Genetics and Human Brain Evolution

It is important to bear in mind that fixation of a single indel could easily account for more than 100KB of difference.Other than your incredulity at the rapid evolution of the Har1 gene in the human lineage (Pollard et. al, 2006) you don't really seem to be making an argument here. You are bringin up lots of data but you seem to think that this alone is a substitute for a coherent statement.You say you want a discussion but your OP doesn't really provide anything to discuss.The one discursive point you have raised is how Har1 has evolved so rapidly in humans. The obvious answer would be that the gene was subject to some selective pressure which favoured its divergence from the conserved sequence, either that or it was released from some strongly stabilising negative selective pressure.The paper mentions that the bias of substitutions from W(A or T )->S(C or G) may be linked to their position in the chromosome or possibly to selection for higher levels of expression. This may be connected to the different levels of Har1F and Har1R which the study observes in humans but not in mice.As the paper mentions there are a number of other genes involved in brain development which have similarities in terms of being subject to strong positive selection and in terms of showing conserved patterns of expression but apparent functional differences. One example they mention is ASPM research on which you previously referenced.What makes you think that there is a problem with mutations in such genes being responsible for the enlargement and other changes we see between human and chimpanzee brains?TTFN,WK

Except that you haven't provided any innformation for where those mutation rates come from. I have seen values around 2x10^-8 quoted as a mutation rate for single nucleotide polymorphism, but this would obviously not be a sufficient value to account for larger scale indels or chromosome rearrangements. On paper on this topic (Nachman and Crowell, 2000) gives the 2.5x10^-8 figure but cautions that the actual rate may be between 1.3 x 10-8 and 3.4 x 10-8. The largest indel they see is 4bp, can you see how 100Kb indels could throw off such calculations?My point was that for large indels, and especially for large chromosomal rearrangments, large chunks of your divergence which needs accounted for will be achieved. you don't need 7 million years with 20 sites fixed per year if the fixation of one indel or chromosomal rearrangement will account for thousands to millions of bases itself.Also, as I pointed out previously, the region in which the Har1 gene is located is more prone to mutation and consequently is highly likely to be above the average rate of mutation both in terms of specific types of nucleotide substitution, i.e. W->S, and of chromosomal recombination. The problem with such a simple formulation is that it is in fact overly simplistic. I'm not sure why this is necessary in the absence of any evidence suggesting that such a mutation would be lethal. At best you have the indirect evidence that the 118bp non-coding region has been highly conserved in a number of vertebrate species, this is not the same as showing that any of the substitutions in the human gene are lethal in other animals. Indeed if you look at the supplementary data you will see that at least 3 of the mutations in the human are found in other species, and on assumes without lethal consequences and there are a further ten mutations seen in other species which are not present in the human gene. So at present there is no evidence to suggest that theHar1 region cannot accept a number of mutational changes without any lethal effect on offspring.So why would we assume that any of these mutations would kill off the offspring in the absence of any evidence that this is the case?TTFN,WK

Come on, the simplest knowledge of genetics shows this to be untrue. In almost a 3rd of cases a nucleotide substitution will have no effect on the amino acid due to third base wobble. Even in those cases where an amino acid substitution does take place there is still plenty of scope for a functionally equivalent substitution or at least one which does not severely impair the function of the protein. Of course this doesn't actually apply in the case of Har1Fwhich isn't even a protein coding gene. So while such highly conserved non-coding regions may show more conservation that coding regions there is still no evidence to support, and some to contradict, your claims as to changes in that region being necccessarily detrimental or lethal. Any actual evidence for this assertion? Just showing genes linked to geentic developmental abnormalities would be insufficient since that is a highly biased reporting set. Do you have any link to research showing, say, that induced point mutations in developmental neural genes usually lead to detrimental effects on the cerebral cortex? Because we see spontaneous mutations occurring all the time. It is a question of an observed phenomenon with which we are well familiar and one based on a cloud of wishful thinking and religious dogma. What are you trying to say here? By 'altered gene' do you mean something which has been rendered non-functional? I am basing this on the supplemental data supplied in the paper, it is the data from which the comparison with the chick gene is derived. There are more than 3 mutations in other species, but there are 3 that are shared with the human mutations in the Har1 region sequence.I can go back and check the papers exact methodology if you wish but I suspect that they got the data from the published genome sequences for the organisms they looked at, in which case the data is culled from more than one animal and is not likely to be a rare mutation. It certainly isn't likely to be a rare lethal mutation which is what you were suggesting any mutation in the gene would be.TTFN,WK

