The evolution of the protein coding genes

[mark kennedy]

A couple of intellectually curious TEs wandered into the Creationist subforum and brought up the protein coding genes. The actual issue is genomics and in this high tech age genetics is multiplying our understanding of living systems by leaps and bounds. I am interested in discussing the particulars once again with evolutionists in the hopes of keeping the discussion and debate out of a fellowship forum.

Here is the issue in a nutshell:

The popular media did not quite know what to make of the initial analysis of PTR22 [1]. "Chimp DNA almost identical to ours" announced Reuters, whereas Asian News International informed its readers that "Chimps and men are indeed very different!" Unwittingly, the authors of these two headlines may have summarized many years' worth of scientific debate over human and chimpanzee evolution [10]. We can now count the exact number of genetic differences between humans and chimpanzees, but whether this number is high or low is entirely in the eye of the beholder.​

What makes us human?
Tarjei S Mikkelsen


I don't have a complicated arguement here, evolution of protein coding genes on this level is simply impossible. There have been no less then fifteen gross stuctural changes that would have had to occur in a single chromosome.

Let's discuss this here and leave the creationist subforum alone.

Grace and peace,
Mark

 

[gluadys]

I don't have a complicated arguement here, evolution of protein coding genes on this level is simply impossible. There have been no less then fifteen gross stuctural changes that would have had to occur in a single chromosome.

You are very quick to come to this conclusion.

I found the following comments in the paper interesting:

But are the data reported by Watanabe et al. [1] - based on less than 1% of the known human complement of genes - representative of human and chimpanzee evolution in general? There are a few observations that suggest caution is needed. First, survey sequencing (sequencing of random short regions over the whole genome) has suggested that HSA21 and PTR22 are diverging faster than most of the other autosomes [6], implying that comparing these chromosomes may overestimate the genome-wide rate of divergence somewhat. Second, approximately two-thirds of the orthologs reported to show length differences between humans and chimpanzees are uncharacterized or poorly characterized genes whose coding sequences have typically been annotated on the basis of a small number of cDNAs or expressed sequence tags. Few of these predicted genes have an unambiguous mouse ortholog, whereas it is estimated that approximately 80% of all human genes do [5]. Genes that differ in length between human and chimp also dominate the list of orthologs that have high ratios of nonsynonymous to synonymous substitutions [1], implying that they are evolving under more relaxed constraints than the average human-chimpanzee ortholog pair.

Thus, a significant proportion of the genes reported to be rapidly diverging by Watanabe et al. [1] appear to be novel to the primate lineage and of largely unknown function. In contrast, better characterized genes with known functions and recognizable mouse orthologs are highly conserved. This suggests that the relatively high number of genes with putative structural changes may not be so surprising after all, because earlier estimates of the structural change rate were probably based on highly conserved genes.​

Bolding added.

All in all, I think caution is needed in coming to any definitive conclusion about what is and is not possible.

 

[shernren]

I asked MK to reference these statements:

Gross structural indels occur within reading frames and yet the reading frames are virtually all still functional.

.........

There is also a real problem with what kind of indels are represented. Most of the human sequence would have had to result from deletions in the hominid line, this makes absolutely no sense at all.

on a semantic level I only asked him questions about what he brought up. Nevertheless I'm glad that this is out of the creationist subforum. MK responded on that thread with this: (I had to peek to remember what I asked him to reference )

Comparing 231 orthologous genes on the chromosomes, Watanabe et al. [1] found 179 cases in which the human and chimpanzee protein-coding sequences were of equal lengths. Of these, approximately 80% have at least one amino-acid difference between the two species, leading to an average amino-acid divergence of 0.82%. Interestingly, of the remaining 52 orthologs, 15 were found to have indels within their coding sequences and 32 were found to have changes in the first ATG (start codon) or the stop codon, changes that would potentially lead to gross structural differences between the human and chimpanzee protein products. Given that fewer than 54% of human-mouse orthologs have coding sequences of different lengths [5], it seems rather surprising that as many as 20% have changed between humans and chimpanzees, despite the significantly shorter time since their divergence. Watanabe et al. [1] hypothesized that indels and structural changes may represent one of the major mechanisms of proteome evolution in the higher primates.
​

All that this excerpt is saying is that of 231 orthologous genes:

179 are of equal length
15 have indels in coding sequences
32 have alterations in start or stop codons.

