Is the Human Brain the Null Hypothesis for Darwin's Theory?

mark kennedy · #31 25th July 2008, 08:58 AM

Originally Posted by birdan

This will be my only post in this forum, and it is just to make a factual correction. There are variations in the ASPM gene (and other brain-associated genes) in the human population which are not deleterious. That is, people with physiologically and functionally normal brains have variations of these genes. I suggest you google 'Bruce Lahn' for his research on variations of the ASPM gene within the 'normal' human population. You can also google for the PDYN gene and the microcephalin gene for variations that are not deleterious.

So, the part of your argument that I bolded above is not factually correct.

I have read a lot of Lahn's stuff and I don't deny that there are a number of neutral mutations. When there is an effect strong enough for selection to act it's deleterious 100% of the time. I do realize there are different alleles of the ASPM or Microcephalin but ten indels indels accumulating in such a large and vital coding gene isn't an allele, it's an overhaul. It's not that I think there are no variations in the genes, it's the range of variation required.

This is what most often happens when you have an indel in a protein coding gene, it's called a frameshift

In the living cell, DNA undergoes frequent chemical change, especially when it is being replicated (in S phase of the eukaryotic cell cycle). Most of these changes are quickly repaired. Those that are not result in a mutation. Thus, mutation is a failure of DNA repair...

Extra base pairs may be added (insertions) or removed (deletions) from the DNA of a gene. The number can range from one to thousands. Collectively, these mutations are called indels.

Indels involving one or two base pairs (or multiples thereof) can have devastating consequences to the gene because translation of the gene is "frameshifted". This figure shows how by shifting the reading frame one nucleotide to the right, the same sequence of nucleotides encodes a different sequence of amino acids. The mRNA is translated in new groups of three nucleotides and the protein specified by these new codons will be worthless. Scroll up to see two other examples (Patients C and D).

Frameshifts often create new STOP codons and thus generate nonsense mutations. Perhaps that is just as well as the protein would probably be too garbled anyway to be useful to the cell.

Indels of three nucleotides or multiples of three may be less serious because they preserve the reading frame (see Patient E above). Mutations

Which is exactly what happens when they are introduced into the ASPM gene. This is what they know happens:

We identified a homozygous mutation introducing a premature stop codon into the predicted ASPM (abnormal spindle−like microcephaly associated) open reading frame in each of the four affected families. The four mutations are 719−720delCT (exon 3), causing a frameshift leading to a premature termination 15 codons downstream. ASPM is a major determinant of cerebral cortical size

This is what would have had to happen for us the have evolved from an ape ancestor:

The ASPM gene while 99.3% the same for the human–chimpanzee comparison is marked by ten insertions/deletions equal to or longer than 50 bp, all of them located within introns. Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by global reduction in cerebral cortical volume.(Genetics, Vol. 165, 2063-2070, December 2003)

See the problem?

mark kennedy · #32 25th July 2008, 10:12 AM

Originally Posted by busterdog

Why should he assume that all genetic variations represent "mutations?"

Absolutely not, in fact I get irritated with the word because I believe there are mechanisms that create new alleles (variations of the genes). I suspect it's some kind of an RNA strand or something but there is definitely something.

How do we know that any of these expressions were not found in Adam OR Eve or the sons of Noah or their wives? I am not sure how many genes you are talking about.

In the HAR (Human Accelerated Regions) they found 210 showing signs of major divergence. I really don't know how many brain related, protein coding and regulatory, genes would be involved but the simple answer is a lot.

In order to focus on human-specific changes that have functional importance, we first identified a set of genomic regions which are at least 100 bp in length and identical between chimp (P. troglodytes), mouse (Mus musculus), and rat (Rattus norvegicus) in at least 96% of alignment columns...Bioinformatic analysis of the 34,498 predicted functional elements shows that they are very similar to previously described highly conserved elements in the human genome. Only 19.6% overlap coding regions of human genes, while the remaining non-coding regions are mostly intergenic (45.4%) and intronic (31.0%)...
Forces Shaping the Fastest Evolving Regions in the Human Genome

By way of analogy, you can get a camry with four cyl. or six. In the factory of meiosis, things are created that are not "mutations", but are a different options packages.

