In common with Indigenous populations elsewhere, Indigenous Australians have higher incidence of end-stage kidney disease (ESKD), but lower transplantation rates than their non-Indigenous counterparts. Understanding how the demands of dialysis impact on, and are impacted by, the lives of Indigenous patients may provide important insight into treatment pathways and decision-making.We conducted semi-structured interviews in 2005–06 with 146 Indigenous and 95 non-Indigenous patients from nine hospital renal wards and 17 associated dialysis centres, which together treat the majority of Indigenous Australian ESKD patients.all factors.Factors influencing treatment experience included: the impacts of late diagnosis; family separations associated with relocating for treatment; the physical and psychosocial demands of hemodialysis; and ineffective communication between health care providers and patients. Although not unique to them, Indigenous patients were more likely to experience the combined effect of Social/situational circumstances profoundly affect Indigenous Australian dialysis patients’ ability to fully engage with treatment. This may ultimately affect their likelihood of receiving optimal treatment, including transplantation. Areas for improvement include: earlier diagnosis; improved linkages between specialist renal services and primary care in regional settings; more effective communication and patient education; and more systematic, transparent approaches to patient “compliance” in transplant and home dialysis guidelines. In common with Indigenous populations in the US, Canada and New Zealand, Indigenous Australians have higher incidence of end-stage kidney disease (ESKD), but lower transplantation rates than their non-Indigenous counterparts -4. For eMost Indigenous Australian ESKD patients attend in-centre hemodialysis , generaltaken together – significantly increase the challenges of dialysis …[I was there for] three and a half years – yes, might be more. ""Recalling their first experiences of dialysis, Indigenous patients described shock, fear and bewilderment:P: I was shocked first. Yeah, shocked because nobody had ever said anything to me about [kidney disease] … I went to the hospital and when I got there [it was] late - late at night in the hospital. And the next day the doctor came and had a look at me and they were looking at my - you know - which side they’re gonna put [the fistula]. I didn’t say anything, I was wondering what they was doing, you know, I thought somebody might come up and tell me about it. Then when it was time for them to do it, that’s when the doctor said that they was gonna put a tube down here [pointing to site of vascath access in neck]. And they didn’t say anything [to explain] that they was getting me ready [for dialysis]… I had to find out myself.""They put that thing on, and then I was wondering, ”What that’s for”, you know? …they put me in a wheelchair to this part [of the hospital] where they had dialysis. I looked and I see this thing one side of me and then I said - I was thinking to myself: “So this is what it’s like to be on the machine”. ""By contrast, most non-Indigenous patients were aware of and being monitored for loss of kidney function well before commencing dialysis. This tended to lessen the shock of starting treatment.P: I mean I was expecting it you know, for some time, and so [I was] very prepared, yeah. Well, if it’s an acute thing, I can understand it’s probably a huge shock to people, and things like that, but … I was quite prepared, even though when they said, “Oh look you’ve got to go on dialysis next week”, it was sort of that I knew it was going to happen, but it was something I would sort of rather not heard. I just didn’t want it to interrupt my lifestyle and things like that mainly. ""Most Indigenous participants had had to leave home permanently to access dialysis treatment. Thrice weekly dialysis sessions severely limit opportunities to visit distant home communities. Indigenous participants spoke of the sometimes overwhelming difficulties of constant separation from their families, communities and land.P: I am living without my children, living far away from them. I have had to leave my home behind, and the lands, and am living in [major town] away from my friends and family. I have been living  a long time. So I would like [the doctors] to think about what I have said, to discuss the situation and put us on the [transplant] list. If [an Indigenous patient] gets another kidney and everything goes okay on return, he or she would be able to go home to family - see the children. To go home - this is what a lot of [Indigenous people] want. They don’t want to be waiting for such a long time, they are getting really weary, the poor things. ""Indigenous patients were, on the whole, younger than non-Indigenous patients as well as more likely to be caring for dependent family members, including children. Although some non-Indigenous participants were also caring for children, they were less likely to have relocated for treatment. Indigenous parents faced a grim choice between bringing their children with them to an unfamiliar town/city life or leaving them behind in the care of others. Finding housing, social networks and support services for families and children all present difficulties; many patients expressed concerns about exposing their families to alcohol and drugs and/or the likelihood of homelessness. The alternative was a life undergoing a difficult treatment in virtual exile from their families, communities and support networks.In addition to family responsibilities, dialysis requirements may cut across or conflict