I have no idea what MK is trying to say by "Gross structural indels occur within reading frames and yet the reading frames are virtually all still functional." - the reason most of the genes are functional and reasonably identical is precisely because they don't have indels. The ones that have indels have altered reading frames, and the ones that don't, don't (besides start/stop alterations).

And again, "There is also a real problem with what kind of indels are represented. Most of the human sequence would have had to result from deletions in the hominid line, this makes absolutely no sense at all." This is also meaningless. An indel is called an "insertion/deletion" precisely because it cannot be determined to be one or the other without a proper outgroup comparison, which doesn't seem to have been commented on in this extract.

 

[mark kennedy]

I asked MK to reference these statements:



on a semantic level I only asked him questions about what he brought up. Nevertheless I'm glad that this is out of the creationist subforum. MK responded on that thread with this: (I had to peek to remember what I asked him to reference )

Comparing 231 orthologous genes on the chromosomes, Watanabe et al. [1] found 179 cases in which the human and chimpanzee protein-coding sequences were of equal lengths. Of these, approximately 80% have at least one amino-acid difference between the two species, leading to an average amino-acid divergence of 0.82%. Interestingly, of the remaining 52 orthologs, 15 were found to have indels within their coding sequences and 32 were found to have changes in the first ATG (start codon) or the stop codon, changes that would potentially lead to gross structural differences between the human and chimpanzee protein products. Given that fewer than 54% of human-mouse orthologs have coding sequences of different lengths [5], it seems rather surprising that as many as 20% have changed between humans and chimpanzees, despite the significantly shorter time since their divergence. Watanabe et al. [1] hypothesized that indels and structural changes may represent one of the major mechanisms of proteome evolution in the higher primates.
​

All that this excerpt is saying is that of 231 orthologous genes:

179 are of equal length
15 have indels in coding sequences
32 have alterations in start or stop codons.

Did you miss this part:

"...it seems rather surprising that as many as 20% have changed between humans and chimpanzees, despite the significantly shorter time since their divergence."

Like they said, the differences are in the eye of the beholder. So we have 83% of the protein coding genes in Chromosome 21 that diverge, on average, by a single codon in the respective genomes. That sounds fine until you realize that 20% of the protein coding genes have gross structural differences.

The most conserved region was at about the 12.5-Mb region (0.87%, over 100 kb), corresponding to the distal boundary region of the gene desert. Notably, no protein-coding genes have been identified in this highly conserved region...

...Taken together, gross structural changes affecting gene products are far more common than previously estimated (20.3% of the PTR22 proteins, as listed in Supplementary Tables 4 and 5). DNA sequence and comparative analysis of chimpanzee chromosome 22
, Nature 27 May 2004​

The most highly conserved region had no genes and gross structural changes are 20%. This has come to be one of those ironies for me, the noncoding region being more conserved then the coding region.

Point mutation rates in exons (synonymous sites) and noncoding (introns and intergenic) regions are generally assumed to be the same. However, comparative sequence analyses of synonymous substitutions in exons (81 genes) and that of long intergenic fragments (141.3 kbp) of human and chimpanzee genomes reveal a 30%–60% higher mutation rate in exons than in noncoding DNA.Neutral substitutions occur at a faster rate in exons than in noncoding DNA in primate genomes.Entrez PubMed 2003 May
​

Can you honestly say that this makes perfect sense to you or that this does not come as a big supprise? The researchers are certainly supprised when asked what they think of this.

Sakaki said their analysis found about 68,000 insertions or deletions. "That is almost one insertion/deletion every 470 bases," he said. In addition, a small proportion of genes showed a relatively higher rate of evolution than most other genes. "We haven't known what proportion of the genes shows adaptive evolution. This study shows it to be about 2 to 3%," he said.

