Thursday, 7 November 2013

"20 scientific facts seldom taught to students" critically reviewed #3 - On fruit flies and mutations

Collyer's third claim is "[m]utations, said to be the source of new genetic material, are harmful to life and often lethal. Deliberately induced mutations in over 3,000 consecutive generations of fruit flies have failed to produce a better fruit fly, or to increase its viability. Collyer's response unsurprisingly shows a considerable ignorance of evolutionary genetics and the significance of the fruit fly experiments. In short:
  • Some mutations are deleterious, some are beneficial, while most are neutral. The literature is replete with examples of beneficial mutations.
  • The fruit fly experiments were not conducted to breed a 'superfly' but were designed to expand our knowledge of genetics. Having said that, speciation of fruit flies, and beneficial changes did occur in these experiments.
  • Each human is born with between 60-100 mutations – if they were invariably deleterious, we'd pretty quickly be dead.
  • Modern evolutionary biology recognises the importance of networks of genes, in which single mutations often have a negligible effect.
Collyer's use of the special creationist argument that 'mutations are harmful to life' shows a poor understanding of evolutionary genetics. Some mutations are harmful, some are beneficial but others are neutral. Collyer ignores the fact that a mutation that is beneficial in one environment may be positively harmful in another. The literature is replete with examples of beneficial mutations:
  • A point mutation in the apolipoprotein A gene results in the creation of a mutant version of apolipoprotein A, apoA-IM. This beneficial mutation has been linked with reduced rates of atherosclerosis in those heterozygous for the apoA-IM mutation. [1] The clinical significance of this mutation has been explored in many studies. [2][3]
  • The CCR5 gene codes for a chemokine receptor that, along with the CD4 T cell co-receptor is used by the HIV-1 virus as an entry point. A mutation in the CCR5 gene conveys resistance to HIV infection in people homozygous for the mutation, while HIV-1 infected individuals heterozygous for the mutation have a two to three year delay before they develop AIDS. The particular mutation is a 32 base pair deletion that results in loss of the CCR5 receptor. [4]
  • Bacteria have evolved the ability to metabolise nylon breakdown products. This was achieved by a frameshift mutation which created a unique enzyme that gave the bacteria the opportunity to access a never-before utilised food source. [5]
  • In 2008, the evolutionary biologist Richard Lenski published a landmark paper on the evolution by a colony of E. coli bacteria of the ability to metabolise citrate under oxic conditions, something that E. coli is not normally able to do. Over the previous twenty years, Lenski had cultured 12 colonies of E. coli, taking samples every 500 generations to provide a “fossil record”. After 31,500 generations, one colony evolved the ability to metabolise citrate in an oxic environment. The two hypotheses to explain this were (1) an extremely rare mutation or (2) a mutation that was contingent on an earlier mutation to evolve the ability to metabolise citrate. Lenski’s analysis favoured the latter, “Our results instead support the hypothesis of historical contingency, in which a genetic background arose that had an increased potential to evolve the Cit_ phenotype.” [6]
  • Evolution of vertebral steroid receptors and the endocrine systems associated with them involved duplication of an ancestral steroid receptor gene, and mutation of the duplicate. [7][8] 
Evolution of specific aldosterone-MR signaling by molecular exploitation. (A) Synthesis pathway for corticosteroid hormones. Ligands for the ancestral CR and extant MRs are underlined; cortisol, the ligand for the tetrapod GR, is overlined. The terminal addition of aldosterone is in green. Asterisks, steps catalyzed by the cytochrome P-450 11β-hydroxylase enzyme; only the tetrapod enzyme can catalyze the step marked with a green asterisk. (B) MR's aldosterone sensitivity preceded the emergence of the hormone. The vertebrate ancestor did not synthesize aldosterone (dotted circle), but it did produce other corticosteroids (filled circle); it had a single receptor with affinity for both classes of ligand. A gene duplication (blue) produced separate GR and MR. Two changes in GR's sequence (red) abolished aldosterone activation but maintained cortisol sensitivity [see (C)]. In tetrapods, synthesis of aldosterone emerged due to modification of cytochrome P-450 11β-hydroxylase. mya, million years ago. (C) Mechanistic basis for loss of aldosterone sensitivity in the GRs. Phylogenetically diagnostic amino acid changes that occurred during GR evolution were introduced into AncCR-LBD by mutagenesis. Dose-response is shown for aldosterone (green), DOC (blue), and cortisol (red). The double mutant (bottom right) has a GR-like phenotype. Arrows shows evolutionary paths via a nonfunctional (red) or functional (green) intermediate.  (From ref 7)
  • Evidence of chromosomal translocation and segmental duplication in Cryptococcus neoformans. [9]
  • Genome duplication in yeast as a source of evolutionary novelty. [10]
  • Whole genome duplication as a source of genetic variety is not restricted to yeasts. Examination of the genomes of chordates has shown the existence of multiple copies of genes in the same gene family. None of this is remotely controversial; as long ago as 1999, one paper noted:
Duplication of genes and entire genomes are two of the major mechanisms that facilitated the increasing complexity of organisms in the evolution of life. Gene duplications might be responsible for the functional diversification of genes, the creation of gene families and the generally increased genomic, and possibly also phenotypic, complexity. Protostomes, such as Drosophila, and deuterostome ancestors of vertebrates tend to have single copies of genes whereas chordate genomes typically have more genes, often four; the copies belong to the same gene family. [11]
  • Proviral elements from ancient retroviral infections have served as the source of genetic novelty. Placental morphogenesis would not be possible without the cooption of an ancient retroviral envelope protein to perform an entirely different task. [12]
  • Horizontal gene transfer in bacteria is responsible for more than just the transfer of antibiotic resistance. One example involves the Salmonella PhoP-PhoQ system which senses environmental magnesium ions, allowing the bacterium to tell whether it is inside a host cell. If this is the case, it activates a molecular pathway that permits it to survive inside the cell. The genes that permit Salmonella to do this are not part of its original genome but were obtained by horizontal gene transfer. [13]
  • Evolution of complexity has been simulated and occurs in a Darwinian manner. [14]
Collyer’s claim that mutations are harmful to life and often lethal is simply wrong, and ignores the fact that as we have shown, mutations can be beneficial. More importantly, he overlooks the fact that most mutations are neutral. Lenski’s long term evolutionary experiment highlights the fact that neutral mutations can linger in the genome until another mutation arrives which effects a beneficial phenotypic change. The average human being has around 175 mutations, [15] according to one study so clearly, most of these are not life-threatening, and otherwise we wouldn’t be here! Really serious mutations tend to be purged from the gene pools via purifying selection. Crippling mutations such as those causing Huntingdon’s disease, CADASIL or other genetic disorders are noticeable because of their characteristic phenotype. Neutral mutations are invisible from a phenotypic perspective, so the special creationist simply overlooks their existence.