This is just complete nonsense. Where did you come up with such a ludicrous 'fact'. Take a look at the genetic code, this figure uses the RNA codons so for the DNA counterparts substitute Ts for Us.Looking at this it should be clear that of the 64 possible codons only 3 do not code for 'one of the amino acids of life'.This is such an incredible failure to grasp one of the most basic principles of molecular biology that I don't see how you can possibly hope to give anyone a 'biology primer'.The chances are only very roughly something like 1/3 that any particular nucleotide substitution will lead to a change to a different 'one of the amino acids of life'.I see that Mick has already addressed this, but I think the figure is still useful.TTFN,WKEdited by Wounded King, : No reason given.

So in your alternative universe form of molecular biology what does transfer RNA do?I would highly reccommedn you to read some of the textbooks available on the pubmed bookshelf especially the RNA to protein section of 'Molecular Biology of the Cell' by Alberts et al. This is pure fantasy, Watson and Crick may have worked on the problem but the didn't solve the nature of the genetic code. It was Gamow who proposed that there were codons in mucleotide triplets and Khorana, Holley and Nirenberg who did the first experiments showing what certain particular triplets coded for; work for which they won the nobel prize. Perhaps you are thinking of Crick's work with Sidney Brenner which bears some relation at least to what you are suggesting (Crick et al, 1961). There is an interesting historical review of the several different theories proposed for the gentic code in an American Scientist article (Hayes, 1998)Of course if you have a refeerence for this paper of Watson and Crick's I think now would be the time to provide it. So true, and so amusing. Perhaps you may understand now why the discussions of comparative genomics have stuck. Because it is you who lacks a rudimentary understanding of the principles involved. You obviouly think of yourself as an educated layman but in fact you are just a layman.I really think you should start providing some references for where you are getting your basic information from because either it or your understanding of it is fundamentally wrong.TTFN,WKEdited by Wounded King, : No reason given.Edited by Wounded King, : No reason given.

Care to show where this happened? I see where Mick said... A sequence of nucleotides is not a single nucleotide.TTFN,WK

I think Crash has done a great job of representing the 'reality based' approach to the central dogma. In case Eggasai once again completely fails to engage the substance of a c;ear contradiction of his fantasy molecular biology approach I'd like to suggest the Flash animations DNA transcription and RNA translation at communicating at an unknown rate as a nice visual presentation of the same processes.TTFN,WK

I doubt that anyone realises this since there is nothing to suggest that it is the case. Do you have any actual reference which suggests that the mutations would need to be in-frame indels, let alone of considerable length? This is a very strange way to think of things, it is more usual to talk of conservation with a particular group of organisms such as the mammals or vertebrates. Being conserved within the human body just suggests that they aren't likely candidates for somatic mutation. This also seems directly contradicted by a lot of the evidence you yourself have shown showing that many neural genes have been subject to mutation and in many cases apparently to very strong selection leading to many more changes than might be expected under neutral selection. This only seems obvious to you, and you have yet to produce a scrap of reasoned argument why anyone should accept your contention. You have produced no evidence to suggest that any of the difference between human genes and their highly conserved counterparts in other species have a deleterious effect. Your argument also seems to fail through basic logic. A relaxation of functional constraint by its very nature means that there are more possible non-deleterious mutations possible. What is this supposed to mean? Why should mutations occur during cleavage? I assume you mean cleavage during mitosis or meiosis rather than an embryonic cleavage stage but the reasoning behind your statement escapes me.TTFN,WK