Early molecular comparisons between humans and chimpanzees suggested that the species are very similar to each other at the nucleotide sequence level—a difference of between 1.23% and 5%, Sakaki said. The results reported this week showed that "83% of the genes have changed between the human and the chimpanzee—only 17% are identical—so that means that the impression that comes from the 1.2% [sequence] difference is [misleading]. In the case of protein structures, it has a big effect," Sakaki said.(Chimps are not like humans, The Scientist 2004)​

I have no idea what MK is trying to say by "Gross structural indels occur within reading frames and yet the reading frames are virtually all still functional." - the reason most of the genes are functional and reasonably identical is precisely because they don't have indels. The ones that have indels have altered reading frames, and the ones that don't, don't (besides start/stop alterations).

I can only conclude that you are not looking at the differences. There are dramatic differences in the protein coding genes as shown above and in regulatory genes as seen below:

This question has been asked many times by researchers of human evolution. Like many questions in biology, the answer is probably not simple. For example, our brain is roughly three times bigger than that of chimpanzees and contains many more levels of organization than their brains, including a greater degree of asymmetry between sides of the brain (Hill and Walsh, 2005), but many of the mechanisms behind our unique brain development are unknown.

Are There Genes That Made Us Human?
The HAR1 gene and its role during brain development -
An Analysis of Scientific and Popular Literature
​

You don't have to take my word for anything, it's in the scientific literature if you want to know what the problem is.

בּרא

And again, "There is also a real problem with what kind of indels are represented. Most of the human sequence would have had to result from deletions in the hominid line, this makes absolutely no sense at all." This is also meaningless. An indel is called an "insertion/deletion" precisely because it cannot be determined to be one or the other without a proper outgroup comparison, which doesn't seem to have been commented on in this extract.

It makes no sense because there is no demonstrated or directly observed genetic mechansim that can account for the anatomical and genetic differences.

One of my biggest problems with TEs is that they are apologists for evolution with no skeptical views on ape/human common ancestry. I don't really mind so much if you come to that conclusion but to ask none of the hard questions makes it hard to take seriously.

 

[shernren]

Did you miss this part:

"...it seems rather surprising that as many as 20% have changed between humans and chimpanzees, despite the significantly shorter time since their divergence."

Like they said, the differences are in the eye of the beholder. So we have 83% of the protein coding genes in Chromosome 21 that diverge, on average, by a single codon in the respective genomes. That sounds fine until you realize that 20% of the protein coding genes have gross structural differences.

And again, define a "gross structural difference". From what I can see, deleting a single nucleotide would easily constitute a "gross structural difference" for the simple reason that it would completely alter the reading frame. If 20% of protein coding genes have a nucleotide or two's length difference, is that a big thing?

The most conserved region was at about the 12.5-Mb region (0.87%, over 100 kb), corresponding to the distal boundary region of the gene desert. Notably, no protein-coding genes have been identified in this highly conserved region...

...Taken together, gross structural changes affecting gene products are far more common than previously estimated (20.3% of the PTR22 proteins, as listed in Supplementary Tables 4 and 5). DNA sequence and comparative analysis of chimpanzee chromosome 22
, Nature 27 May 2004​

The most highly conserved region had no genes and gross structural changes are 20%. This has come to be one of those ironies for me, the noncoding region being more conserved then the coding region.

Point mutation rates in exons (synonymous sites) and noncoding (introns and intergenic) regions are generally assumed to be the same. However, comparative sequence analyses of synonymous substitutions in exons (81 genes) and that of long intergenic fragments (141.3 kbp) of human and chimpanzee genomes reveal a 30%–60% higher mutation rate in exons than in noncoding DNA.Neutral substitutions occur at a faster rate in exons than in noncoding DNA in primate genomes.Entrez PubMed 2003 May
​

Can you honestly say that this makes perfect sense to you or that this does not come as a big supprise? The researchers are certainly supprised when asked what they think of this.

