequence information in nematodes (at least for now), limits our analysis to the latter methods. (Positive selection, Washington University)​

The first bolded part is the directly observed and demonstrated effect of mutations on the human brain. The second bolded part is how adaptive/positive selection is measured, the changes of codons (triplet codons) in amino acid sequences producing a protein with a beneficial effect in the phenotypes expressed traits. It is only at this point that natural selection can act, there must be an effect strong enough for selection to detect. Want to know how big a role selection played in human evolution?

Other potential evolutionary forces are positive or negative selection. Although it is more difficult to quantify the expected contributions of selection in the ancestral population, it is clear that the effects would have to be very strong to explain the large-scale variation observed across mammalian genomes. There is tentative evidence from in-depth analysis of divergence and diversity that natural selection is not the major contributor to the large-scale patterns of genetic variability in humans. For these reasons, we suggest that the large-scale variation in the human–chimpanzee divergence rate primarily reflects regional variation in mutation rate. (Chimpanzee Genome, Nature 2005)​

Why? Why would they say that natural selection had very little to do with it?

Interesting indeed, of course you've conspicuously left out that gorillas DO exhibit this evidence of positive selection -- in fact, it's been determined that the strong positive selection preceeded hominid brain expansion by millions of years!
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0020126

I know you are not really into genetics so I'm going easy on this one. Look at the comparison of gorilla and human sections of the ASPM gene...well....see for yourself:

Complete ASPM

Look at the decimal the ratio is reduced to at the end of the tree. Your thoughts...

 

[gluadys]

When are you finally going to realize these research papers are nothing more then comparisons. We are talking about ratios that are over one when converted to a decimal.

So?

I don't think Deamiter is confused,

Well, you said you thought he was.

I think he spliced the definition for evolution in some place it doesn't belong. You on the other hand don't seem all that interested in the classic measure of positive selection. You are certainly not responding to detailed descriptions of it or facts concerning it. I think maybe your confused.

I am saying you are in error to reject the definition Deamiter gave. As the quote from Washington University says:

Two major classes of methods are currently in use to detect positive selection: population methods, based on analyzing the nature and frequency of allele diversity within a species, and codon analysis methods, based on comparing patterns of synonymous and nonsynonymous changes in protein coding sequences.​

Deamiter referred to the first. You are referring to the second. But both are useful definitions of postive selection. In rejecting the first, you are expressing your prejudice against anything to do with measuring changes in population. But it is the expression of genetics in populations that defines evolution.

I thought that is what I said, relaxed functional constraint is not viable due to the energetic costs. We have been through this a number of times and you don't seem to realize what my interest in all of this is.

Indeed, I was agreeing with you on this point. Is that so unthinkable?

It is a comparison gluadys, it is a ratio and you just said the same thing to me like you understood that and I didn't. They are calling it positive selection because that is the only explanation for how the differences got there given the assumption of a common ancestor.

And what else would you call it? If it is not positive selection, what is it? How else does the ratio of a new mutation increase when functional constraint is not relaxed?

Relaxed functional contraint would allow too many deleterious effects and selective sweeps restrict the gene flow. All you are left with at that point is positive/adaptive evolution.

Exactly. So where is your problem with this?

Pay attention this time:

"The human brain, particularly the cerebral cortex, has undergone a dramatic increase in its volume during the course of primate evolution, but the underlying molecular mechanisms that caused this expansion are not known." (Accelerated Evolution of the ASPM Gene Controlling Brain Size Begins Prior to Human Brain Expansion, PloS 2004)​

That is from the first line of the introduction,

All this time reading scientific papers, and apparently you have not yet twigged onto the convention of using the introduction to state the problem the paper proposes to address. The rest of the paper explores the underlying molecular mechanisms that caused the expansion of the brain. Or at least one of them.

Where is the demonstrated or directly observed mechanism because the researchers are virtually unanimous in saying they don't have a clue.

It is explained in the rest of the paper cited above.


PS. Note the title. This paper is also saying that the evolution of hominid brain size began before human brain expansion.

 

[shernren]

One thing is crystal clear to me, the human brain is unique. Positive selection as an explanation is really nothing more then an assumption since the only other possibility has been rejected before actually looking at the evidence (a priori).

That claim is really ironic. Tell me something. What kind of analytical results on the human ASPM gene would convince you that positive selection has been acting on it?

 

[crawfish]

Today you could call someone a vine and it would be ok. But, the age thing would be lying. It seems to need a little more evidence to make it ok then but not ok now. Lots of people do it now and it is regarded as vanity. Does it help that lots of people did it then?