Right, the genes cross over from the diploid chromosomes, one set from each parent. Obviously, that's not a mutation, traits being inherited in this way can even adapt to new environments but mutations are not required. I know certain genes can be turned off and on, I'm not really sure how that works exactly but I know it happens.

Crossing-over also occurs during meiosis I. Crossing over is an exchange of genetic material by non-sister chromatids of a homologous pair of chromosomes. This exchange of genetic material is the basis for additional variation in the offspring (another being the recombination of genetic material from two different genetic sources, the parents). This can lead to better adaptations and hence is a part of the process of evolution. Meiosis

How do we know that the information that is optional did not reside in our ancestors and is not carried? That is a question, not a rhetorical question, since I don't know the answer.

A lot of times the scientists who research this sort of thing don't know. Here is an interesting example.

The finding grew out of a research project started three years ago in which Dr. Pruitt and Dr. Lolle were trying to understand the genes that control the plant's outer skin, or cuticle. As part of the project, they were studying plants with a mutated gene that made the plant's petals and other floral organs clump together. Because each of the plant's two copies of the gene were in mutated form, they had virtually no chance of having normal offspring.

But up to 10 percent of the plants' offspring kept reverting to normal. Various rare events can make this happen, but none involve altering the actual sequence of DNA units in the gene. Yet when the researchers analyzed the mutated gene, known as hothead, they found it had changed, with the mutated DNA units being changed back to normal form.
Startling Scientists, Plant Fixes Its Flawed Gene

And Mark, what is the latest on where such information would be stored. One thing that research seems to show is that our simplistic notion of what the genetic code is seems to have a less defined boundary that was taught 20 years ago. Does the fact that you don't see the information in the strands of the 46 base pairs mean that the information isn't otherwise there? Remember that geneticists must rely upon notions like "self organizing", which implies that the information is present somewhere that we have no idea about.

The article above suggest the RNA may have had a copy somewhere:

Dr. Pruitt said he favored the idea that there is an RNA backup copy for the entire genome, not just the hothead gene, and that it might be set in motion when the plant was under stress, as is the case with those having mutated hothead genes.

He and other experts said it was possible that an entire RNA backup copy of the genome could exist without being detected, especially since there has been no reason until now to look for it.

I kind of like this idea since they are finding out that the RNA is coming from all kinds of places that were previously thought to be junk DNA:

TANGLED GENES. In the classic view of the genome (top), individual genes were distinct segments of DNA that a cell transcribed into RNA whole and in one direction. New data show that multiple and overlapping genes can occupy a single strip of DNA that also produces several functional RNAs that don't encode proteins

The results from ENCODE were even more striking. In the slice of DNA studied in that project, between 74 percent and 93 percent of the genome produced RNA transcripts. What becomes of this tremendous output is uncertain. John M. Greally of the Albert Einstein College of Medicine in New York says it's likely that some portion of it is made accidentally and simply discarded. But the discovery that so much of the genome is being transcribed into RNA underscores how out-of-date the central dogma has become.
Mountains of new data are challenging old views

mark kennedy · #33 25th July 2008, 10:18 AM

Originally Posted by busterdog

Why should he assume that all genetic variations represent "mutations?"

Absolutely not, in fact I get irritated with the word because I believe there are mechanisms that create new alleles (variations of the genes). I suspect it's some kind of an RNA strand or something but there is definitely something.

How do we know that any of these expressions were not found in Adam OR Eve or the sons of Noah or their wives? I am not sure how many genes you are talking about.

In the HAR (Human Accelerated Regions) they found 210 showing signs of major divergence. I really don't know how many brain related, protein coding and regulatory, genes would be involved but the simple answer is a lot.