Sakaki said their analysis found about 68,000 insertions or deletions. "That is almost one insertion/deletion every 470 bases," he said. In addition, a small proportion of genes showed a relatively higher rate of evolution than most other genes. "We haven't known what proportion of the genes shows adaptive evolution. This study shows it to be about 2 to 3%," he said.

Early molecular comparisons between humans and chimpanzees suggested that the species are very similar to each other at the nucleotide sequence level—a difference of between 1.23% and 5%, Sakaki said. The results reported this week showed that "83% of the genes have changed between the human and the chimpanzee—only 17% are identical—so that means that the impression that comes from the 1.2% [sequence] difference is [misleading]. In the case of protein structures, it has a big effect," Sakaki said.(Chimps are not like humans, The Scientist 2004)​

Mutation rates are higher in coding regions than in non-coding regions. That is no indication of a miracle.

I can only conclude that you are not looking at the differences. There are dramatic differences in the protein coding genes as shown above and in regulatory genes as seen below:

This question has been asked many times by researchers of human evolution. Like many questions in biology, the answer is probably not simple. For example, our brain is roughly three times bigger than that of chimpanzees and contains many more levels of organization than their brains, including a greater degree of asymmetry between sides of the brain (Hill and Walsh, 2005), but many of the mechanisms behind our unique brain development are unknown.

Are There Genes That Made Us Human?
The HAR1 gene and its role during brain development -
An Analysis of Scientific and Popular Literature
​

You don't have to take my word for anything, it's in the scientific literature if you want to know what the problem is.

What you said was: "Gross structural indels occur within reading frames and yet the reading frames are virtually all still functional."
It's quite obvious that if 20% of proteins have major indels, then 80% (and more) of proteins will have intact reading frames. If that was what you were trying to say, then alright. What I don't get is what your usual "We have bigger brains hence we didn't evolve" canard has to do with any of that.

It makes no sense because there is no demonstrated or directly observed genetic mechansim that can account for the anatomical and genetic differences.

You said: "There is also a real problem with what kind of indels are represented. Most of the human sequence would have had to result from deletions in the hominid line, this makes absolutely no sense at all." Show me where it is stated that "deletions in the hominid line" are the main kind of indels, and please specify: "deletions in the hominid line" as compared to what?

One of my biggest problems with TEs is that they are apologists for evolution with no skeptical views on ape/human common ancestry. I don't really mind so much if you come to that conclusion but to ask none of the hard questions makes it hard to take seriously.

And an impassionate observer will see that the only thing I have really done in this thread is to pick at two phrases that may indicate a faulty understanding of genetics on your behalf. That is a long, long way from being an "apologist for evolution".

 

[Mallon]

I don't care much for genetics because it simply doesn't interest me, and I certainly won't claim to be able to debate the subject, but it does strike me that most of mark kennedy's posts end with the same point, "There are too many differences between chimpanzees and humans than can be accounted for in 6 million years of evolution."
That's fair enough. Not having a formal education beyond a couple of university courses on genetics, I won't pretend to be as qualified as mark to debate the matter. What confuses me, though, is why the same argument that mark spouts against hominid evolution does not also work against the kind of 'post-Flood hyperevolution' that so many creationists espouse. You know what I'm talking about -- the idea that all of today's biodiversity descended from a select few created "kinds" in the span of just a few thousand years (so that only each "kind" needed to fill the ark, rather than 30,000,000+ individual species).
If the differences between this skull...

...and this skull...

... are too great to have evolved over a period of 3 million years, then what are the repercussions for creationists who insist that, over just a few thousand years, this...

... evolved into this?

Or Archaeopteryx evolved into subsequent birds?

Let's think through this one. I've got many more examples of supposed creationist "holobaramins" that seem to upset mark's counter-evolution criteria.

 

[laptoppop]

Of course one creationist answer is that there is a range of variation that is built into each creature. There is significant evidence that there are DNA repair mechanisms at work in many cases. The thought is that there is a tolerated range of variation before the repair mechanisms kick in.