Have you ever studied the decisions that are made when translating the bible from its original languages? Many, many times, the absolute literal word-for-word translation will have either no meaning to our times, or alternatively a completely different meaning.

Truth is, the concept he's putting forth is something we're all familiar with even though most don't know it. Only fairly recent discoveries (in the latter 20th century) have put light to the Genesis age question. Rest assured, those discoveries will make God's word far more powerful in the years to come. Almost as if God planned it that way.

 

[mark kennedy]

That claim is really ironic. Tell me something. What kind of analytical results on the human ASPM gene would convince you that positive selection has been acting on it?

A directly observed or demonstrated molecular mechanism capable of altering the amino acid sequence in a highly conserved gene involved in the development of the human brain. With a beneficial effect of course.

 

[mark kennedy]

So?

Don't worry about it.

Well, you said you thought he was.

I didn't say he was confused, I said I think he has confused the definition of evolution with an adaptation.

I am saying you are in error to reject the definition Deamiter gave. As the quote from Washington University says:

I haven't rejected anything and did my best to keep this thread on track.

Two major classes of methods are currently in use to detect positive selection: population methods, based on analyzing the nature and frequency of allele diversity within a species, and codon analysis methods, based on comparing patterns of synonymous and nonsynonymous changes in protein coding sequences.​

Which is on the one hand expressed traits and on the other the classic measure of synonymous and nonsynonymous changes at an amino acid sequence level. Nevermind! I have said the same thing repeatedly and you keep arguing as if I denied it.

Deamiter referred to the first. You are referring to the second. But both are useful definitions of postive selection. In rejecting the first, you are expressing your prejudice against anything to do with measuring changes in population. But it is the expression of genetics in populations that defines evolution.

Oh for crying out loud, I know he is a science student. I thought he might be interested in the ratio I have brought up again and again but this is going nowhere.

Indeed, I was agreeing with you on this point. Is that so unthinkable?

I'd say it's unusual.

And what else would you call it? If it is not positive selection, what is it? How else does the ratio of a new mutation increase when functional constraint is not relaxed?

I'm saying that is the only explanation possible, just one problem. You still don't have a directly observed or demonstrated mechanism for the evolution/adaptation (or whatever you want to call it) of this gene.

They say that in the first line of the introduction and virtually all of the papers on this subject start out the same way.

My dear, does that tell you anything?

Exactly. So where is your problem with this?

You still don't get it do you? This is just a comparison of two sequences, nothing more. The reason they decided the differences must have been positive selection is because every known effect from mutations in this gene are harmful.

All this time reading scientific papers, and apparently you have not yet twigged onto the convention of using the introduction to state the problem the paper proposes to address. The rest of the paper explores the underlying molecular mechanisms that caused the expansion of the brain. Or at least one of them.

Natural selection is not a cause, it's an effect. There is not directly observed or demonstrated mechanism that results in a beneficial effect from mutations in this gene known to science, there just isn't.

Is it so unreasonable to believe God created Adam fully formed when science can't provide the most important to the question of human ancestry?

It is explained in the rest of the paper cited above.

No it isn't.

PS. Note the title. This paper is also saying that the evolution of hominid brain size began before human brain expansion.

The evolution of the gene that is key to brain size started before the expansion...no kidding?

Grace and peace,
Mark

 

[sfs]

When comparing the ASPM gene in human populations the polymorphisms result in sever reduction in brain size.

In humans, mutations in ASPM result in severe reduction in brain size -- except when they don't. The first post in this thread was talking about a common nonsynonymous polymorphism in ASPM that does not result in any reduction in brain size (or anything else, as far as anyone knows).

 

[sfs]

I thought that is what I said, relaxed functional constraint is not viable due to the energetic costs. [...]
They are calling it positive selection because that is the only explanation for how the differences got there given the assumption of a common ancestor. Relaxed functional contraint would allow too many deleterious effects and selective sweeps restrict the gene flow. All you are left with at that point is positive/adaptive evolution.

I am finding this discussion quite confusing. Relaxed functional constraint is unlikely because the gene obviously still has an important function, although that doesn't actually rule it out -- it's the elevated Ka/Ks ratio that argues most strongly for adaptive, rather than neutral evolution. (Relaxed functional constraint can't "allow too many deleterious effects", since all a relaxed constraint means is that mutations no longer have deleterious effects.)

What "selective sweeps restrict the gene flow" is supposed to mean I don't know (what gene flow?), especially since selective sweeps are then contrasted with positive evolution. A selective sweep is a possible side effect of positive evolution, so they should not be contrasted.

