Not always. And, in fact, not even very often. Very few mutations are out and out deleterious.
Even fewer are adaptive.
Among the mutations that affect a typical gene, different kinds produce different impacts. A very few are at least momentarily adaptive on an evolutionary scale. Many are deleterious. Some are neutral, that is, they produce no effect strong enough to permit selection for or against; a mutation that is deleterious or advantageous in a large population may be neutral in a small population, where random drift outweighs selection coefficients. The impact of mutation is quite different in different DNA sequences. It is maximal in a conventional gene or exon, and at least transitorily less in a gene whose function is required rarely or is redundant. If adaptive mutations are rare, as seems to be the case, then rates of DNA sequence evolution are driven mainly by mutation and random drift, as KIMURA 1983A has argued. In this case, the proportion of neutral mutations at a site or locus is the ratio of its rate of evolution to that of a region that can be considered neutral, such as a pseudogene. Most newly arisen mutations in functional genes are deleterious, but the fraction may approach zero for spacer DNAs such as introns and intergenic regions. Of course, some protein evolution certainly results from favorable mutations, and to this extent the neutral fraction is overestimated. (Rates of Spontaneous Mutation, Drake et al, Genetics, Vol. 148, 1667-1686, April 1998)
What you focus on only is cases of purifying selection. Once an allele is such that it is at maximal fitness, then of course any change in it is going to decrease fitness. But remember, the allele didn't start out that way. It started out at lesser fitness and then mutated to what we see now.
That will never work, they have to accumulate with neutral effect for millions of years.
Not even most times. Most mutations are silent. They change the 3rd codon, which is usually redundant, and give the exact same protein when translated to amino acids.
Other mutations are conservative. They may change the amino acid, but the new one has very similar chemical properties to the old one and the protein folding does not change. For instance, change leucine to isoleucine and the protein doesn't change in its 3-D structure.
Notice I am not now nor have I ever argued anything to the contrary.
Yes. Limb development. After all, the arrangement of a humerous, radius and ulna, 5 wrist bones, and carpals are highly conserved across all vertebrate lineages.
Skeleton structures are more conserved then a gene involved in the regulation of mitotic spindle orientation in proliferating cells of the neuroepithelium? I'll tell you what, we will get back to that one.
http://www.hhmi.org/news/lahn.html
"For each species, the researchers identified changes in the
ASPM gene
that altered the structure of the resulting protein, as well as those that did not affect protein structure. Only those genetic changes that alter protein structure are likely to be subject to evolutionary pressure, Lahn said. Changes in the gene that do not alter the protein indicate the overall mutation rate - the background of random mutations from which evolutionary changes arise. Thus, the ratio of the two types of changes gives a measure of the evolution of the gene under the pressure of natural selection."
The measure of natural selection is a ratio and the jump from ape to human was a dramatic one with no known molecular mechanism to account for it.
Figure 3 Hum. Mol. Genet. -- Evans et al.
From the original paper by Lahn and colleagues in
Science:
"Phylogenetic analysis of
ASPM has revealed strong positive selection in the primate lineage leading to
Homo sapiens (
3–
5), especially in the past 6 million years of hominid evolution in which ASPM acquired about one advantageous amino acid change every 350,000 years (
4). "
This test also reveals that, on average, 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. (Adaptive Evolution of ASPM a Major Deteriminant of a Cerebral Cortex, Human Molecular Genetics 2004)
Want to know the really interesting part, for at least half that time these accumulated mutations had no effect on the size of the brain.
Because the brain size of a typical microcephaly patient is comparable with those of early hominids such as the 2.3- to 3.0-MY-old Australopithecus africanus (430 g) I hypothesize that ASPM may be one of the genetic components underlying the human brain expansion. (Evolution of the Human ASPM Gene, a Major Determinant of Brain Size, Genetics 2003)
I thought positive selection was when there was an advantage so it was preserved. This scenario seems to think that neutral mutations accumulated steadily for millions of years and our ancestors still had a little head. Then from 2.5 mya to 1.9 mya it literally doubles in size.
You can look at the papers referenced for the specific advantageous amino acid changes.
You can't find a molecular mechanism or a dimes worth of proof it's possible but you can sure find the assumption made throughout.
"The unusually high frequency of haplotype 63 is strongly suggestive of positive selection (
8). We tested the statistical significance of the possibility of positive selection using coalescent modeling (
7). The frequency of haplotype 63 is notably higher in Europeans and Middle Easterners (including Iberians, Basques, Russians, North Africans, Middle Easterners, and South Asians), as compared with other populations (table S1). We therefore focused on this group to take advantage of its relatively simple and homogeneous demographic structure (
9). Because 7 of the 50 Europeans and Middle Easterners were homozygous for haplotype 63, we tested the probability of obtaining 7 or more homozygotes (among 50) for a single haplotype across a 62.1-kb region containing 122 segregating sites (the number of polymorphic sites found in Europeans and Middle Easterners). ... These parameters produced a highly significant departure from the neutral expectation (
P < 0.00001). "
Not genetic drift, but positive selection.
Positive selection of neutral effects from random mutations that only cause sever reduction in brain size and fitness produced this dramatic adaptive giant leap.
No. That's a false premise. Humans and chimps differ by less than 2% of their amino acid sequences in expressed genes. Since there have been 7 million years since the split and we take a generation time of 20 years, that works out to 350,000 generations. In one experiment with fruit flies, a different species was produced by natural selection after only 5 years or 2500 generations. This species differed from the original by over 3% in expressed genes. There have been over 100 times the number of generations between us and the apes. Plenty of time.
No, false assumption. The advantages did not express themselves for millions of years so they had no reason to accumulate.
19% of the total 1019 indels are of sizes that are multiples of three nucleotides. A simulation was then performed for 20,000 replications with the inferred ASPM coding sequence of the common ancestor of humans and chimpanzees. Under no functional constraints, the substitution rate is identical to the mutation rate and mutations are assumed to be random. An ORF is interrupted when an indel of a size that is not a multiple of three nucleotides or a nonsense point mutation occurs...Human ASPM has 28 coding exons, spanning 62 kb in chromosome 1p31 and encoding a huge protein of 3477 amino acids.... A gene may occasionally exhibit dN/dS > 1 when a large fraction of nonsynonymous mutations are advantageous and are driven to fixation by positive selection. I estimated the dN/dS ratio for ASPM in each of the three tree branches (Fig 2), using a maximum-likelihood method, and found that dN/dS is lowest in the orangutan branch (0.43), higher in the chimpanzee branch (0.66), and highest in the human branch (1.03). (Evolution of the Human ASPM Gene, a Major Determinant of Brain Size, Genetics 2003)
Positive selection is inferred despite the fact that the gene is currently under strong purifying selection, the only known effects of mutations in this gene are neutral or deleterious and there is no known molecular mechanism for producing them.
That's a false "if". See the references to the Science article.
Here, I'll list them:
3. J. Zhang,
Genetics 165, 2063 (2003).
[Abstract/Free Full Text]
4. P. D. Evans
et al., Hum. Mol. Genet. 13, 489 (2004).
[Abstract/Free Full Text]
5. N. Kouprina
et al., PLoS Biol. 2, E126 (2004).
[CrossRef] [Medline]
6. S. L. Gilbert, W. B. Dobyns, B. T. Lahn,
Nat. Rev. Genet. 6, 581 (2005).
[CrossRef] [ISI] [Medline]
I've read them, more then once.
OK, here are some:
{snip the cut and pace PubMed search results}
Don't you think I have tried that, for hours at a time before asking an evolutionist? You haven't changed a bit but nice to see you again just the same.