Collyer’s disparaging reference to the Drosophila experiments failing to breed a “super-fly” demonstrate specific ignorance of what these experiments are aimed to achieve. [16] The authors of a recent review paper on experimental evolution using a Drosophila model point out:
Experimental evolution with laboratory populations is an alternative tool with which to study adaptation. One of the most attractive applications of experimental evolution is to create a replicated set of populations that have been differentiated relative to replicated control populations, using a well-defined selection protocol, and then compare the allele frequencies at various loci for associations between particular types of phenotypic and genetic differentiation. In short, laboratory evolution allows biologists to use strong inference tests of hypotheses concerning phenotypic and genetic responses to selection. In addition, the recent development of cost-effective genomic tools has allowed broad and systematic assays of the molecular foundations of the effects of experimental evolution. [17]
If one remembers that evolution is a change in allele frequencies in a population, then the problem posed by Collyer becomes simply an artefact of the straw man he has once again created. Examples of evolution observed in Drosophila abound:
Stress-resistance characters respond to direct and reverse selection. Laboratory selection for increased resistance to starvation and desiccation produces rapid responses within populations of D. melanogaster, and high heritability estimates have been reported for both traits. Direct selection for increased starvation (Rose system “SO” and SB” lines) and desiccation (Rose system “D” lines) resistance results in a correlated increase in longevity in the absence of acute starvation or desiccation, along with decreased fecundity...Furthermore, some experiments suggest that lines selected for increased desiccation resistance have decreased preadult viability and slower development time than control lines. There appear to be complex trade-offs connecting resource acquisition during larval stages, adult stress resistance, and life history generally. [18]
Pseudocomparative surveys and reverse-selection experiments reveal correlations between stress resistance and life history characters. The mean longevity of Drosophila populations has been demonstrated to change as a result of manipulating the age of reproduction in a population over multiple generations. Furthermore, longer-lived lines (Rose system “O” lines) have generally been found to tolerate starvation and desiccation significantly better than lines with shorter average lifespans (Rose system “B” lines). These pseudocomparative results were interpreted to mean that resistance to starvation and desiccation might be general physiological mechanisms necessary for maintaining health at late ages. [19]
It hardly needs stressing that there is no ‘limit’ to evolutionary change, but a reference to documented speciation [26] in Drosophila should make this clear, and prevent any further creationist attempts to peddle the usual misunderstandings about Drosophila experiments.

The final – and most important – comment on Collyer’s assertions focuses on the fact that modern evolutionary biology recognises the importance of networks of genes, and that fixating on single beneficial or deleterious mutations is trivialising evolution. The developmental biologist Paul Myers makes this clear:
Mutations are the root of biological variation, of course, but we often have a naive view of their consequences. Most mutations are neutral. Even advantageous mutations are subject to laws of chance in their propagation, and a positive selection coefficient does not mean there will be an inexorable march to fixation, where every individual has the allele. This is also true of deleterious mutations: chance often dominates, and unless it is a strongly negative allele, like an embryonic lethal mutation, there's also a chance it can spread through the population.