 

[Mallon]

The thought is that there is a tolerated range of variation before the repair mechanisms kick in.

Do you have any actual molecular evidence to back that up, or is this just ad hoc?

 

[mark kennedy]

And again, define a "gross structural difference". From what I can see, deleting a single nucleotide would easily constitute a "gross structural difference" for the simple reason that it would completely alter the reading frame. If 20% of protein coding genes have a nucleotide or two's length difference, is that a big thing?

Two things really, the gene desert is highly conserved while 20% of the protein coding genes show gross structual changes would be required.

Mutation rates are higher in coding regions than in non-coding regions. That is no indication of a miracle.

No of course the brain triples in size and undergoes dramatic structural changes, no reason to conclude that a miracle is required for apes to do that overnight. What was I thinking?

What you said was: "Gross structural indels occur within reading frames and yet the reading frames are virtually all still functional."

Which seems highly unlikely since the only demonstrated effect of an indel on a neural gene is brain damage.

It's quite obvious that if 20% of proteins have major indels, then 80% (and more) of proteins will have intact reading frames. If that was what you were trying to say, then alright. What I don't get is what your usual "We have bigger brains hence we didn't evolve" canard has to do with any of that.

Actually what I am saying is that 83% of the genes show divergence on an amino acid sequence level and 20% show gross structural differences. That means the protein coding genes would have had to be overhauled in a dramatic way, with dramatic affects on the brain.

If I seem a little skeptical it's just because for one thing I trust God's Word more then a priori assumptions and this simply does not happen in nature.

Calculations from the indels in the 300–5,000-bp range indicate that both chromosomes have undergone a net loss in size since speciation despite frequent insertion events: HSA21q has gained 32 kb but lost 39 kb, whereas PTR22q has gained 25 kb and lost 53 kb. This suggests that the ancestral chromosome was larger than both HSA21q and PTR22q, and that PTR22q has suffered more losses than HSA21q since speciation. The large indels (>5 kb) detected in the sequences, which were experimentally confirmed, are found in the pericentromeric, 10 Mb, 17 Mb and 29 Mb regions. HSA21q has more indels greater than 10 kb than PTR22q.​

You said: "There is also a real problem with what kind of indels are represented. Most of the human sequence would have had to result from deletions in the hominid line, this makes absolutely no sense at all." Show me where it is stated that "deletions in the hominid line" are the main kind of indels, and please specify: "deletions in the hominid line" as compared to what?

I've played this game before and it should really have better rules. The thing is that I have seen it more then once and it's rather curious, more indels but the ancestral genome was bigger.

And an impassionate observer will see that the only thing I have really done in this thread is to pick at two phrases that may indicate a faulty understanding of genetics on your behalf. That is a long, long way from being an "apologist for evolution".

I qualified that by saying that TEs had no skeptical views of ape/human common ancestry. Actually, TEs are among the most zealous evolutionists I have encountered. Don't get me wrong I much prefer the company of TEs over the run of the mill scoffers in the common forum but I sometimes wonder why creationism is such a problem for them.

Grace and peace,
Mark

 

[mark kennedy]

I don't care much for genetics because it simply doesn't interest me, and I certainly won't claim to be able to debate the subject, but it does strike me that most of mark kennedy's posts end with the same point, "There are too many differences between chimpanzees and humans than can be accounted for in 6 million years of evolution."

I just love it when people address my posts in the third person. I makes me wonder if I'm not intruding when I respond. Now, the six million years of evolution since the common ancestor show very little difference until two million years ago. It is the dramatic growth of the brain size and complexity that is at the heart of the issue for me, specifically the genetic basis for adaptive evolution of the human brain.

My arguments are not even arguements anymore, there just clearly stated facts. Facts that there is no real genetic basis for and researchers are well aware of this.

That's fair enough. Not having a formal education beyond a couple of university courses on genetics, I won't pretend to be as qualified as mark to debate the matter.