with patients’ family, community and/or cultural responsibilities. Patients described the dilemma of having their personal health needs set against their social and cultural responsibilities.P: I’m a very special person [there] with the other young men because they take part in special ceremonies. It’s very important for my people. And I felt - about the ceremony - I felt guilty in myself because I’m not over there. I got a lot of phone calls - the Land Council, the [community] Council - my people ring me up and say, “Oh, we need you to come over for this funeral”. And I keep saying to them, “I can't travel”. That’s the word I’m getting to them …I feel no good when I keep saying, “No” to my people. My wife and I, we both talked over many times… She said “Listen, you can't keep going there for ceremony, otherwise you [will] have a heart attack or stroke or something… Tell your people you got to think about your health first. It’s very important.” ""This patient was a senior community member with ceremonial obligations to younger kin. He asks: how can I put my own health above my responsibilities to my family and kin? His far-distant relatives have no comparable experience to really understand his situation – he feels guilty and uncaring. On the other hand, travelling and thus missing treatments flies in the face of his health carers’ advice and the pleas of his wife.All participants spoke of a range of physical and/or psychosocial demands associated with the dialysis treatment itself, including fear, pain, nausea, fatigue, faintness, and a range of negative feelings such as deep sadness, loneliness, and homesickness.P: Because of the time lying there on the [dialysis] machines, four hours like that … the back becomes really painful… When it’s finished, the sisters pull out the needles and get everything, give us medicine. And the patients feel paralysed - they can’t go[walk]. They feel really tired. The bus driver has to lift them up into the bus. When they get off the bus they move slowly using walking frames. … So it’s because of all this that people are sad. Also the dialysis affects their eyesight - after the machine some can’t see properly. They recover later after going home and having a sleep… The dialysis machine has some bad side effects. ""While non-Indigenous patients also noted some physical discomforts associated with dialysis, their commentary did not reflect a similar experience of distress, with its suggestions of alienation, social isolation, confusion, and sadness.Communication difficulties, associated variously with differences of language, literacy, conceptual frameworks, values, and preferred communication styles between patients and health providers, were recurrent themes of Indigenous commentary. Patients noted that medical jargon, and/or overly complex English, made it difficult for them to understand information and instructions. This was particularly so for specialists. Some participants reported apprehension and confusion as a result. Others spoke of feeling uncomfortable and uncertain in the hospital environment, which reduced their willingness to engage with health professionals. As an experienced Indigenous interpreter observed:People [i.e. Indigenous patients] will go along and shake their head and agree to things [just] to get away from that person [clinician] that’s firing all these big questions at them …[but] they’re lost for answers. They can’t understand all that. So the easiest way is to agree … because you know you’re out [quickly] then. … And [the health providers are] … happy; … Oh well at least they feel as if they’ve done their job so they [feel] good about it. But the full story hasn’t been given.""Perceiving clinicians as reluctant to provide information, several Indigenous participants expressed uncertainty and/or scepticism about whether health staff wanted to give them the whole story. This was keenly felt by some:P: … When I ask the doctor I don't get anything [clear information]. Have I got something else wrong [with me]? The doctors keep it a secret, they hide it. We want them to tell us plainly, “This is the problem”. They don't talk. ""Moreover, the busyness of the daily dialysis routine can itself mask a lack of patient understanding and participation in their own care. Asked what he knew of his current situation, a longer term Indigenous patient replied:P: Well, we don’t know. We really only just go in and out and have the treatments. We don’t know where we stand with how we’re going. So we don’t know whether we’re getting a bit better or things are getting a bit worse. They don’t tell us whether we’re improving or getting worse. We’re just going in and out of the sessions. ""In contrast, only a small proportion of non-Indigenous patients did not speak English as their first language. Most reported few difficulties understanding their health providers; those who did report difficulties focused primarily on language differences with little mention of medical jargon or overly complex language. Notably, while most major treating units routinely used interpreter services for non-Indigenous, non-English languages, only one unit involved in this study made regular use of Indigenous language interpreter services.Despite the challenges most Indigenous patients described themselves as following their health providers’ advice with its emphasis on attending dialysis and maintaining dietary and medication requirements. Those who reported being unable or unwilling to maintain the regimen gave a variety of reasons, including transport problems, not understanding what was expected, difficulty in adjusting to dialysis, needing to travel home for