On the question of whether common descent is (illegitimately) assumed for this analysis, please go and look at the Evans et al paper. You will find that the ASPM sequences from different primate species form a very nice tree, something that is a strong prediction of common descent. I predict that if you look only at the synonymous differences (which all seem to agree have no functional consequences), you will still see the same tree. Go ahead, check it out -- the paper provides the aligned sequences as supplementary material. If you can think of a alternative explanation for why nonfunctional sequence differences should form exactly the tree predicted by common descent, I'd love to hear it.

It is worth noting that the classes of genes that show evidence for the most rapid evolution from neighboring species are also the classes that show evidence for the most rapid evolution within our species' recent past. Since the two kinds of evidence are quite different, it's quite a coincidence that they agree, if the first class really represents design differences. (The rapidly evolving classes, by the way, are genes involved in sensory perception (especially olfaction), genes involved in reproduction (especially sperm-related genes) and immune response genes.)

 

[mark kennedy]

In humans, mutations in ASPM result in severe reduction in brain size -- except when they don't. The first post in this thread was talking about a common nonsynonymous polymorphism in ASPM that does not result in any reduction in brain size (or anything else, as far as anyone knows).

Hi Steve, long time no see.

I understand that just fine, I never said that they must always be deleterious. I realize that most mutations simply do not have an effect at all. The point I was driving home is that when mutations occur in this gene and it does have an effect, it's deleterious.

 

[Deamiter]

Hi Steve, long time to see.

I understand that just fine, I never said that they must always be deleterious. I realize that most mutations simply do not have an effect at all. The point I was driving home is that when mutations occur in this gene and it does have an effect, it's deleterious.

Can you show this or are you simply inferring that because we're more likely to notice a mutation when it's deleterious, all mutations that "have an effect at all" must be deleterious?

That seems quite a huge leap of logic to me! When it's been shown that non-deleterious mutations exist in ASPM, isn't it likely that SOME of those mutations would increase brain volume? I mean, you used to claim that when a mutation occurs in ASPM, it's deleterious, but when we show that not all mutations in ASPM are harmful, you change your claim to, "when it has an effect it's always deleterious." The only problem is that now you're just making an argument based on incredulity (i.e. "I don't think a mutation that has an effect could increase brain size") which is a pretty baseless argument.

We know mutations exist that are not harmful to the organism. We know that this gene shows signs of positive selection. Doesn't that by itself suggest that some of these mutations are more beneficial than others?

 

[gluadys]

I'm saying that is the only explanation possible, just one problem. You still don't have a directly observed or demonstrated mechanism for the evolution/adaptation (or whatever you want to call it) of this gene.

Why do you assume that the molecular mechanism for a mutation that leads to an adaptation must be different in nature from the molecular mechanism for a mutation that leads to a maladaptation?

After all, you have never defined the directly observed or demonstrated mechanisms that lead to mutations that produce diseases and deformities?

If you know what that mechanism is, why do you claim not to know what mechanism produces adaptive mutations?

They say that in the first line of the introduction and virtually all of the papers on this subject start out the same way.

My dear, does that tell you anything?

Yes, indeed it does. It tells me that is the problem they intend to address in this paper, and that I can expect to find in the rest of the paper a proposed remedy (or at least partial remedy) for this problem.

You still don't get it do you? This is just a comparison of two sequences, nothing more. The reason they decided the differences must have been positive selection is because every known effect from mutations in this gene are harmful.

No, the reason they decided the differences must have been due to positive selection is the measurement of the KA/KS ratio.

Natural selection is not a cause, it's an effect.

Yes, it is an effect of differential reproductive success due to differences in adaptive fitness. And that makes it a contributing cause of evolution (change in the frequency of allele distribution in a population.)

There is not directly observed or demonstrated mechanism that results in a beneficial effect from mutations in this gene known to science, there just isn't.

So what is it that you are looking for? An actual experiment that says Change A in this gene produces Change X in the expression of the gene, and this provides Benefit Q?

How would you go about setting up this experiment?

Is it so unreasonable to believe God created Adam fully formed when science can't provide the most important to the question of human ancestry?

I am not sure what question you are referring to. But yes, to me it is unreasonable, in the face of so many correlations of the human genome to that of the other great apes, all independently confirming a similar if not identical phylogeny, to deny that the human species is a biological descendant of a common primate ancestor.

No it isn't.

It may not be an answer that satisfies you, but it is an answer. I am not sure what sort of answer would satsify you.

Perhaps you could start by showing what their answer is and why, in your opinion, it is inadequate.

 

[mark kennedy]

Can you show this or are you simply inferring that because we're more likely to notice a mutation when it's deleterious, all mutations that "have an effect at all" must be deleterious?