In order to focus on human-specific changes that have functional importance, we first identified a set of genomic regions which are at least 100 bp in length and identical between chimp (P. troglodytes), mouse (Mus musculus), and rat (Rattus norvegicus) in at least 96% of alignment columns...Bioinformatic analysis of the 34,498 predicted functional elements shows that they are very similar to previously described highly conserved elements in the human genome. Only 19.6% overlap coding regions of human genes, while the remaining non-coding regions are mostly intergenic (45.4%) and intronic (31.0%)...
Forces Shaping the Fastest Evolving Regions in the Human Genome

By way of analogy, you can get a camry with four cyl. or six. In the factory of meiosis, things are created that are not "mutations", but are a different options packages.

Right, the genes cross over from the diploid chromosomes, one set from each parent. Obviously, that's not a mutation, traits being inherited in this way can even adapt to new environments but mutations are not required. I know certain genes can be turned off and on, I'm not really sure how that works exactly but I know it happens.

Crossing-over also occurs during meiosis I. Crossing over is an exchange of genetic material by non-sister chromatids of a homologous pair of chromosomes. This exchange of genetic material is the basis for additional variation in the offspring (another being the recombination of genetic material from two different genetic sources, the parents). This can lead to better adaptations and hence is a part of the process of evolution. Meiosis

How do we know that the information that is optional did not reside in our ancestors and is not carried? That is a question, not a rhetorical question, since I don't know the answer.

A lot of times the scientists who research this sort of thing don't know. Here is an interesting example.

The finding grew out of a research project started three years ago in which Dr. Pruitt and Dr. Lolle were trying to understand the genes that control the plant's outer skin, or cuticle. As part of the project, they were studying plants with a mutated gene that made the plant's petals and other floral organs clump together. Because each of the plant's two copies of the gene were in mutated form, they had virtually no chance of having normal offspring.

But up to 10 percent of the plants' offspring kept reverting to normal. Various rare events can make this happen, but none involve altering the actual sequence of DNA units in the gene. Yet when the researchers analyzed the mutated gene, known as hothead, they found it had changed, with the mutated DNA units being changed back to normal form.
Startling Scientists, Plant Fixes Its Flawed Gene

And Mark, what is the latest on where such information would be stored. One thing that research seems to show is that our simplistic notion of what the genetic code is seems to have a less defined boundary that was taught 20 years ago. Does the fact that you don't see the information in the strands of the 46 base pairs mean that the information isn't otherwise there? Remember that geneticists must rely upon notions like "self organizing", which implies that the information is present somewhere that we have no idea about.

The article above suggest the RNA may have had a copy somewhere:

Dr. Pruitt said he favored the idea that there is an RNA backup copy for the entire genome, not just the hothead gene, and that it might be set in motion when the plant was under stress, as is the case with those having mutated hothead genes.

He and other experts said it was possible that an entire RNA backup copy of the genome could exist without being detected, especially since there has been no reason until now to look for it.

I kind of like this idea since they are finding out that the RNA is coming from all kinds of places that were previously thought to be junk DNA:

TANGLED GENES. In the classic view of the genome (top), individual genes were distinct segments of DNA that a cell transcribed into RNA whole and in one direction. New data show that multiple and overlapping genes can occupy a single strip of DNA that also produces several functional RNAs that don't encode proteins

The results from ENCODE were even more striking. In the slice of DNA studied in that project, between 74 percent and 93 percent of the genome produced RNA transcripts. What becomes of this tremendous output is uncertain. John M. Greally of the Albert Einstein College of Medicine in New York says it's likely that some portion of it is made accidentally and simply discarded. But the discovery that so much of the genome is being transcribed into RNA underscores how out-of-date the central dogma has become.
Mountains of new data are challenging old views

birdan · #34 25th July 2008, 10:20 AM

Originally Posted by mark kennedy

I have read a lot of Lahn's stuff and I don't deny that there are a number of neutral mutations. When there is an effect strong enough for selection to act it's deleterious 100% of the time. I do realize there are different alleles of the ASPM or Microcephalin but ten indels indels accumulating in such a large and vital coding gene isn't an allele, it's an overhaul. It's not that I think there are no variations in the genes, it's the range of variation required.

