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[Note: I really hate to put this post on the "Chit-Chat" forum, since it is science heavy. It would fit much better on a (longed-for) "Non-CR Health and Longevity" forum. But its too far from CR to justify posting it to "CR Science", so here goes...] I'm reading philosopher Thomas Nagel's most recent book, Mind and Cosmos in which he argues that the "neo-Darwinian conception of nature is almost certainly false" - in fact, that is the subtitle of the book. Key to his argument is that it doesn't appear that the cornerstone of neo-Darwinism, namely random mutation to genes that turn out to be fitness enhancing, could ever come up with the vast variety of large scale variations in body morphology and physiological systems we see in the world, many of which are argued to be "irreducibly complex" (i.e. all-or-nothing from an evolutionary fitness perspective). The architecture of the eye, and the molecular motor that powers flagellum in bacteria are examples of these complex biological structures that would seem (to some) impossible to evolve through simple random mutation. Nagel, and others (and not just intelligent design (ID) folks, some of whom think God orchestrates evolution) see the need for some more directed form of evolution to explain the diversity and complexity of life on our planet. Nagel seems to think mind / consciousness, and not God in the traditional conception of the term, might fit the bill. But to me that seems rather extreme, and goes against "reductive materialism / naturalism" that has been so successful at explaining how the world works over the last few hundred years. One wonders if a less drastic solution that tweaks the mechanism of neo-Darwinian evolution, might be invoked to save the day for materialism / naturalism. As discussed elsewhere (see this post for details), I've recently been studying epigenetics, where gene expression can be modulated by methylation (among other mechanisms). In methylation, a methyl groups can attach to a particular DNA base pair, causing the gene to "wrap up" around a histone, preventing it from being transcribed into RNA, thereby suppressing expression of the protein that the gene codes for. This methylation can be driven by environmental factors, is quite localized, specific, and repeatable, and can occur not only in somatic cells, but also in germ-line cells (eggs and sperm), and thereby get passed down to several subsequent generations. While the epigenetic changes can be adaptive both for the organism in which they first occur, as well as their progeny, they aren't permanent changes to the base-pair sequence of genes, so they aren't heritable variations over thousands or millions of years, like we see across species in the world. So they are "Lamarkian" to a point, but not in the true sense of the world - giraffe necks could get longer for a generation or two after (hypothetical) epigenetic changes occurred as a result of a giraffe stretching to reach the high leaves on a tree, but eventually the epigenetic changes would "wear off" and subsequent generations would go back to having short necks. But what if epigenetic changes via methylation not only silences genes, but also made those silenced genes more prone to mutation? The methylation would not only be a signal that "this gene isn't worth expressing in the current environment", it would also be signaling "this gene is not very useful in is current form in the current environment, so target it for mutation". With an elevated mutation rate specific to maladaptive genes lasting several generations, new variations should more readily arise in subsequent generations, accelerating experimentation with parts of the genome where changes would be mostly likely to be beneficial in a rapidly changing environment. This sort of elevated mutation rate in parts of genes that have been methylated (silenced) is exactly what this study  found. To quote the abstract: Our results ... provid[e] the first supporting evidence of mutation rate variation at human methylated CpG sites using the genome-wide sing-base resolution methylation data. It's not clear that this targeting of random mutations to specific maladaptive genes could result in the type of big changes Nagel and others point to when criticizing neo-Darwinian evolution. But it seems like a way to facilitate a sort of "semi-Intelligent Design", without an explicit designer, by focusing "random tinkering" with the genome in places where genetic changes could do the most good in the current environment. Anyway, while not (directly) related to CR, I thought it was interesting nonetheless. Comments appreciated. --Dean ----------  Full text: http://www.biomedcentral.com/1471-2164/13/S8/S7 BMC Genomics. 2012;13 Suppl 8:S7. doi: 10.1186/1471-2164-13-S8-S7. Epub 2012 Dec 17.Investigating the relationship of DNA methylation with mutation rate and allele frequency in the human genome. Xia J1, Han L, Zhao Z. Author information AbstractBACKGROUND:DNA methylation, which mainly occurs at CpG dinucleotides, is a dynamic epigenetic regulation mechanism in most eukaryotic genomes. It is already known that methylated CpG dinucleotides can lead to a high rate of C to T mutation at these sites. However, less is known about whether and how the methylation level causes a different mutation rate, especially at the single-base resolution. RESULTS:In this study, we used genome-wide single-base resolution methylation data to perform a comprehensive analysis of the mutation rate of methylated cytosines from human embryonic stem cell. Through the analysis of the density of single nucleotide polymorphisms, we first confirmed that the mutation rate in methylated CpG sites is greater than that in unmethylated CpG sites. Then, we showed that among methylated CpG sites, the mutation rate is markedly increased in low-intermediately (20-40% methylation level) to intermediately methylated CpG sites (40-60% methylation level) of the human genome. This mutation pattern was observed regardless of DNA strand direction and the sequence coverage over the site on which the methylation level was calculated. Moreover, this highly non-random mutation pattern was found more apparent in intergenic and intronic regions than in promoter regions and CpG islands. Our investigation suggested this pattern appears primarily in autosomes rather than sex chromosomes. Further analysis based on human-chimpanzee divergence confirmed these observations. Finally, we observed a significant correlation between the methylation level and cytosine allele frequency. CONCLUSIONS:Our results showed a high mutation rate in low-intermediately to intermediately methylated CpG sites at different scales, from the categorized genomic region, whole chromosome, to the whole genome level, thereby providing the first supporting evidence of mutation rate variation at human methylated CpG sites using the genome-wide sing-base resolution methylation data. PMID: 23281708