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Why should physiologists be concerned about these questions?

A major problem with the modern synthesis from the viewpoint of physiology is that it excludes phenotypic function from having any role whatsoever in influencing the direction and frequency of genomic change. This is what neo-darwinists really mean when they refer to gene changes as ‘random’. It doesn’t really matter to them whether the changes are ‘truly’ random. What matters is whether function can influence those changes. Through that crack, if it exists, will flow all that they wish to exclude, including strong forms of the inheritance of acquired characteristics. If the modern synthesis is correct, then physiology really is dealing with the disposable carrier of genes. If however, on this central point, it is incorrect then, as I say in the article “It is hard to think of a more fundamental change for physiology and for the conceptual foundations of biology in general”. That, incidentally, is the justification for the title of the article. I did not choose the title light-heartedly.

PLEASE NOTE that the answer to this very important question is necessarily very technical. But I think it is necessary to give the full details. The angel in this case lies in the detail. The devil will lie with those who are unprepared to study the detail but who still wish to claim that the ‘earth has not moved’.

The key to this question lies in four major discoveries:

First, some of the non-random changes in the genome are functionally significant.

“Changes in the speed of change are well known already from the way in which genome change occurs in immunological processes. The germ line has only a finite amount of DNA. In order to react to many different antigens, lymphocytes ‘evolve’ quickly to generate extensive antigen-binding variability. There can be as many as 1012 different antibody specificities in the mammalian immune system, and the detailed mechanisms for achieving this have been known for many years. The mechanism is directed, because the binding of the antigen to the antibody itself activates the proliferation process. Antigen activation of B-cell proliferation acts as a selective force.”

This example was given first because targeted genome change in the immune system is well-documented and has been known for a long time. That it can happen in B-cells as they ‘evolve’ to generate the variability shows that the mechanism of such targeted genome change is not new. We should not therefore be surprised to find that it is used elsewhere in the organism. Now let’s move to the part of the article that deals with evidence beyond the immune system.

“Similar targeted genomic changes occur outside the context of the immune system. The reader is referred to table II.7 (Shapiro, 2011, pp. 70–74;

http://shapiro.bsd.uchicago.edu/TableII.7.shtml) for many examples of the stimuli that have been shown to activate this kind of ‘natural’ genetic engineering, while table II.11 from the same book  documents the regions of the genomes targeted. (pp. 84–86; http://shapiro.bsd.uchicago.edu/TableII.11.shtml). Thirty-two examples are given. One example will suffice to illustrate this. P element homing in fruit flies involves DNA transposons that insert into the genome in a functionally significant way, according to the added DNA. There is up to 50% greater insertion into regions of the genome that are related functionally to DNA segments included within the P element. Thus, ‘Insertion of a binding sequence for the transcriptional regulator Engrailed targets a large fraction of insertions to chromosomal regions where Engrailed is known to function.’ (Shapiro, 2011, p. 83)”

 The reference and abstract for this example is

 Cheng, Y., Kwon, D. Y., Arai, A. L., Mucci, D., and Kassis, J. A. (2012) P-Element Homing Is Facilitated by engrailed Polycomb-Group Response Elements in Drosophila melanogaster PLoS ONE 7, 1. http://www.ncbi.nlm.nih.gov/pubmed/22276200

 ABSTRACT: P-element vectors are commonly used to make transgenic Drosophila and generally insert in the genome in a non-selective manner. However, when specific fragments of regulatory DNA from a few Drosophila genes are incorporated into Ptransposons, they cause the vectors to be inserted near the gene from which the DNA fragment was derived. This is called P-element homing. We mapped the minimal DNA fragment that could mediate homing to the engrailed/invected region of the genome. A 1.6 kb fragment of engrailed regulatory DNA that contains two Polycomb-group response elements (PREs) was sufficient for homing. We made flies that contain a 1.5kb deletion of engrailed DNA (enΔ1.5) in situ, including the PREs and the majority of the fragment that mediates homing. Remarkably, homing still occurs onto the enΔ1.5 chromosome. In addition to homing to en, P[en] inserts near Polycomb group target genes at an increased frequency compared to P[EPgy2], a vector used to generate 18,214 insertions for the Drosophila gene disruption project. We suggest that homing is mediated by interactions between multiple proteins bound to the homing fragment and proteins bound to multiple areas of the engrailed/invected chromatin domain. Chromatin structure may also play a role in homing.

 The end of this abstract echoes another point I make in the article:

 “Structural organization also represents information that is transmitted down the generations. DNA is not merely a one-dimensional sequence. It is a highly complex physiological system that is regulated by the cells, tissues and organs of the body.”

 Finally, another well-known functionally-driven form of genome change is the response to starvation in bacteria.

 “An important point to note is the functionally significant way in which this communication can occur. In bacteria, starvation can increase the targeted transposon mediated reorganizations by five orders of magnitude, i.e. by a factor of over 100,000 (Shapiro, 2011, p. 74).”


Second, some forms of non-DNA (epigenetic) inheritance have been shown to be as robust as DNA inheritance and to be transmitted for many generations.

The details on this point are given in the answer to the question how widespread non-DNA inheritance is.

 Third, inherited changes that occur by whatever mechanism can become locked into the genome by genetic assimilation. This was the major conclusion of Waddington’s experiments in fruit flies – see

Bard JBL (2008). Waddington’s legacy to developmental and theoretical biology. Biological Theory 3, 188–197. http://www.deepdyve.com/lp/mit-press/waddington-s-legacy-to-developmental-and-theoretical-biology-o0mS0JjRau

Waddington showed a form of inheritance of an acquired characteristic that was initially ‘soft’ in the sense that it required repetition of the environmental stimulus in each generation to maintain it. But after about 14 generations it became ‘hard’, i.e. assimilated into the genome. I think that what was happening was that the separate alleles necessary for the characteristic were already present in the population but not in the right combination to be expressed without the stimulus. The environmental stimulus was eventually not needed because by that generation the correct combination of alleles was now present in individuals who could pass this pattern of alleles on to the next generation in the standard genetic way. I summarise this point in the article by writing “After all, the pattern of the genome is as much inherited as its individual components, and those patterns can be determined by the environment.”

 Fourth, some trans-generational effects can occur reliably by bypassing the genome.

“Epigenetic effects can even be transmitted independently of the germ line. Weaver and co-workers showed this phenomenon in rat colonies, where stroking and licking behaviour by adults towards their young results in epigenetic marking of the relevant genes in the hippocampus that predispose the young to showing the same behaviour when they become  adults (Weaver et al. 2004; Weaver, 2009).”

Weaver ICG, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M & Meaney MJ (2004). Epigenetic programming by maternal behavior. Nat Neurosci 7, 847–854 http://www.ncbi.nlm.nih.gov/pubmed/15220929

Weaver ICG (2009). Life at the interface between a dynamic environment and a fixed  genome. In Mammalian Brain Development. ed. Janigro D, pp. 17–40. Humana Press, Springer, New York, NY, USA.

Neo-darwinists tend to dismiss this kind of example as a form of cultural inheritance. So it is. But it works by marking the genome of the next generation. It is therefore just as relevant as and just as robust as epigenetic inheritance in general. Rats and other rodents do it all the time.



  The MUSIC of Life: Biology Beyond the Genome                                                                                                                                 ©Denis Noble