important events, and feelings of mistrust, anger or frustration.Although Indigenous patients commonly noted that information from their care providers had been inadequate, either in its comprehensiveness or, more usually, its appropriateness (e.g. diet-related advice), most also expressed a reticence about asking for clarification or additional information.Several Indigenous patients recalled how anger and frustration at their vastly changed circumstances led to neglecting their treatment:I: Okay, so you have missed your dialysis on some days? Only in the initial part when you were getting used to coming here?""P: Coming here, yeah, because I was really agitated, angry. ""Others explained how they tested treatment boundaries:P: I mucked up … for a little while there, I didn’t come to dialysis.""I: What made you change your mind about it?""P: Well, because of the body, how the body functions. While I’m not being dialysed it’s becoming poison inside my body. Toxins. And that’s what I realised… I went five days without treatment. It was stupid I think but I wanted to push the limit to see how far I can go too… ""full realisation that their need for treatment was permanent – that despite prolonged and aggressive medical intervention their illness could not be cured.After the initial shock of starting dialysis and adjusting to its physical demands, many Indigenous participants described coming later to the P: It took me nearly two years to get used to it, you know, just worrying to go back [home] - but I couldn’t. ""For many Indigenous participants, the eventual “acceptance” of dialysis was accompanied by a somewhat bleak sense of resignation described graphically by one Indigenous patient:P: Well, a lot of them know they’re stuck here for life until they die, you know. And they know it, and it’s really upsetting to them. ""P: I was thinking sad [about] everything – [I] keep looking back to my family. ""In essence, these participants experienced their lives as being simultaneously saved – and devastated – by dialysis.only identified by Indigenous patients. Some non-Indigenous patients also experienced the effects of some factors: some non-Indigenous patients had communication problems; some had a rushed and frightening start to dialysis; some had to deal with family separation and so on. However, in contrast to other patient groups, the majority of Indigenous patients experienced all or most factors combining in varying levels of intensity throughout the period of their dialysis. As a result, centre-based hemodialysis presents distinct - and particularly complex - challenges for Indigenous patients. Despite such challenges, the majority of Indigenous participants reported their endeavours to maintain the treatment regimen. However, there was also a sense that patients, isolated from family and support networks, became worn down and lost motivation over time. In a setting of serious illness and limited understanding, a range of responses including alienation, isolation, confusion, frustration, anger, denial, resentment and/or mistrust led some patients to act against their own best interests. Often unknowingly, they were also potentially reducing their chances of being deemed suitable for transplantation or for self-care, home-based dialysis modalities.As a group, Indigenous patients’ dialysis experiences were shaped by several factors including: late referral and unplanned initiation of dialysis; family separation associated with relocation to an urban centre for treatment; barriers to meeting family and community responsibilities; the physical and psychosocial demands of dialysis; and ineffective communication between care providers and patients. As noted, none of these factors were A key finding of this study concerns the extent and implications of social hardships on the experience of dialysis treatment for many Indigenous patients. Indigenous participants’ narratives revealed how feelings of alienation and isolation substantially increased the challenge of coping with an already demanding treatment. Our findings also support those of similar studies undertaken with Native Canadian ESKD patients, which found that relocation for dialysis disrupts patients’ social support patterns and creates ongoing psychosocial problems for both patients and their families ,18. All Non-Aboriginal [health] carers rightly exhort patients to focus on their own health requirements. But many are apparently unaware of the enormity of the patient’s own dilemma who seeks to have not only life rather than death, but a life that has meaning in their terms.  terms. “a life that has meaning in their terms”, Indigenous dialysis patients draw on a cultural and social wellspring that differs greatly from that of their carers and, importantly, includes specific and different notions of illness causality as well as ideas of how health and well-being are achieved.In constructing A second key finding of this study was the degree to which miscommunication and/or ineffective communication accounted for patients’ treatment-related difficulties. When combined with relocation and family separation, social dislocation and unplanned treatment initiation, communication difficulties often took patients to the breaking point. Language differences, the failure to use interpreters routinely, and staff - particularly specialists - using inaccessible medical language added further to dissatisfaction and potential disengagement among Indigenous patients. Low levels of literacy and education also hampered effective communication and knowledge transfer. Patients confirmed their difficulties in understanding their situation, treatment and options. Some