This is a casual discussion forum and my primary interest was originally doctrinal and philosophical. The extent of my University education was a Biology 101 course and strangely I never used the textbook in that class. I used it regularly on here though, not that anyone cares if it's from sacred text or McGraw Hill.

What confuses me, though, is why the same argument that mark spouts against hominid evolution does not also work against the kind of 'post-Flood hyperevolution' that so many creationists espouse.

I'm with you there, I can't understand why creationists are not pushing themselves off as radical evolutionists. We would just about have to be when you think about it. It had my creationist views on the ropes for a while until I started realizing one very important thing. Most of the adaptations that happen in nature do not change the genes. More on that later if this discussion sticks to the topic for very long.

You know what I'm talking about -- the idea that all of today's biodiversity descended from a select few created "kinds" in the span of just a few thousand years (so that only each "kind" needed to fill the ark, rather than 30,000,000+ individual species).

The counter arguements come in the form of the Cambrian explosion:

The “Cambrian explosion” refers to the geologically sudden appearance of many new animal body plans about 530 million years ago. At this time, at least nineteen, and perhaps as many as thirty-five phyla of forty total, made their first appearance on earth within a narrow five- to ten-million-year window of geologic time. Many new subphyla, between 32 and 48 of 56 total, and classes of animals also arose at this time with representatives of these new higher taxa manifesting significant morphological innovations. The Cambrian explosion thus marked a major episode of morphogenesis in which many new and disparate organismal forms arose in a geologically brief period of time.(The origin of biological information and the higher taxonomic categories Stephen C. Meyer)
​

That's the thing, there are long periods of stasis then sudden evolutionary changes like the primate brian doubling in size over night two million years ago.

If the differences between this skull...

I like the fact that the skulls came up but we are really going to have to focus on size and time frame for me to get a handle on it.

Ok, I don't get the strange string of images...snip...

Let's think through this one. I've got many more examples of supposed creationist "holobaramins" that seem to upset mark's counter-evolution criteria.

Which is it, am I a hyperevolutionists or a counter-evolutionist? When it comes to birds, butterflys and polor bears class me as an evolutionary extremist. When it comes to human evolution or the origin of basic taxamonic catagories then yea, I am a died in the wool young earth creationist. Make no mistake about it, my religious views do influence my opinion greatly.

 

[laptoppop]

Do you have any actual molecular evidence to back that up, or is this just ad hoc?

Its an ad-hoc sort of informed speculation. The existence of DNA repair mechanisms is well-established. Presumably, there must be some limit before they kick in or there would never be any variation.

 

[mark kennedy]

Its an ad-hoc sort of informed speculation. The existence of DNA repair mechanisms is well-established. Presumably, there must be some limit before they kick in or there would never be any variation.

Just a couple of things to add here, there are some repair mechanisms that challenge this buisness of accumulated mutations. Check this out:

NPR's Alex Chadwick speaks with Ira Flatow, host of Talk of the Nation Science Friday, about recent experiments that suggest some plants may be able to either repair genetic damage, or "remember" and copy their "grandparents'" genes.​

Plants Repair Own Genetic Damage


Then there is this little scientific fact evolutionists forget:

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​

(Rates of Spontaneous Mutation, Genetics 1998)

A very few are momentarily adaptive. That does not sound like a formula for a major overhaul of the protein coding genes.

Grace and peace,
Mark

 

[shernren]

Actually what I am saying is that 83% of the genes show divergence on an amino acid sequence level and 20% show gross structural differences. That means the protein coding genes would have had to be overhauled in a dramatic way, with dramatic affects on the brain.

And of course it's only you who claims that

"83% of genes show divergence in one or two amino acids on average
and 20% of genes show gross structural differences of one or two nucleotides on average"

equals

"protein coding genes overhauled in a dramatic way"

The matter of the fact is that since small genomic changes result in large proteomic changes, there isn't a problem for natural selection here.

 

[Xaero]

I've played this game before and it should really have better rules. The thing is that I have seen it more then once and it's rather curious, more indels but the ancestral genome was bigger.

