This is definitely interesting. https://www.eurekalert.org/news-releases/941828
Contrary to the widely accepted expectations, the results supported the nonrandom pattern. The HbS mutation originated de novo not only much faster than expected from random mutation, but also much faster in the population (in sub-Saharan Africans as opposed to Europeans) and in the gene (in the beta-globin as opposed to the control delta-globin gene) where it is of adaptive significance. These results upend the traditional example of random mutation and natural selection, turning it into an example of a nonrandom yet non-Lamarckian mutation.
Before I posted this, I decided to re-read this post in an earlier thread - this paper reminded me of it as it also said mutations are non-random.
What do you think this time @Rumraket ?
The authors discuss possibilities in their paper. Paper here: Genome Res | Mobile
Knowing that the HbS mutation is advantageous in heterozygotes under malarial pressure, how shall we interpret these results? One possibility is that, for a reason unrelated to adaptation, some individuals have a genomic fragility in HBB that generates the HbS mutation at a high rate. Accordingly, it is merely a coincidence that HbS provides protection against malaria, even more so if that fragility applies more to Africans.
Another possibility is modifier theory (Feldman and Liberman, 1986; Altenberg et al., 2017), according to which alleles affecting the mutation rate may be favored by selection under certain conditions. (Leigh Jr, 1970; Moxon et al., 1994). However, since the benefit of a
modifier allele that increases the mutation rate is tied to the excess beneficial mutations it helps generate, and since mutations are rare, it is normally expected that, for selection to be effective, it must act on a modifier allele that increases the mutation rate across a long enough stretch of the genome with which it remains linked for a long enough period of time, so that many different
mutations potentially induced by this allele over space and time are factored into its selective benefit (Hodgkinson and Eyre-Walker, 2011; Martincorena and Luscombe, 2013; Walsh and Lynch, 2018). Thus, modifier theory does not predict an increase in the rate of particular DNA mutations at specific base positions, let alone in sexual, complex organisms, nor the complex
genetic and/or epigenetic influences on such mutation rates suggested by the current data (cf. Leigh Jr, 1970; Moxon et al., 1994; Altenberg et al., 2017; Walsh and Lynch, 2018). On the contrary, the “reduction principle”—the first-order principle in modifier theory—underscores
the general difficulty of accounting for increased mutation rates (Feldman and Liberman, 1986;
Altenberg et al., 2017).
Finally, a recently proposed theory predicted that mutation-specific origination rates are influenced by the complex genetic and epigenetic background, that genetic relatedness in mutational tendencies exist, and that the HbS mutation arises more frequently in Africans than in Europeans (Livnat, 2013, 2017). It holds that novelty in evolution arises from emergent interactions which are then simplified through the generations by mutational mechanisms while being checked by natural selection (Livnat, 2017), one hypothetical example being that A→I RNA editing can mechanistically increase the A→G mutation rate in the corresponding positions (cf. Popitsch et al., 2020). Based on these and other previous work (Livnat and Pa-padimitriou, 2016), we hypothesize that recurring, evolved processes acting on DNA and/or RNA through epigenetic modifications (Klose and Bird, 2006), RNA editing (Nishikura, 2010)
and other mechanisms may lead directly to their own replacement and simplification via DNA mutations that arise in the course of evolution from these processes’ molecular nature, mechanistically linking regulatory activity with structural mutational changes—though whether and by what specific mechanism this “replacement” hypothesis explains the HbS case specifically (alternative decoding of A→I editing, Licht et al. 2019, or other mechanisms) is yet to be investigated. This raises the possibility that a mutation of adaptive value such as the HbS one need not initiate the process of adaptation but can arise later in an evolutionary process where adaptations and mutation-specific rates jointly evolve (Livnat, 2013, 2017), and thus studies on the fundamental nature of mutation need to test for not only a short-term response to environmental
pressures (Luria and Delbruck, 1943; Cairns et al., 1988) but also a long-term one.
Unlike previous methods that could explore only diffuse relationships between long-term selection pressures and the evolution of GWA mutation rates, the present method offers the refined ability needed to explore such relationships, if they exist, at the mutation-specific resolution. Because this method examines the mutation-specific resolution for the first time, it provides only initial estimates of mutation rates, which will require further investigation and refinement. Furthermore, it cannot be applied currently to all mutations, because it requires a special RE for each ROI. However, given the numerous REs available and their short recognition sequences, which imply large representation of these sequences across the genome, it likely applies across many loci and organisms. Therefore, some of the most important tasks now are to examine the high-resolution mutation rate variation across additional loci of interest and to explore the molecular mechanisms responsible.
For my part, I would like to see evidence it’s not a coincidence…