even perceived this as evidence of staff reluctance to share the “full story” with patients. These findings are in line with our previous research, which found that many Indigenous patients feel uninformed about their illness and eager for more information . There aThe findings of this study indicate that dialysis treatment is likely to be more challenging for Indigenous patients than for other patients. Yet our findings also suggest that the large majority of Indigenous participants see themselves as either managing a difficult situation or persevering under very onerous circumstances. This may not add up to the “compliance” proposed by staff but neither could it be said to constitute “non-compliance”. In contrast with views expressed by health professionals , we founThis study, which draws upon self-reported views, attitudes and experiences of 241 Indigenous and non-Indigenous ESKD patients, has some potential limitations. Most importantly, patients’ self-reports can only represent a partial account of the situation. For example, some patients may have over-estimated the extent to which they followed the regimen, particularly if they thought this could affect their chances of being wait-listed for transplantation; others may not have been sufficiently well-informed to assess whether their behaviour accorded with expectations. These limitations aside, the value in garnering the personal experiences and perspectives of a large number of dialysis patients is the rare insight it affords into challenges and obstacles faced by Indigenous patients in maintaining their dialysis treatment.The impact that social and situational circumstances have on the ability of Australian Indigenous dialysis patients to fully engage with treatment has important implications for health services. While factors such as place of residence, educational attainment and language are not easily modifiable, treatment practices can be adjusted more readily. Earlier diagnosis could reduce some of the trauma associated with unplanned start to dialysis. Some progress has been made, with late referral declining from 33.8% of Indigenous patients starting treatment in 2005 to 21.2% in 2009 [The authors declare that they have no competing interests.JC participated in the overall management and design of the IMPAKT study, in data analysis and interpretation, and in writing and editing the manuscript. KA coordinated data management, conducted interviews, participated in the coding, analysis and interpretation of data, and drafted the manuscript. JD participated in the design of the IMPAKT interview study protocol, and coordinated and participated in data collection, management, coding, analysis and interpretation. CP participated in study design, coordinated the Indigenous community engagement component, and participated in data collection, management, analysis and interpretation. AC conceived of the study, participated in design and overall management and in data analysis and interpretation. All authors participated in the drafting and/or critical revision of the manuscript and read and approved the final version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/13/114/prepub


Constructive neutral evolution (CNE) suggests that neutral evolution may follow a stepwise path to extravagance. Whether or not CNE is common, the mere possibility raises provocative questions about causation: in classical neo-Darwinian thinking, selection is the sole source of creativity and direction, the only force that can cause trends or build complex features. However, much of contemporary evolutionary genetics departs from the conception of evolution underlying neo-Darwinism, resulting in a widening gap between what formal models allow, and what the prevailing view of the causes of evolution suggests. In particular, a mutationist conception of evolution as a 2-step origin-fixation process has been a source of theoretical innovation for 40 years, appearing not only in the Neutral Theory, but also in recent breakthroughs in modeling adaptation , and in practical software for sequence analysis. In this conception, mutation is not a source of raw materials, but an agent that introduces novelty, while selection is not an agent that shapes features, but a stochastic sieve. This view, which now lays claim to important theoretical, experimental, and practical results, demands our attention. CNE provides a way to explore its most significant implications about the role of variation in evolution.Alex Kondrashov, Eugene Koonin and Johann Peter Gogarten reviewed this article. Occasionally, nature startles us with baroque and apparently gratuitous complexity. Several recent articles -5 have dIt is hard to imagine an idea less congenial to the adaptationist habit of thought that has dominated biology from pre-evolutionary times. The classic paradigm of an evolutionary explanation is an adaptive rationale: feature X exists by virtue of benefit Y. If one version of “Y explains X” doesn’t work, the adaptationist imperative compels us to revise the rationale (Y’), or re-define the feature (X’), a cycle that may be repeated indefinitely .Skeptics— from Bateson a century ago  to Lynchraison d’être. Our neo-Darwinian intellectual ancestors— who derided the notion of internal forces as an appeal to vitalism— would have scoffed at CNE.CNE seems to provide something completely different: not features that are noisy, limited manifestations of an adaptive reason-for-being, but complex features that emerge by an internal dynamic without an adaptive Yet if we peek inside CNE, there is no magic. The most well known model of this type is the neutral sub-functionalization