I don't see any problem here loss of nucleotides is not necessarily a loss of important information

[...] genomes reveal a 30%–60% higher mutation rate in exons than in noncoding DNA. [...]
Can you honestly say that this makes perfect sense to you or that this does not come as a big supprise? The researchers are certainly supprised when asked what they think of this.

I've said it once, that has to do with the overabundance of methylated CpG sites which show a higher mutation rate. That's no surprise, only biochemistry.


It's hard to follow your claims, since i don't see the problems you are raising.

 

[shernren]

I don't see any problem here loss of nucleotides is not necessarily a loss of important information

I've said it once, that has to do with the overabundance of methylated CpG sites which show a higher mutation rate. That's no surprise, only biochemistry.


It's hard to follow your claims, since i don't see the problems you are raising.

Glad to see I'm not the only bewildered soul here.

 

[mark kennedy]

I don't see any problem here loss of nucleotides is not necessarily a loss of important information

Your missing the most important issue here, whether it's a loss or gain the results of indels are most often either neutral, harmful or even deadly. This becomes increasingly dangerous when it is happening in reading frames:

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.Mutations​

I've said it once, that has to do with the overabundance of methylated CpG sites which show a higher mutation rate. That's no surprise, only biochemistry.

Contribution of CpG dinucleotides. Sites containing CpG dinucleotides in either species show a substantially elevated divergence rate of 15.2% per base; they account for 25.2% of all substitutions while constituting only 2.1% of all aligned bases...Because of the high rate of CpG substitutions, regional divergence rates would be expected to correlate with regional CpG density. CpG density indeed varies across 1-Mb windows (mean = 2.1%, coefficient of variation = 0.44 compared with 0.0093 expected under a Poisson distribution), but only explains 4% of the divergence rate variance. (Initial sequence of the chimpanzee genome and comparison with the human genome, Nature 2005)​

Only account for 2.1% of the aligned bases...hmmm...I'd say they have an elevated divergence rate. I guess we will get into this later because there should be an explanation for the elevated mutation rate.

It's hard to follow your claims, since i don't see the problems you are raising.

You don't see the problem with indels in the reading frame of protein coding genes, high mutation rates in distal regions...etc. There is no real problem that arises in your mind when there is an elevated mutation rate in regions with high gene density and high recombination rates?

The terminal 10 Mb of chromosomes (including distal regions and proximal regions of acrocentric chromosomes) averages 15% higher divergence than the rest of the genome (Mann&#8211;Whitney U-test; P < 10-30), with a sharp increase towards the telomeres. The phenomenon correlates better with physical distance than relative position along the chromosomes and may partially explain why smaller chromosomes tend to have higher divergence. These observations suggest that large-scale chromosomal structure, directly or indirectly, influences regional divergence patterns. The cause of this effect is unclear, but these regions ( 15% of the genome) are notable in having high local recombination rate, high gene density and high G + C content.​

My only question at this point would be, are you putting me on or what?

 

[mark kennedy]

Glad to see I'm not the only bewildered soul here.

I really don't think for a minute that you are bewildered, nor do I think it has escaped your attention that a gross structual difference includes more then a couple of amino acids.

 

[Melethiel]

that a gross structual difference includes more then a couple of amino acids.

Why? Changing a single amino acid in a protein can alter its form and function drastically.

 

[mark kennedy]

Why? Changing a single amino acid in a protein can alter its form and function drastically.

A point mutation can cause a frameshift, just imagine what a major change can cause.

gross structural changes affecting gene products are far more common than previously estimated (20.3% of the PTR22 proteins) Nature 2004

The ironic thing here is that the PTR22 is the Chimpanzee Genome. It is the human line that underwent a major change, not the chimpanzee.

 

[Assyrian]

Presumably the vast majority of frameshifting indels will be immediatly lethal and get removed from the genome, often before even going full term. This will leave only the non frameshifting indels, the ones that are a multiple of three base pairs, to play any role.

How does the lethality of the +1 or +2 have any bearing on the effects of non frameshift indels?