That seems quite a huge leap of logic to me! When it's been shown that non-deleterious mutations exist in ASPM, isn't it likely that SOME of those mutations would increase brain volume? I mean, you used to claim that when a mutation occurs in ASPM, it's deleterious, but when we show that not all mutations in ASPM are harmful, you change your claim to, "when it has an effect it's always deleterious." The only problem is that now you're just making an argument based on incredulity (i.e. "I don't think a mutation that has an effect could increase brain size") which is a pretty baseless argument.

We know mutations exist that are not harmful to the organism. We know that this gene shows signs of positive selection. Doesn't that by itself suggest that some of these mutations are more beneficial than others?

First of all you misunderstood, when I say most of the mutations do nothing I mean they are neutral, that is they do not have enough of an effect for natural selection to act. I'm not exaggerating and this is certainly not limited to the ASPM gene, most mutations do nothing at all and we are talking something like 98%. The ones that have an effect are like the sever reduction in brain size and that makes of the vast majority of the rest.

shedding light on the molecular mechanisms of brain evolution is the analysis of the gene mutations that lead to defects in brain development. Among the best examples of such defects is the human primary microcephaly syndrome. Primary microcephaly (MCPH) is an autosomal recessive neurodevelopmental disorder in which the brain fails to achieve normal growth. The affected individuals have severe reduction in brain size; however, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. (Accelerated Evolution of the ASPM Gene Controlling Brain Size Begins Prior to Human Brain Expansion PLoS)​

Why do you think they used a mutation that results in a sever reduction in brain size? It's because the only directly observed or demonstrated effects are neutral or deleterious. They are not demonstrating that they know how it could have happened, in fact they openly admit they have no idea.

Now as far as mutations having a beneficial effect on the brain, well, I have never seen nor heard of one. I could give you a very long list of diseases and disorders, anyone who was read the research papers, heck, the authors even say it:

Attempts to detect order in these mutation rates have revealed certain underlying patterns. We describe these patterns, note some of their consequences, and consider their evolutionary origins.

Among the mutations that affect a typical gene, different kinds produce different impacts. A very few are at least momentarily adaptive on an evolutionary scale. Many are deleterious. Some are neutral, that is, they produce no effect strong enough to permit selection for or against; a mutation that is deleterious or advantageous in a large population may be neutral in a small population, where random drift outweighs selection coefficients. (Rates of Spontaneous Mutation, Genetics 1998)
​

Notice that only a few are adaptive, but don't we know for sure that things adapt and evolve? The fact is that modern biology has identified a lot of molecular mechanisms that produce adaptations and mutations are not how it happens the vast majority of the time.

This is what the ASPM paper from PLoS is saying, the sequence of the gene being examined is thousands of bases long. In order for this gene to be functional the amino acids have to come in groups of threes in order to form the amino acids of life (triplet codons). They simply assume that the mutations are neutral and accumulate until they come up with meaningful and useful amino acid sequences that improve fitness.

This is what has to happen, you can feel free to speculate how, everyone else does:

size in orangutans (430 g in males; 370 g in females) is barely different from that in gorillas (530 g in males; 460 g in females) and common chimpanzees (400 g in males; 370 g in females) (Tobias 1971), yet accelerated ASPM evolution began in the common ancestor of gorillas, chimpanzees, and humans, approximately 7–8 million years ago. Only much later did brain expansion begin in hominids, starting at 400–450 g roughly 2–2.5 million years ago and growing to its final current size of 1350–1450 g approximately 200,000–400,000 years ago​

Two million years sounds like a lot of time for this to happen right? It's not, the cranial capacity would have had to double over night and by half a million years ago it was not at modern levels, it was 10% bigger. The earliest Homo erectus fossilized skulls are about 1000cc while the Homo habilis are comparable to modern chimpanzees.

Do you realize that there are virtually no chimpanzee ancestors from the period of about 4 million years ago until today, do you know why, they are all in natural history museums marked Homo XXX.

A jump from 500cc to 1000cc is not evolution, it's the stuff of myth and legend. As long as I have been doing this not one evolutionists has suggested a mutation in a gene effecting neurogenesis having a beneficial effect. In addition not one evolutionist has made even the most superficial attempt to suggest the molecular mechanism.

Despite that they have unquenchable faith that humans evolved from an ape ancestor. Science never gets away with this except when it comes to evolution.

 

[sfs]

Hi Steve, long time no see.

I understand that just fine, I never said that they must always be deleterious. I realize that most mutations simply do not have an effect at all. The point I was driving home is that when mutations occur in this gene and it does have an effect, it's deleterious.