model for the promulgation of duplicate genes proposed independently by Stoltzfus  and by FHow could evolutionary genetics produce something so odd that it fails to fit, not only the classic adaptationist paradigm, but also the reformed constraints-chance-contingency paradigm?The answer relates to what Orr  calls thThe battle lines of this historic conflict continue to shape contemporary evolutionary discourse. Darwin’s original theory was based on a non-Mendelian view of heredity characterized by blending of environment-induced, continuous variation ,17. WhenThe Modern Synthesis (MS), or modern neo-Darwinism, emerged from the claim that Darwin’s shape-shifting force (#1) could be reconciled with the Mendelian frequency-shifting force (#2) by arguing that a Darwinian process (smoothly shifting a mass of blending differences) occurs at the phenotypic level because, at the genotypic level, Mendelian selection is shifting the frequencies of discretely inherited (non-blending) allelic types at many loci, each with an infinitesimal additive effect on the phenotype ,19. ThisThat was a risky position, because the possible domain of Mendelian evolutionary genetics is (in principle) much broader than that under which the essential claim of the MS— that Mendelism rationalizes “natural selection” (#1)— is valid, as implied in a review of quantitative genetics  that war"If stochastic events, such as genetic drift, fluctuating adaptive landscapes and rare mutations, are more important, then quantitative genetics might not be informative and macroevolution might be decoupled from microevolution. Resolution of this issue is crucial to evolutionary biology as a whole (p. 322)."In Darwin’s original theory, and in the later Fisherian view, individual differences are properly a raw material, like the sand used to make a sand-castle: each individual grain of sand may be unique in size and shape, but its individual nature hardly matters, because it is infinitesimal in relation to the whole that is built by selection. By contrast, if an episode of evolution reflects the individual nature of a significant mutation— a developmental macromutation, a gene or genome duplication, an event of lateral transfer or endosymbiogenesis, etc.—, then the infinitesimal assumption no longer applies, and the verbal theory fails: when variation supplies form (not just substance), it is no longer properly a raw material, and selection is no longer the creator that shapes raw materials into products.That is, modern neo-Darwinism (the MS) is a Mendelian rationalization of Darwin’s “natural selection” (#1), but the conditions of this rationalization are narrow, and “the verbal theory that sits at the heart of neo-Darwinism” begins to break down when these conditions are unsatisfied.The concepts of “chance”, “contingency” and “constraints” allow the original theory to be stretched to fit cases outside of its narrow proper domain. Yet, these flexible concepts don’t change the underlying paradigm— neo-Darwinism plus excuses is still neo-Darwinism—, and this sometimes results in logical gaps. For instance, to suggest that the lack of variation is a constraint or limit on selection only makes sense in regard to Darwinian “natural selection” (#1); while in regard to the other concepts (#2 or #3), invoking the absence of a variation as a constraint or limit is nonsensical, like saying that the absence of mass is a constraint on the force of gravity.That is, sometimes the gap becomes a disconnect, which brings us back to the “curious disconnect” invoked by Orr in regard to the “mutational landscape” model of adaptation. In this model of evolutionary change by discrete steps, movement in a potentially huge genotypic space is reduced to repeatedly applying a purely local move-rule to the sub-space within 1 mutational step of the current genotype. Orr is trying to explain why this model— which seems obvious in retrospect— was not developed until the 1980’s, and then was ignored for over a decade. He argues that the belief that the problem of adaptation was solved by Fisher’s infinitesimal model stifled further research by defining away all the interesting questions: "we cannot, after all, construct a meaningful theory of adaptation if we assume away the existence of mutations that have different-sized phenotypic effects" . This reBy suggesting that the steps through which an adaptive mechanism arose were indefinite and insensible, all further trouble is spared. While it could be said that species arise by an insensible and imperceptible process of variation, there was clearly no use in tiring ourselves by trying to perceive that process .Indeed, the mutational landscape model treats selection as a stochastic sieve, reflecting a conception of evolution more in line with the thinking of de Vries, Bateson and Morgan, than of Darwin, Fisher and Mayr  arranged on a desk, with their power cords plugged into sequential outlets on a power strip. A fastidious person would arrange the devices first, and then install the cords in the same left-to-right order Figure a. This iOver time, however, there are many ways that linkage may increase to the point that some devices cannot be removed without untangling Figure c. For inentail the tangling of cords, optimization per se is not the cause of tangling, because the same tangling would happen even if we repositioned devices arbitrarily, with no objective. Indeed, so long as our reasons for moving devices are unrelated to the topology of the cords— if we move devices on top of the desk, without looking below it—, it is as if these movements were “neutral”.Note that we cannot account for cord-tangling by