Pete Harcoff said:
But you're looking that the entire genome, while all I care about is the protein-coding protion. If you want to compare the entire genome, then you have to look at it respective to mutation rates in general, and not a restricted subset of mutations.
You take the overall mutation rate of bacteria and apply it to the divergance of humans and chimps but you are only interested in the effective genome. The effective genome of the chromosomes being compared is 20% and overall the divergance is 5% clearly described in the paper but you take this estimate:
So what does that mean? Well, the estimated difference between human and chimp genomes is typically less than 2% (though one study put the difference between critical genes at only 0.6%). I'll assume 2%
If I indicate the divergance overall you say 'no I am only interested in the effective genome' but you never gave us a mutation rate for the effective genome. Pete, the tolerance for mutations for the effective genome is far lower then that of the noncoding parts:
"The fraction of amino acid mutations that is neutral is estimated to be 0.20 from the ratio of common amino acid (A) to synonymous (S) single nucleotide polymorphisms (SNPs) at frequencies of 15%. Among the 80% of amino acid mutations that are deleterious at least 20% of them are only slightly deleterious and often attain frequencies of 110%. We estimate that these slightly deleterious mutations comprise at least 3% of amino acid SNPs in the average individual or at least 300 per diploid genome. "
http://www.genetics.org/cgi/content/abstract/158/3/1227
Dispite that 20% of the protein coding genes are showing differences while only 5% of the chromosome comparison is different overall. There are only two explanations for this, it is either relaxed functional constraint or adaptive evolution. Nevermind that there is no genetic basis for either lets let blind chance take the credit:
Just like winning the lottery may be rare, if enough people play, someone will win.
Its more like Russian Roulette with a deleterious mutation being a bullet that brings genetic death. The occasional beneficial effect, like your often repeated example CCR5D32 mutation only provides a slight selective advantage, in the short; term for a small minority:
"The β-chemokine receptor 5 protein, which acts as an entry co-receptor for the HIV-1 virus, is coded for by the CCR5 gene which sometimes presents a 32 bp deletion mutation (the CCR5D32 allele) that results in a truncated protein associated with resistance to HIV-1 infection (Dean et al. 1996; Berger et al., 1999). There are rare reports of HIV-infected individuals who are CCR5D32 homozygous (Hogan and Hammer, 2001). Epidemiological studies have associated the CCR5/CCR5D32 heterozygotic state with a delay in the onset of AIDS and a higher degree of resistance against HIV infection than the wild type CCR5/CCR5 homozygous state (Venkatesan et al., 2002)."
http://www.scielo.br/pdf/gmb/v27n3/a02v27n3.pdf
If you look at the total number of possible mutations over a 10 million year period, @ 20 years / generation, with a stable population of 100000, and 120 mutations per individual, you end up with 6 trillion possible mutations (but obviously not all will be fixed). So this 3 million bps difference becomes trivial, at least with respect to rates of mutation.
You can't just have random mutations spinning the genetic death roulette wheel and getting lucky every now and then with a defective receptor. Effective parts of the genome have to be altered in such a way as to provide a selective advantage at every stage of evolutionary development.
Divergance of 5% means you multiply it by 0.05, not divide. So the difference is 2.3 million base pairs, not 920 million. And that's looking at the entire chromosome, not just the functional part.
That is what you used, the 68,000 indels was the overall chromosome and you are still ignoring the 5% difference. Now if you want to focus exclusivly on the protein coding genes then it jumps 4X to 20% and still you don't have anyway to account for the deleterious effects or a genetic mechanism for adaptive evolution.
Also, indels can (and do) affect more than a single base pair. So the number of indels is not proportional to the number of base substitutions with respect to the number of mutations per base pair.
Yes they are very different because the indels represent almost 3x as many differences. When you look at the observed effects of single base substitutions as compared to the indels the consequence are greater, for indels. Frankly, the odds of a gross structural change resulting from a random series of mutations is so far fetched that it is science fiction. You can't have a peicemeal series of mutations altering a protein coding gene, it would all have to happen at once. One amino acid sequence is wrong and
*bang* 
genetic death.
I think where we keep getting our wires crossed is I keep focusing on the functional part of the genome, while you keep looking at the whole thing. So I'm basing my numbers on a portion of the genome, while you try to apply them to the entire thing. But you can't do that. If you want to talk divergence in the entire genome, you have to look at the total mutation rate.
That is because there is no beneficial mutation rate for the human effective genome. We only know the effects of mutations on protein coding genes in humans from disease and disorder. Why should I assume that any of the hundreds, if not thousands of mutations effecting vital organs are capable of anything beneficial? The more mutations you have and the longer they accumulate in human populations, the more devastating they become.
"Every deleterious mutation must eventually be eliminated from the population by premature death or reduced relative reproductive success, a 'genetic death'. That implies three genetic deaths per person! Why aren't we extinct? If harmful mutations were eliminated independently, as in an asexual species, it has been estimated that this would lower population fitness to a fraction e-3, or 5%, of the mutation-free value, leading to the inevitable extinction of species with limited reproductive capacity. A way out is for mutations to be eliminated in bunches...The existence of a high deleterious mutation rate strengthens the argument that a major advantage of sex is that it is an efficient way to eliminate harmful mutations. It also raises again the possibility of fitness decline or even extinction in rare species from too many harmful mutations."
http://www.colband.com.br/ativ/nete/biot/textos/geral/007.htm