Stop thinking of mutations as unitary events that either get swiftly culled, because they're deleterious, or get swiftly hauled into prominence by the uplifting crane of natural selection. Mutations are usually negligible changes that get tossed into the stewpot of the gene pool, where they simmer mostly unnoticed and invisible to selection. Look at human faces, for instance: they're all different, and unless you're looking at the extremes of beauty or ugliness, the variations simply don't make much difference. Yet all those different faces really are the result of subtly different combinations of mutant forms of genes.

"Combinations" is the magic word. A single mutation rarely has a significant effect on a feature, but the combination of multiple mutations may have a detectable or even novel effect that can be seen by natural selection. And that's what's going on all the time: the population is a huge reservoir of genetic variation, and what we do when we reproduce is sort and mix and generate new combinations that are then tested in the environment. [20]

It can be quite difficult to get this simple point across – really serious mutations tend to kill in utero. Even then, some deleterious mutations can be beneficial in some environments, as the persistence of sickle cell anaemia in malaria-endemic areas demonstrates.

Thinking in terms of networks of genes helps realise the fallacy behind the “mutations are deleterious therefore evolution can’t occur” fallacy. Below is the signalling network for the epidermal growth factor pathway.

A creationist likely would argue that a just a single mutation would destroy this cellular pathway, but this is actually not the case. Often, the effect of a mutation in one of the genes involved in such complex pathways is negligible. Myers again: 
The curious thing is, though, that the more elaborate the network, the more pieces tangled into the pathway, the smaller the effect of any individual component (in general, of course). What we find over and over again is that many mutations to any one component may have a completely indetectable effect on the output. The system is buffered to produce a reliable yield.

Now do you see what's wrong with the simplistic caricature of evolution at the top of this article? It's superficial; it ignores the richness of real biology; it limits and constrains the potential of evolution unrealistically. The concept of evolution as a change in allele frequencies over time is one small part of the whole of evolutionary processes. You've got to include network theory and gene and environmental interactions to really understand the phenomena. And the cool thing is that all of these perspectives make evolution an even more powerful force.
Collyer’s argument is based on a parody of evolutionary theory, as well as an appalling level of ignorance of the primary literature. As long ago as the 1970s, a simple search of the literature would have shown him evidence of Drosophila speciation, which alone would have shown his assertions as being utterly devoid of support.


1. Sirtori C.R. et al “Cardiovascular Status of Carriers of the Apolipoprotein A-IMilano Mutant” Circulation. 2001;103:1949-1954.
2. Shah P.K. et al “High-Dose Recombinant Apolipoprotein A-IMilano Mobilizes Tissue Cholesterol and Rapidly Reduces Plaque Lipid and Macrophage Content in Apolipoprotein E–Deficient Mice” Circulation. 2001;103:3047-3050.
3. Stevens J.C. et al “Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.” Am J Hum Genet. 1998 Jun;62(6):1507-15.
4. Ohno S “Birth of a unique enzyme from an alternative reading frame of the preexisting, internally repetitious coding sequence” Proc. Natl. Acad. Sci. USA (1984) 81:2421-2425
5. Blount Z.D., Borland C.Z., Lenski R.E. "Historical contingency and the evolution of a key innovation in an experimental population of Escherichia coli" Proc. Natl. Acad. Sci. USA 2008 105:7899-7906
6. Thornton J.W. "Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions" Proc. Natl. Acad. Sci. USA (2001) 98:5671-5676
7. Bridgham J.T., Carroll S.M., Thornton J.W. “Evolution of Hormone-Receptor Complexity by Molecular Exploitation” Science (2006) 312:97-101 
8. Fraser J.A. et al "Chromosomal Translocation and Segmental Duplication in Cryptococcus neoformans" Eukaryotic Cell (2005) 4:401-406
9. Kellis M, Birren B.W, Lander E.S. “Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiaeNature (2004) 428:617-624
10. Meyer A, Schartl M "Gene and genome duplications in vertebrates: the one-to-four (-to-eight in fish) rule and the evolution of novel gene functions" Curr Opin Cell Biol 1999, 11:699-704
11. Mi S et al "Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis" Nature (2000) 403:785-789
12. McAdams H.H. Srinivasan B, Arkin A.P "The Evolution of Genetic Regulatory Systems in Bacteria" Nat Rev Genet (2004) 5:169-178
13. Lenski R.E., Ofria C, Pennock R.T., Adami C “The evolutionary origin of complex features” Nature (2003) 423:139-144
14. Nachman, M.W., Crowell, S.L. Estimate of the mutation rate per nucleotide in humans. Genetics 2000 156(1): 297-304.
15. Burke M.K., Rose M.R., “Experimental evolution with DrosophilaAm J Physiol Regul Integr Comp Physiol 296:R1847-R1854, 2009
16. ibid, p R1847
17. ibid, p R1849
18. loc cit.
19. Dobzhansky, T, Pavlovsky, O "An experimentally created incipient species of Drosophila", 1971 Nature 23:289-292.
20. Myers PZ “It’s more than genes, it’s networks and systems.Pharyngula July 24th 2010.