invoking local benefits. Imagine that, in order to make more space for the mouse, we move the printer to the other side of the monitor, tangling the cords in the process. Over time, we may make many such improvements. However, while optimization of our desktop organization via device movements would Instead, we can explain the tangling of cords by noting that, for any given order of devices, there is only one fully unlinked topology of cords, and an enormous universe of increasingly tangled topologies. The global or ultimate cause of tangling is that the system starts out in a topologically distinctive untangled configuration; the corresponding local cause for initial increases in tangling is that the set of available device movements  provides more ways to increase tangling rather than to decrease it.With the example of cord-tangling in mind, let us consider the bizarre case of gene-scrambling in Ciliates, single-celled organisms with both a small germ-line micronucleus, and a larger somatic macronucleus, in which gene expression occurs. Thus, information transfer in ciliates goes, not DNA→RNA→protein, but micDNA→macDNA→RNA→protein. The extra step provides a niche (in genome ecology) for selfish elements with a propensity to excise during macronuclear development . Ciliates have such elements in abundance: germ-line genes are split into macronuclear-destined sequences (MDSs) by internal eliminated sequences (IESs) that are excised in development Figure .Furthermore, in some ciliates, the MDSs of a gene may be scrambled in order and orientation  Figure . The CNEIn the language of CNE, the initial capacity for developmental unscrambling— presumed in an ancestor prior to the first scrambled gene— is called an “excess capacity”, meaning a capacity that could be removed (in principle) without compromising fitness.Likewise, in the CNE gene duplication (DDC) model, the excess capacity is the capacity of one duplicate copy to compensate for defects in the other. In the CNE model for spliceosome complexification, an ancestral intron is presumed to have the gratuitous capacity to reassemble and splice when split into pieces— as shown experimentally for group II introns and even for protein-based inteins — , and tWhile an excess capacity, by definition, is not “functional”, this can be changed. For instance, once a scrambled gene has evolved, the capacity for unscrambling is no longer a side effect but— by the normal standards of biological discourse— a “function”, conserved by negative selection against mutations that would compromise it.n-1n! = 23040 configurations). Just as for the case of cord-tangling, scrambling is favored for entropic reasons. Over time, if a scrambled gene can evolve (by mutation and drift), it will evolve, and by subsequent changes it will be less likely to revert than to wander, by a drunkard’s walk, more deeply into a vast space of scrambled possibilities , and it may undergo selective fixation due to this effect. A small subset of these beneficial changes will invert or translocate an MDS segment, increasing or decreasing scrambling. Other things being equal, we expect such beneficial rearrangements to lead, over time, to extensive scrambling.Finally, note that the tendency toward scrambling is just that— a tendency. Changes to a less scrambled state are possible. Furthermore, just as one might take remedial action to untangle the cords under a desk, nature is capable of dramatic reversals: an extensively scrambled ciliate gene could become unscrambled in one step by fixation of a mutation that introduces the unscrambled macronuclear DNA into the micronuclear genome.The ultimate cause of scrambling, in the CNE model, is not an adaptive rationale, but a dynamic in which a gratuitous unscrambling capacity opens the door for the system to wander into a morass of scrambled configurations. This tendency, which reflects an asymmetry in the space of possibilities, is present whether changes take place by drift or by selection.Yet, our claim to have identified an intrinsic tendency is unsatisfying, because we have not implicated a proper mechanism. Evolution does not look ahead: for every effect, there must be a blind, local cause. The doctrine of mechanism demands that we identify such causes. To invoke, as a causal mechanism, a global asymmetry in a possibility-space— a mere abstraction about future potentialities—would be to leave the mechanistic imperative unanswered.The lack of a properly construed cause for intrinsic tendencies is an issue with implications beyond CNE. An argument about tendencies arising from abstract possibility-spaces has been made before, e.g., by Kauffman , or by MSuch claims have been dismissed for precisely the reasons we would expect. In his stark rejection of evo-devo’s claim for novelty, Lynch writes "No principle of population genetics has been overturned by an observation in molecular, cellular, or developmental biology, nor has any novel mechanism of evolution been revealed by such fields" . To satiThe MS theory of causal forces  follows Note that mutation occupies a dual place in the MS. Mutation may be conceived both as a mass-action pressure that shifts the frequencies of alleles already present, and as a process that introduces new alleles at random intervals. In the MS, the former concept fits the definition of a mechanistic cause or “force”, while the latter does not. This is why one may find, in a contemporary textbook, the otherwise nonsensical claim that “mutation's role as the source of genetic variation is usually more important than its role as a mechanism of evolution" , i.e., “This view of evolutionary causes seems to offer little