My post was in reply to your assertion that all mutations to ASPM were deleterious, for instance from post #5:

"You say that despite the fact that the only effect of mutations on the ASPM gene is a reduced cranial capacity and it would have required ten insertions/deletions equal to or longer than 50 bp, all of them located within introns."

Which is exactly what happens when they are introduced into the ASPM gene. This is what they know happens:
We identified a homozygous mutation introducing a premature stop codon into the predicted ASPM (abnormal spindle−like microcephaly associated) open reading frame in each of the four affected families. The four mutations are 719−720delCT (exon 3), causing a frameshift leading to a premature termination 15 codons downstream. ASPM is a major determinant of cerebral cortical size
This is what would have had to happen for us the have evolved from an ape ancestor:
The ASPM gene while 99.3% the same for the human–chimpanzee comparison is marked by ten insertions/deletions equal to or longer than 50 bp, all of them located within introns. Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by global reduction in cerebral cortical volume.(Genetics, Vol. 165, 2063-2070, December 2003)
See the problem?

No, I don't see the problem. Your second quote above specifically says all the ASPM mutations were within introns, which would not affect the resultant protein structure. Your first quote is talking about a mutation that does effect the protein structure. What the two quotes together imply is that the protein structure is highly conserved.

As for your 'no time for brain mass to evolve' scenario, what about my previous post? A microcephalic version of ASPM can undergo a single mutation and increase brain mass from 1 pound to 3 pounds. So clearly there can exist 'molecular mechanisms' that can produce radical changes quickly.

P.S. I hope you read all of Sean Carroll's paper and understand how minor cis-regulatory mutations can have profound effects on anatomy and physiology. Since the ASPM gene is a neuro-developmental gene with low pleiotropic effects ....

mark kennedy · #35 25th July 2008, 11:56 AM

Originally Posted by birdan

My post was in reply to your assertion that all mutations to ASPM were deleterious, for instance from post #5:

"You say that despite the fact that the only effect of mutations on the ASPM gene is a reduced cranial capacity and it would have required ten insertions/deletions equal to or longer than 50 bp, all of them located within introns."
No, I don't see the problem. Your second quote above specifically says all the ASPM mutations were within introns, which would not affect the resultant protein structure. Your first quote is talking about a mutation that does effect the protein structure. What the two quotes together imply is that the protein structure is highly conserved.

Let's cut to the chase, ever see or hear of a mutation in a brain related gene that has a beneficial effect.

I identified 16 nonsynonymous and 6 synonymous mutations that have been fixed in the human lineage...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 Accelerated Evolution of the ASPM Gene Controlling Brain Size Begins Prior to Human Brain Expansion

http://www.genetics.org/content/vol1...EN9778.f2.jpeg

Accelerated evolution would be required for a large number of genes that simply don't respond well to mutations. The neutral theory doesn't work so there would have had to be a functional sequence fully intact. Mutations in this gene result in mental retardation and a severely reduced brain size. Mutations never produce improved form and function and the patients with this disorder have truncated proteins because of premature stop codons. That's what happens and the small allele variations are not going to get you an improved brain.

As for your 'no time for brain mass to evolve' scenario, what about my previous post? A microcephalic version of ASPM can undergo a single mutation and increase brain mass from 1 pound to 3 pounds. So clearly there can exist 'molecular mechanisms' that can produce radical changes quickly.

What molecular mechanisms overhaul brain related genes? Bear in mind the are costs to an increased brain size and the ASPM gene alone won't get you a human brain from that of apes and it's not just one mutation, it's a new one with a beneficial affect once every 300,000-400,000 years. Chimpanzees and Humans: What Made Us Smarter?

Using a statistical test known as the McDonald-Kreitman test, the authors were able to determine that 45 amino acids had been mutated and fixed over the past 25-30 million years, as humans evolved from their simian ancestors. This is an astoundingly high rate of evolution.

ASPM fixed one advantageous amino acid change in every 300,000 – 400,000 years since the human lineage diverged from chimpanzees some 5–6 million years ago. Chimpanzees and Humans: What Made Us Smarter?