You don't actually have any basis for that point, however. As has already been pointed out, it is vastly easier to detect the effect of a seriously deleterious mutation than any other kind of functional mutation, whether beneficial or mildly deleterious. So we in fact know nothing at all about the effect of most ASPM mutations.

This is illustrated by what we do know about ASPM, in fact. I can find reference to a total of 32 nonsynonymous or indel mutations in ASPM. Of those, 30 cause microcephaly, and are severely deleterious. "Ah ha", you say, "this proves how deleterious mutations in ASPM are." No, it doesn't. 29 out of those 30 deleterious mutations completely disable the gene: they are frameshift mutations or premature stop codons, leading to no functioning gene product at all. Only three missense mutations (ones that change the content of the gene product by substiting one amino acid for another) are known, one of which causes microcephaly and two of which don't. The great majority (perhaps 75%) of all nonsynonymous mutations are missense mutations, however, meaning that we must have missed the bulk of mutations at ASPM, simply because they don't cause gross abnormalities.

Do any of these missense mutations, including the two known missense polymorphisms, cause subtle differences in gene function? Do they produce greater or lesser intelligence, or better or worse motor control, or anything else? No one knows. If they do, why is is it implausible that some of these subtle differences could provide a selective advantage? And if they don't, if the vast majority of missense mutations have no functional effect at all, why are you going on about the differences between human ASPM and chimpanzee ASPM? All of those differences are missense changes too.

I also note that you didn't reply to part of my post. Why do you say that common descent is just an assumption, when nonfunctional differences between species in this same gene point to common descent? Do you have an alternative explanation for that tree?

 

[mark kennedy]

You don't actually have any basis for that point, however. As has already been pointed out, it is vastly easier to detect the effect of a seriously deleterious mutation than any other kind of functional mutation, whether beneficial or mildly deleterious. So we in fact know nothing at all about the effect of most ASPM mutations.

With all due respect I think we do know the effect and it is most often nothing at all, then there are actual effects on the phenotype or expressed traits and they are deleterious.

This is illustrated by what we do know about ASPM, in fact. I can find reference to a total of 32 nonsynonymous or indel mutations in ASPM. Of those, 30 cause microcephaly, and are severely deleterious. "Ah ha", you say, "this proves how deleterious mutations in ASPM are." No, it doesn't. 29 out of those 30 deleterious mutations completely disable the gene: they are frameshift mutations or premature stop codons, leading to no functioning gene product at all. Only three missense mutations (ones that change the content of the gene product by substiting one amino acid for another) are known, one of which causes microcephaly and two of which don't. The great majority (perhaps 75%) of all nonsynonymous mutations are missense mutations, however, meaning that we must have missed the bulk of mutations at ASPM, simply because they don't cause gross abnormalities.

That's what I'm saying about mutations, they disrupt the normal function of the gene. What is required is for there to be a huge adaptive evolutionary process that does not slightly improve things but accelerate growth in highly conserved regions. You tell me, does it get any more highly conserved then neurogenesis? You have just said what researchers are publishing on a regular basis, mutations in this region are disrupting this gene or doing nothing at all. Feel free to correct me if I'm wrong, isn't it a little presumptive to say there is evidence of positive selection if you can't identify the molecular mechanism?

Do any of these missense mutations, including the two known missense polymorphisms, cause subtle differences in gene function? Do they produce greater or lesser intelligence, or better or worse motor control, or anything else? No one knows. If they do, why is is it implausible that some of these subtle differences could provide a selective advantage? And if they don't, if the vast majority of missense mutations have no functional effect at all, why are you going on about the differences between human ASPM and chimpanzee ASPM? All of those differences are missense changes too.

You do realize that human evolution from apes would require accelerated evolution in highly conserved genes I'm sure. Ok, so the missense changes don't do anything, I realize that most mutations are neutral. That kind of leaves dramatic adaptation on an evolutionary level in the ether does it not?

I also note that you didn't reply to part of my post. Why do you say that common descent is just an assumption, when nonfunctional differences between species in this same gene point to common descent? Do you have an alternative explanation for that tree?

If you can't even produce a viable molecular mechanism for the adaptive trait what other explanation is there for the unwaivering confidence in common descent? An a priori assumption is not just an assumption anymore then a scientific theory is just a theory. A priori assumptions make tremendous predictions that prove themselves reliable over time. This one has of common descent has been very unreliable as far as making predictions with regards to adaptations on a molecular level.

I'm going to stray a little but I want to make this as clear as I can. I have no problem with the Canadian Black Bear and the Arctic Polar Bear having a common ancestor, I don't think any Creationist would. They live in fairly close proximity to one another but one is black and the other white.