hope for understanding CNE. Based on the intuitive argument given above, we wish to identify an intrinsic source of directionality toward increased scrambling: but this cause is not the force of selection (because it is present when fixations happen by drift); nor of drift (because drift can’t favor one outcome over another); nor of migration (which isn’t involved); nor can it be the force of mutation .Thus, either the intuitive argument we developed (above) to explain scrambling is wrong, or the theory of forces fails to describe a true cause that is right in front of our faces.bias in the introduction of variants, and its lack of concordance with the classical forces theory arises because it is not based on the “shifting gene frequencies” view of the MS, which assumes abundant variation as a pre-condition for “evolution”, but on the mutationist conception of evolution as a 2-step proposal-and-acceptance process [That cause is  process . Such a  process .This fits our intuitive understanding of CNE. In the case of scrambled genes in Figure Mathematical formalisms of this 2-step view represent evolution in terms of events that follow origin-fixation dynamics, characterized by the product of (1) the rate at which some mutant type is introduced into a population and (2) the chance that a newly introduced mutant of that type will go to fixation. Such models have played an increasingly prominent role in evolutionary genetics over the past 40 years, with applications including Kimura’s Neutral Theory , the mutGiven a population of N individuals, a type of allele that emerges by mutation with a rate μ per gene per generation is introduced into the population at a rate 2Nμ , where it faces acceptance with probability π fixations per introduction. The bias in rates of two types of changes is then i/μj  and a second factor representing the relative probability of fixation, πi/πj. When i and j are classes of neutral variants in the strict sense, the probability of fixation is πi = πj = 1/(2N), and Eqn 1 reduces to μi/μj. For selective fixations, where a useful approximation is Haldane’s πi ≈ 2si, it follows that πi/πj ≈ si/sj. The verbal “other things being equal” assumption that we invoked earlier corresponds to the condition of si = sj, in which case, the overall bias reduces to μi/μj, just like the case for neutral evolution, even though fixations take place by selection!That is, the relative rate of the two types of changes jointly reflects one factor representing the relative rate of introduction μFor such a model to apply, the rate of introduction of new mutations (2Nμ) must be small, i.e., the “pressure” of mutation is low, which explains why they sometimes are called “weak mutation” models .This 2-step view accounts for much of the novelty of the mutational landscape model underlying recent advances in the study of adaptation ,37,44. IImportantly, Eqn 1 implies that the introduction process can bias the course of adaptation systematically. This particular implication is lost in Orr’s simplified version of the mutational landscape model, which assumes that mutation rates are all the same . Thus, iSome evolutionary thinkers  take a Yet the actual history of evolutionary thought reveals the vital role of contested, conflicting, or otherwise non-shared concepts. As noted above, the MS endorses Darwin’s creative concept of selection (#1) with its “raw materials” view of variation, while rejecting the mutationist view (#3) with its emphasis on the distinctiveness of individual mutations. Thus Mayr, in a piece  entitledThose authors who thought that mutations alone supplied the variability on which selection can act, often called natural selection a chance theory. They said that evolution had to wait for the lucky accident of a favorable mutation before natural selection could become active. This is now known to be completely wrong. Recombination provides in every generation abundant variation on which the selection of the relatively better adapted members of a population can work (p. 38).Given that “evolution” in the MS is defined as shifting from one multi-locus distribution of allele frequencies to another, the mutational introduction of new alleles is not part of “evolution”, except as an implicit pre-condition . AccordiThis has important implications for evolutionary reasoning. Evolutionists use the language of “forces”, believing that it provides a generalized framework for reasoning about evolution, even when origin-fixation dynamics are relevant. Sometimes the inappropriate use of the “forces” language is innocuous , but inIn particular, the theory of forces leads to errors in reasoning about variation-biased evolution. The classical reasoning of Fisher and Haldane  rejectsRather than rejecting this “opposing pressures” argument, contemporary evolutionists (as explained in ) have exHowever, in the realm of origin-fixation dynamics, these are errors in reasoning: they result from applying a theory of causes that doesn’t fit, based on a theory of evolution that doesn’t fit. To suggest, by “opposing pressures” logic, that mutation-biased evolution must be neutral, is to imply fixation by mutation, as though mutation “pressure” drives alleles to fixation when selection is looking the other way. Yet fixation by mutation, given the low rate of mutation, is typically an absurdity that would take huge numbers of generations . In neuEvolutionists have been using mathematical equations of 2-step origin-fixation dynamics with increasing frequency for 40 years, while interpreting the results using an incommensurable “forces” theory from the MS, which deliberately rejected the 2-step view in the guise