P.S. I hope you read all of Sean Carroll's paper and understand how minor cis-regulatory mutations can have profound effects on anatomy and physiology. Since the ASPM gene is a neuro-developmental gene with low pleiotropic effects ....

Hey, thanks, that's the sort of thing I like. I take it this is the paper you are referring to :

The crucial insight from the evolution of Pitx1, yellow, and Hoxc8 is that regulatory mutations provide a mechanism for change in one trait while preserving the role of pleiotropic genes in other processes. This is perhaps the most important, most fundamental insight from evolutionary developmental biology. While functional mutations in a coding region are usually poorly tolerated and eliminated by purifying selection, even complete loss-of-function mutations in regulatory elements are possible because the compartmentation created by the modularity of cis-regulatory elements limits the effects of mutations to individual body parts.
Evolution at Two Levels: On Genes and Form

SLP · #36 14th August 2008, 04:57 PM

Originally Posted by mark kennedy

You say that despite the fact that it would require 18 substitutions in a regulatory gene that has only allowed 2 since the Cambrian.

"Require"?

So, after a forest fire was started by a lightening strike, do you declare it so unlikley as to have not really occurred becasue the fire would have required a lightening strike?

You say that despite the fact that the only effect of mutations on the ASPM gene is a reduced cranial capacity and it would have required ten insertions/deletions equal to or longer than 50 bp, all of them located within introns.

Are you really sure about that?

Please cite the paper that has documented all possible mutations in that gene, please.

All that despite the fact that there is not a single example of a beneficial effect from a mutation in a brain related gene known to modern science.

What about the mutations cited in the Lahn paper you refer to?

Now one of the other factors would be gene expression which a comparisons is 10% different in human brain related genes as compared to chimpanzes. It's all in the OP.

Well, if everything were the same, wouldn't we BE chimpanzees?

The fact remains that 2 mya our ancestors would have had chimpanzee size brains, within a couple of hundred thousand years it had doubled. The genetic basis for the unprecedented expansion of the human brain from that of apes remains unknown to science and yet remains unquestioned.

So, if something is unknown, it must have been created by God?

Why are you so obsessed with these size issues? Why do you think that a doubling - heck, a quadrupling - of brain size in 2 million years is insurmountable?

Tell us all, with your indepth knowledge of genetics and development, why this size increase is impossible.

Just not believing it is not evidence nor an explanation.

SLP · #37 14th August 2008, 05:56 PM

Originally Posted by mark kennedy

Special creation is the only alternative to descent with modification and there is ample research in this area:

Where's the research?

SLP · #38 14th August 2008, 06:06 PM

Originally Posted by mark kennedy

Let's cut to the chase, ever see or hear of a mutation in a brain related gene that has a beneficial effect.

I identified 16 nonsynonymous and 6 synonymous mutations that have been fixed in the human lineage...

YOU did?
Interesting. Can you tell us what a nonsynonymous mutation is? And no copy and pastes, please, just explain it.

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 Accelerated Evolution of the ASPM Gene Controlling Brain Size Begins Prior to Human Brain Expansion

http://www.genetics.org/content/vol1...EN9778.f2.jpeg

Accelerated evolution would be required for a large number of genes that simply don't respond well to mutations.

So you keep saying. But it is interesting - this gene that you say doesn't respond well to mutations, it differs by how many substitutions between human and chimp?
16 and 6?
Apparently, it can handle at least that many. So please explain how it is you know that this gene is so sensitive to mutation.

The neutral theory doesn't work so there would have had to be a functional sequence fully intact.

I fail to see a connection between the first part of that sentence and the second. What do you mean a 'fully intact' sequence?

Mutations in this gene result in mental retardation and a severely reduced brain size.

Are you saying then that chimpanzees are all retarded?
I don't see your point.

Mutations never produce improved form and function and the patients with this disorder have truncated proteins because of premature stop codons.

So, is it your position that all mutations in this gene produce premature stop codons?

That's what happens and the small allele variations are not going to get you an improved brain.

And yet you have quoted Lahn claiming that there are - what was it - hundreds of genes involved in brain formaiton? Why are you so sure that THIS gene is the only relevant one?