Just think about it for a minute, does their common ancestor really have time for the accumulation of missense mutations to start having a beneficial effect? For one thing the deleterious effects will manifest and there will be a restriction of gene flow from a bottleneck in order for them to be fixed.

What I am thinking is that there is another reason for this adaptation and may well include variables in amino acid sequences. I think, but can't really prove, that there are molecular mechanisms that create adaptations that don't need missense mutations.

What alternative do I propose? Normative molecular mechanisms directly observed and demonstrated with limits beyond which they cannot evolve.

As many times as we have done this Steve, why have we never discussed the molecular mechanisms for known adaptations? Instead you are talking about missense mutations that don't do anything except shut down the reading frame or nothing at all or you can get this:

Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APPSw,Ind) mice

I'll eventually figure this out but I wanted to ask you because I know you could save me a lot of time if you had a mind to.

Grace and peace,
Mark

 

[lucaspa]

Read an interesting article in the latest edition of Newsweek.

It seems that about 5800 years ago, homsapiens finally got the benefits of the ASPM gene and it was about this time that the first cities were constructed in the Near East.

I think you misread the article. Going back to the original journal, the ASPM gene was evolving in the period 2 million years ago to 200,000 years ago. Not 5800 years ago.

"The size of human brain tripled over a period of

2 million years (MY) that ended 0.2–0.4 MY ago. This evolutionary expansion is believed to be important to the emergence of human language and other high-order cognitive functions, yet its genetic basis remains unknown. An evolutionary analysis of genes controlling brain development may shed light on it. ASPM (abnormal spindle-like microcephaly associated) is one of such genes, as nonsense mutations lead to primary microcephaly, a human disease characterized by a 70% reduction in brain size. Here I provide evidence suggesting that human ASPM went through an episode of accelerated sequence evolution by positive Darwinian selection after the split of humans and chimpanzees but before the separation of modern non-Africans from Africans. Because positive selection acts on a gene only when the gene function is altered and the organismal fitness is increased, my results suggest that adaptive functional modifications occurred in human ASPM and that it may be a major genetic component underlying the evolution of the human brain. " http://www.genetics.org/cgi/content/abstract/165/4/2063

This is in rough accord with Genesis that indicates that one of the first activities of mankind was the construction of cities in the Near East.

But there are cities built in Asia that are twice as old!
3. WG Solheim II, An earlier agricultural revolution. Scientific American, April 1972 in Scientific American, The Origins of Technology.

I believe it is also possible that they represent the earliest ancestors to which the ancestors of the Jews could trace their lineage. Thus, the children of Adam and Eve did not marry sibling, but married other homsapiens nearby.

This is one of the more popular Talmudic interpretations. Adam and Eve were not the first people, but the first JEWISH people.

I think this could also answer the question of who were the 'sons of God' mentioned in Genesis. I suggest that they were simply the ancestors of the Jews.

Ah, but if you look, those "sons of God" were not mortal. Remember, in Genesis 5 God has to limit the lifespans of the offspring of matings between human women and the "sons of God", because those offspring were apparently immortal.

 

[lucaspa]

With all due respect I think we do know the effect and it is most often nothing at all, then there are actual effects on the phenotype or expressed traits and they are deleterious.

Not always. And, in fact, not even very often. Very few mutations are out and out deleterious.

What you focus on only is cases of purifying selection. Once an allele is such that it is at maximal fitness, then of course any change in it is going to decrease fitness. But remember, the allele didn't start out that way. It started out at lesser fitness and then mutated to what we see now.

That's what I'm saying about mutations, they disrupt the normal function of the gene.

Not even most times. Most mutations are silent. They change the 3rd codon, which is usually redundant, and give the exact same protein when translated to amino acids.

Other mutations are conservative. They may change the amino acid, but the new one has very similar chemical properties to the old one and the protein folding does not change. For instance, change leucine to isoleucine and the protein doesn't change in its 3-D structure.

What is required is for there to be a huge adaptive evolutionary process that does not slightly improve things but accelerate growth in highly conserved regions. You tell me, does it get any more highly conserved then neurogenesis?

Yes. Limb development. After all, the arrangement of a humerous, radius and ulna, 5 wrist bones, and carpals are highly conserved across all vertebrate lineages.

You have just said what researchers are publishing on a regular basis, mutations in this region are disrupting this gene or doing nothing at all. Feel free to correct me if I'm wrong, isn't it a little presumptive to say there is evidence of positive selection if you can't identify the molecular mechanism?

http://www.hhmi.org/news/lahn.html
"For each species, the researchers identified changes in the ASPM gene that altered the structure of the resulting protein, as well as those that did not affect protein structure. Only those genetic changes that alter protein structure are likely to be subject to evolutionary pressure, Lahn said. Changes in the gene that do not alter the protein indicate the overall mutation rate - the background of random mutations from which evolutionary changes arise. Thus, the ratio of the two types of changes gives a measure of the evolution of the gene under the pressure of natural selection."