I neve questioned the existence of in frame insertions, what I questioned was whether you had anything to support your contention that... Rather than support you that the paper mentions only 2 neural genes sepcifically with large indels and in both cases the large indels involved are in intronic regions which will not be translated into protein and consequently there is absolutely no requirement for them to be in frame.None of the gene products they identify in their supplementary data as having internal amino acid insertions or deletions stand out as being neural, in fact several are clearly structural such as keratin and collagen. Again you make the same nonsense statement and again it seems predicated on your failure to understand basic biology which you have yet to adequately address. Why is an indel required? Why is a single nucleotide substitution in a codon leading to a change in the resulting amino acid not sufficient? Or indeed why are all manner of changes in 'non-coding' regions not sufficient given their potential for substantial changes in the expression of genes. Why do you think the paper you just linked to goes into details of their analysis of untranslated regions and upstream regions for transcription factor binding sites? Because they think that changes in gene expression they detected are linked to changes in those regions, regions where questions of frame are wholly irrelevant. I'm not sure how you have managed to fail to notice that I have done just that with several of the papers you have brought up, and in many cases you have just left my analyses lying fallow. None of those papers have supported your major contentions which I have had issue with.Believe me I am well familiar with data on the molecular genetics of evolution, particularly within the developmental area. And my reading of the literature doesn't suggest to me in any way that your points have any support. I'm not sure what you understand by 'relaxed functional constraint'. The reason the 'functional constraint' is 'relaxed' is exactly because more mutations are no longer deleterious due to some change in a nother part of the system, either environmental or in the genetics of the organism. So deleterious mutations are no more likely to occur than ever because deleterious muttions will still be weeded out, it is simply that of all the possible mutations less of them are deleterious due to the relaxation of the functional constraints. In terms of the context of the original gene in its original environment many of these mutations would be deleterious but the deleterious nature of them as it pertains to function is highly context dependent.And then you go on to argue from ARN, this seems to be a real slippage in standard from references to the work of the HGP. Your quote doesn't even seem to be in the article that you linked, making it source completely anonymous, and neither makes a cogent argument for your position, if you think there is such an argument to be made then why not make it in your own words. If you are just culling half understood arguments from creationist sites then why not stop now until you at least fully understand what you are arguing.TTFN,WK

This is the kind of claim that requires evidence, and it is the same claim which required evidence which I have been asking you to back up since the first page of this thread.Could you now provide some evidence to support this claim?TTFN,WK

I know I'm not Eggasai but the origins of some of these mistakes is obvious. Eggasai is mixing and matching bits from his previous posts. The 'hundreds if not thousands' schtick comes from the discussion of the differences in genes relevant to neural development in chimps and humans, in fact it is lifted almost straight from the press release for the Lahn(2004) paper. Because Eggasai's calculation is actually based on the number of Mbs of difference in the genome rather than the actual number of mutations. 145Mb/7 million =20.7. He even said in Message 5 ... What he has done is treat single nucleotide differences and mutations as if they were synonymous.TTFN,WK

wow, I completely missed that!So his second point in his OP ... Is actually based on a paper about the differences between humans and monkeys, doh!!This guy seriously needs to do his homework, maybe I do too since I missed it.TTFN,WK