What molecular mechanisms overhaul brain related genes?

The same ones that 'overhaul' any other gene.

Bear in mind the are costs to an increased brain size and the ASPM gene alone won't get you a human brain from that of apes and it's not just one mutation, it's a new one with a beneficial affect once every 300,000-400,000 years.

A new what? And why do you think all such mutations must be beneficial?

The crucial insight from the evolution of Pitx1, yellow, and Hoxc8 is that regulatory mutations provide a mechanism for change in one trait while preserving the role of pleiotropic genes in other processes. This is perhaps the most important, most fundamental insight from evolutionary developmental biology. While functional mutations in a coding region are usually poorly tolerated and eliminated by purifying selection, even complete loss-of-function mutations in regulatory elements are possible because the compartmentation created by the modularity of cis-regulatory elements limits the effects of mutations to individual body parts.
Evolution at Two Levels: On Genes and Form

It is customary to indicate when you have copy and pasted someone else's words.

mark kennedy · #39 30th August 2008, 06:09 PM

Hi Professor, long time no see. It's surprising to see you making a fellowship post in the Creationism subforum, did you covert?

Originally Posted by SLP

YOU did?
Interesting. Can you tell us what a nonsynonymous mutation is? And no copy and pastes, please, just explain it.

They affect the amino acid sequence, why?

So you keep saying. But it is interesting - this gene that you say doesn't respond well to mutations, it differs by how many substitutions between human and chimp?

I'm not really sure, here, you count them:

Figure 1. Nucleotide polymorphisms and substitutions in the human ASPM gene

16 and 6?

Not really sure, the effects of mutations on the huge protein coding gene is clear enough though.

Apparently, it can handle at least that many. So please explain how it is you know that this gene is so sensitive to mutation.

I'm not following you, what are you asking here? The gene is named for an abnormal spindle that results from mutations.

I fail to see a connection between the first part of that sentence and the second. What do you mean a 'fully intact' sequence?

I'm confused what you are even talking about.

Are you saying then that chimpanzees are all retarded?

No, I'm saying that random mutations don't explain the evolution of the human brain from that of apes.

I don't see your point.

Ditto

So, is it your position that all mutations in this gene produce premature stop codons?

Generally there will be a stop codon resulting in a truncated protein.

And yet you have quoted Lahn claiming that there are - what was it - hundreds of genes involved in brain formaiton? Why are you so sure that THIS gene is the only relevant one? The same ones that 'overhaul' any other gene.

No actually Lahn said hundreds if not thousands of mutations in hundreds if not thousands of genes:

"We've done a rough calculation that the evolution of the human brain probably involves hundreds if not thousands of mutations in perhaps hundreds or thousands of genes -- and even that is a conservative estimate"

A new what? And why do you think all such mutations must be beneficial?

I don't think they ever are in brain related genes.

It is customary to indicate when you have copy and pasted someone else's words.

You must be bored, desperate or just missing me something terrible to show up in the Creationism subforum. Now why don't you just run along to your ivory tower and stop stalking evangelicals with an interest in the Life Sciences.

Only kidding, seriously, if you want to discuss this I'm posting over at CARM these days. The trolls on there will love you and we can discuss these things without disrupting what is supposed to be a fellowship forum. I felt betrayed by CF when 7-7-7 changes opened all the forums to the dogs of debate. Since then I have encouraged Creationists to shun these debates but I'm still very curious about the growing body of work on genomic research.

Hope this post finds you well sir,
Mark

SLP · #40 12th September 2008, 12:09 PM

Originally Posted by mark kennedy

Hi Professor, long time no see. It's surprising to see you making a fellowship post in the Creationism subforum, did you covert?

Just wondering why you decided to post this stuff in the one forum where you were the most likely not to get any actual criticism...

You must be bored, desperate or just missing me something terrible to show up in the Creationism subforum. Now why don't you just run along to your ivory tower and stop stalking evangelicals with an interest in the Life Sciences.

Just thought it interesting to see these same arguments making the rounds, as if they'd not been discussed before.