From the original paper by Lahn and colleagues in Science:

"Phylogenetic analysis of ASPM has revealed strong positive selection in the primate lineage leading to Homo sapiens (3–5), especially in the past 6 million years of hominid evolution in which ASPM acquired about one advantageous amino acid change every 350,000 years (4). "

You can look at the papers referenced for the specific advantageous amino acid changes.

"The unusually high frequency of haplotype 63 is strongly suggestive of positive selection (8). We tested the statistical significance of the possibility of positive selection using coalescent modeling (7). The frequency of haplotype 63 is notably higher in Europeans and Middle Easterners (including Iberians, Basques, Russians, North Africans, Middle Easterners, and South Asians), as compared with other populations (table S1). We therefore focused on this group to take advantage of its relatively simple and homogeneous demographic structure (9). Because 7 of the 50 Europeans and Middle Easterners were homozygous for haplotype 63, we tested the probability of obtaining 7 or more homozygotes (among 50) for a single haplotype across a 62.1-kb region containing 122 segregating sites (the number of polymorphic sites found in Europeans and Middle Easterners). ... These parameters produced a highly significant departure from the neutral expectation (P < 0.00001). "

Not genetic drift, but positive selection.

You do realize that human evolution from apes would require accelerated evolution in highly conserved genes I'm sure.

No. That's a false premise. Humans and chimps differ by less than 2% of their amino acid sequences in expressed genes. Since there have been 7 million years since the split and we take a generation time of 20 years, that works out to 350,000 generations. In one experiment with fruit flies, a different species was produced by natural selection after only 5 years or 2500 generations. This species differed from the original by over 3% in expressed genes. There have been over 100 times the number of generations between us and the apes. Plenty of time.

If you can't even produce a viable molecular mechanism for the adaptive trait

That's a false "if". See the references to the Science article.

Here, I'll list them:

3. J. Zhang, Genetics 165, 2063 (2003).[Abstract/Free Full Text]
4. P. D. Evans et al., Hum. Mol. Genet. 13, 489 (2004).[Abstract/Free Full Text]
5. N. Kouprina et al., PLoS Biol. 2, E126 (2004). [CrossRef] [Medline]
6. S. L. Gilbert, W. B. Dobyns, B. T. Lahn, Nat. Rev. Genet. 6, 581 (2005). [CrossRef] [ISI] [Medline]

As many times as we have done this Steve, why have we never discussed the molecular mechanisms for known adaptations?

OK, here are some:

5: J Bacteriol 1999 Jun;181(11):3341-50. Isolation and characterization of mutations in Bacillus subtilis that allow spore germination in the novel germinant D-alanine. Paidhungat M, Setlow P

7: EMBO J 1999 May 4;18(9):2352-63. The specificity of polygalacturonase-inhibiting protein (PGIP): a single amino acid substitution in the solvent-exposed beta-strand/beta-turn region of the leucine-rich repeats (LRRs) confers a new recognition capability. Leckie F, Mattei B, Capodicasa C, Hemmings A, Nuss L, Aracri B, De Lorenzo G,
Cervone F

9: Genetics 1998 Aug;149(4):1809-22. Gain-of-function mutations in the Caenorhabditis elegans lin-1 ETS gene identify a C-terminal regulatory domain phosphorylated by ERK MAP kinase. Jacobs D, Beitel GJ, Clark SG, Horvitz HR, Kornfeld K

11: EMBO J 1998 Jul 15;17(14):3850-7. Gain-of-function mutations in FcgammaRI of NOD mice: implications for the evolution of the Ig superfamily. Gavin AL, Tan PS, Hogarth PM

The papers are out there if you just take the time for a little PubMed search. Here are 5 references that fit your request after just 30 seconds:

1: Shirai T, Igarashi K, Ozawa T, Hagihara H, Kobayashi T, Ozaki K, Ito S.
Ancestral sequence evolutionary trace and crystal structure analyses of
alkaline alpha-amylase from Bacillus sp. KSM-1378 to clarify the alkaline
adaptation process of proteins.
Proteins. 2007 Feb 15;66(3):600-10.
PMID: 17154418 [PubMed - indexed for MEDLINE]

2: Benderoth M, Textor S, Windsor AJ, Mitchell-Olds T, Gershenzon J, Kroymann
J.
Positive selection driving diversification in plant secondary metabolism.
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9118-23. Epub 2006 Jun 5.
PMID: 16754868 [PubMed - indexed for MEDLINE]