Now why would I do that? Oh right, its beacuse you just said ... So in fact if ayone is making the confusion you just accused me of it was in fact you. You only just claimed in the previous post that all of those gross structural changes were in frame indels, do you see where I might have got the idea that that was what you thought? You were talking about HAR1 again suddenly were you, OK. Why should anyone expect to see in frame indels in a non-coding region of a gene? I have been making this point repeatedly and you have yet to address it. The 118 nucleotide sequence does not functionally code for any amino acids, if anything its function appears to be mediated by the secondary structure of the resulting RNA transcript.I'm not sure why you thought the reference was vague given that you were talking specifically about the chromosome 22 paper in the post I was replying to. I appreciate that you are having to keep track of a number of seperate conversations at once but it isn't hard back to trackback in these threads. 20 whats now? Is it nucleotides or mutations today? If it is mutations then as has been pointed out the figure is wrong. If it is nucleotides then, as has also been pointed out repeatedly, you are failing to take into account the many large scale mutations which can account for hundreds to millions of bases in one event. OK, for someone so keen to talk about how great his references are this is the sort of figure which could do with some evidentiary backing and also some rationale for why it makes any difference whatever to the matter under discussion. What is your evidence that anything has stopped or the the modern mutation rate has leveled off from something. I've seen similar rates quoted in some papers (Kondrashov, 2003) but it would help to know exactly what you are basing your figures on since they report similar rates estimated from the comparison of chimp and human pseudogenes. That paper itself estimates 'that the total number of new mutations per diploid human genome per generation is ~100'. Why do you consider these numbers insufficient? You mean I should do your work for you? I have repeatedly asked you to provide substantiation for your several claims that any mutation in such genes would be lethal despite the obvious counterevidence of the many mutations in such genes seen across different species. Given that it was your claim the onus is traditionally on you to provide some support for it.Simply showing that there are lots of syndromes and genetic disorders related to such genes proves nothing other than that such disorders have significant phenotypes which are easily identified and are the subject of much medical attention. A typical 'Darwinian' picture from ARN? You don't think that a site dedicated to the promulgation of intelligent design propaganda might not be the best place to go for a 'Darwinian' picture? Even so this doesn't explain why your quote and your reference had nothing to do with each other beyond both singularly failing to answer the actual question I asked, beyond making it clear that you meant embryonic cleavages. I'm very happy to go into specifics, and when I have done just that in terms of papers you referenced and your argument you failed to reply to my posts. Sadly you seem to think that being able to pull a number out of a paper means you know what it means when your argument shows that this is not the case. No, it doesn't. I'd shake your calculator and try again. The costs are enormous, but I think there is clearly a case to be made that the substantial quantitative, if not qualitative, increases in our mental activities has had a clear positive effect on our ability to survive so the benefits may have been sufficienty greater than the costs. I don't see in the slightest how this conflicts with any evolutionary biology in an anagenetic model or otherwise. Demonstrate this to be the case, making the same claim over and over again does nothing but show the vacuity of your argument. Why would all random mutations be deleterious? If this is not the case then why wouldn't random mutation and a selective pressure favouring larger and more complex brains be sufficient, other than your simple desire to not believe it? Except the amino acid sequence doesn't have a tinker's cuss to do with the Har1 region since it is a non-coding gene!! And the genetic mechanisms leading to changes in amino acid sequence are well characterised, they are base pair substitutions and frame changing mutations of the kind we have been discussing all along. If you had actually addressed any of the vital failures you display in understanding the basic molecular genetics then this should now be obvious to you. Perhaps that is because you behave in just the same way, using papers to support a claim for which they offer no support, using IDist websites as a reference, showing a failure to grasp the fundamental aspects of the biology we are discussing. I'm afraid these are creationist characteristics with which we are all too familiar.If you want to show you break the mold then actually go back and look at what absolutely everyone else on this thread agrees is how the 'fundamental dogma' actually operates and ask yourself how we could all have got exactly the same wrong idea about it and only you understand how it really works.TTFN,WKEdited by Wounded King, : Edited to expand commentary on mutation rates and add reference.Edited by Wounded King, : Edited for formatting

Ummm, isn't that actually a completely different paper than the one we were talking about?Yup, I'm pretty sure we were talking about the.. Which was from the press release to the 2004 cell paper. So what does a paper from the previous year on ASPM have to do with anything? YOu do remember referencing that 'news item' right at the start in your opening post I hope. You were happy enough to make it the basis of your 2nd 'main point'.Or would you identify the basis of your 'hundreds if not thousands...' rhetoric, if it is not from the quote from Lahn? Sheesh enough with the google already, we are all quite capable of using pubmed. Perhaps if you didn't use google to turn up your references you wouldn't end up with press releases and ARN articles.TTFN,WK

Eh? You only just finished telling me that mutations needed to happen during early embryonic cleavage stages and now this has changed to during meiosis? If it was meiosis you meant why did you post references to embryonic cleavages in response when I asked you if you were talking about mitosis, meiosis or embryonic cleavages?It also stands to reason that while there might be 2 times as many 'transcript' errors, whatever they are, per cell there would not be 2 times as many per diploid genome. Also why single out meiosis since there is a duplication of the chromosomes during mitosis as well.Could you try and give us a coherent idea of where and when you think these mutations must arise, and why?In normal biology a mutation can arise at any time and as long as it occurs somewhere within the germline lineage it may be inherited. The mutation could be as early as the 2 or 4 cell stage and lead to a mosaicism encompassing the germ cells. The mutation might occur, as you suggest, during meiosis and be present in only one of the millions of gametes produced.What exactly are you trying to say?Are you getting transcription confused with DNA replication because except in very exceptional circumstances mRNA transcripts are not re-incorporated into the genome and consequently neither would mistranscribed sequences.The single-stranded state of unwound DNA during transcription does seem to be more susceptible to certain mutations (Huson et al, 2003), is this perhaps what you were thinking of? Admittedly that work was on Salmonella and research on mammals has produced differing results some suggesting an increase (Bachl et al., 2001) and some a decrease (Lippert et al., 1998) in mutation rates associated with transcription.TTFN,WK