3: Bowden SD, Salmond GP.
Exploitation of a beta-lactamase reporter gene fusion in the carbapenem
antibiotic production operon to study adaptive evolution in Erwinia carotovora.
Microbiology. 2006 Apr;152(Pt 4):1089-97.
PMID: 16549672 [PubMed - indexed for MEDLINE]

4: Field SF, Bulina MY, Kelmanson IV, Bielawski JP, Matz MV.
Adaptive evolution of multicolored fluorescent proteins in reef-building
corals.
J Mol Evol. 2006 Mar;62(3):332-9. Epub 2006 Feb 10.
PMID: 16474984 [PubMed - indexed for MEDLINE]

5: Payandeh J, Fujihashi M, Gillon W, Pai EF.
The crystal structure of (S)-3-O-geranylgeranylglyceryl phosphate synthase
reveals an ancient fold for an ancient enzyme.
J Biol Chem. 2006 Mar 3;281(9):6070-8. Epub 2005 Dec 23.

 

[sfs]

With all due respect I think we do know the effect and it is most often nothing at all, then there are actual effects on the phenotype or expressed traits and they are deleterious.

With all due respect, we know nothing of the sort. There are probably thousands of genetic variants that contribute to phenotypic variation between humans, and we only know what a handful of them are. Only in the past couple of years have we made any significant progress in identifying genetic risk factors for common disease, and those are easy phenotypes to identify and have received many millions in funding. We know, for example, precisely nothing about genetic causes for variation in intelligence, even though it is clear that intelligence has a large genetic component.

That's what I'm saying about mutations, they disrupt the normal function of the gene. What is required is for there to be a huge adaptive evolutionary process that does not slightly improve things but accelerate growth in highly conserved regions. You tell me, does it get any more highly conserved then neurogenesis? You have just said what researchers are publishing on a regular basis, mutations in this region are disrupting this gene or doing nothing at all.

No, that's not what I said. I said that phenotypic effects that we can detect are the result of disrupting the gene. I also said that we have no way of telling whether the other mutations are doing something more subtle or not. Zero knowledge. That is the point you are ignoring.

Feel free to correct me if I'm wrong, isn't it a little presumptive to say there is evidence of positive selection if you can't identify the molecular mechanism?

Fine, you're wrong. The molecular mechanism is the same one it always is, mutation followed by positive selection.

You do realize that human evolution from apes would require accelerated evolution in highly conserved genes I'm sure.

Uh, yes, just as human evolution of light colored skin outside Africa required accelerated evolution in a set of highly conserved genes. It happened.

Ok, so the missense changes don't do anything, I realize that most mutations are neutral. That kind of leaves dramatic adaptation on an evolutionary level in the ether does it not?

No, it leaves your argument in the ether. If you want to claim that missense mutations don't have any phenotypic effect (a truly ridiculous claim, by the way), then your argument that the missense changes to ASPM were too fast to have happened by positive selection makes no sense at all.

If you can't even produce a viable molecular mechanism for the adaptive trait what other explanation is there for the unwaivering confidence in common descent? An a priori assumption is not just an assumption anymore then a scientific theory is just a theory. A priori assumptions make tremendous predictions that prove themselves reliable over time. This one has of common descent has been very unreliable as far as making predictions with regards to adaptations on a molecular level.

I'll just note that you have once again failed to respond to my challenge: what is your alternative explanation for the tree we see in nonfunctional differences between species?

Just think about it for a minute, does their common ancestor really have time for the accumulation of missense mutations to start having a beneficial effect? For one thing the deleterious effects will manifest and there will be a restriction of gene flow from a bottleneck in order for them to be fixed.

The answer to the question is yes, there is plenty of time. The response to the sentence that follows is "huh?" Deleterious effects from missense mutations occur all the time and are weeded out by natural selection. The rest of the sentence makes no sense. Bottlenecks have nothing to do with selection for or against missense mutations, and don't involve restricted gene flow.

What I am thinking is that there is another reason for this adaptation and may well include variables in amino acid sequences. I think, but can't really prove, that there are molecular mechanisms that create adaptations that don't need missense mutations.

Molecular mechanisms for adaptive change that don't involve missense mutations are well known: mutations to regulatory regions.

As many times as we have done this Steve, why have we never discussed the molecular mechanisms for known adaptations?

Perhaps because you've never asked. Known adaptations have involved missense mutations, nonsense mutations, and mutations to regulatory regions that control genes, depending on the case, followed by positive selection for the variant. The mechanism you claim isn't adequate.