of mutationism . The “foThe theory of causes that we need  woulone will not find in any textbook: mutation-biased evolution is not the result of the force of mutation pressure, but the result of a bias in the introduction process; it is not the largeness of mutation rates, but the smallness of the rate of introduction (2Nμ) that creates the potential for such biases to influence the course of evolution; this influence does not depend on neutrality, but can occur even when fixations take place by selection [This view immediately suggests some different rules for reasoning, including statements about causation that election .per se, but may be applied to any feature, including phenotypes, thus developmentally mediated biases in variation [Importantly, the notion of a bias in the introduction process is broad. It does not necessarily reflect a global asymmetry in state-space, but may convey purely local effects of mutation, e.g., the role of transition-transversion bias in parallel adaptation cited earlier ; or of aariation  can be cariation . Finallyariation .Two caveats are in order. First, one should not over-estimate the domain of origin-fixation dynamics, nor the relevance of mutationist thinking. While the notion of two perfectly distinct steps— origin and fixation— allows for conceptual clarity, and has encouraged useful models and software, it is an idealization, strictly applicable only in imaginary cases. Furthermore, the underlying conception is not a sufficient basis for a comprehensive theory. That is, the architects of the MS excluded mutationism and proclaimed that all of evolution could be reduced to “shifting gene frequencies”, but we must not make the complementary mistake of imagining that all of evolution can be reduced to an origin-fixation process or to the mutationist conception of selection (#3). While new mutations always are accepted or rejected, ultimately, they aren’t always accepted or rejected in such a way that evolution follows origin-fixation dynamics .Second, to call into question the MS is not to call into question the body of purely analytical truths, known as theoretical population genetics, with which the MS is commonly confused. Instead, the arguments above relate to the MS as a conjectural theory, and to its verbal theory of causes. Relative to the purely abstract truths of theoretical evolutionary genetics, the essential claim of the MS  is approximately equal to the conjecture that evolution can be understood as though its state-space were limited to the domain of classical quantitative genetics. This conjecture ultimately fails, yet there are some realistic cases in which selection drives quasi-continuous change in quantitative traits indefinitely, based on abundant small-effect variation from many loci, thus we need not discard Darwin’s concept of natural selection as a shape-shifting force. Likewise, we need not discard the concept of mutation as a mass-action force: there are realistic scenarios in which a mass-action pressure of mutation is the properly conceived cause of some effect, such as the loss of a gene , or the However, as a general theory of evolutionary causes, the “forces” view is insufficient, and this insufficiency is not remedied by adding chance, contingency and constraints, which are vague explanatory principles, not causes. “Chance” obviously is not a force or cause. “Constraint” is not a force, nor is it any positive cause, but a condition indicating that an imaginary ideal is unsatisfied. “Contingency” is likewise not a cause, but a conceptual placeholder indicating the inapplicability of an ahistorical idealization in which systems reach global equilibria independent of their initial conditions. Patching up the MS with constraints, chance and contingency expands its scope to cover a wide range of cases outside of the core paradigm, yet this expansion entails such an enormous loss of rigor and clarity that the result does not deserve the name of “theory”. Is there anything— evolution, politics, planetary motions, bridge-building— that cannot be explained by the theory of population-genetic forces when it is combined with the 3 catch-all principles that outcomes are contingent on initial conditions, constrained by various factors, and subject to chance?The concept of constructive neutral evolution (CNE) was proposed originally to have both a direct significance  and an indirect significance, as a conceptual tool for exploring the evolutionary role of factors other than positive selection. In the former guise, CNE models provide an alternative to adaptive rationales for some cases of seemingly inordinate complexity. This aspect of CNE will be of interest to those working on systems such as RNA pan-editing or gene-scrambling.For the rest of us, CNE exposes an alternative conception of evolutionary causes. This conception is not based on the “shifting gene frequencies” paradigm of the MS, but instead partakes of the mutationist view of evolution as a 2-step proposal-and-acceptance process whose kinetics depend directly on the introduction of novelty by mutation-and-altered-development. This conception, which is not unique to CNE, now lays claim to important theoretical, experimental, and practical results bearing on the kinetic link between evolution and mutation. Its most striking result is the potential for mutation-biased adaptation shown theoretically in ,42 and oThis innovation has emerged without fanfare, its significance masked by its historical association with molecular sequences and with neutrality.th century neo-Darwinian consensus due to its lack of concordance with Darwin’s views. The result is a curious disconnect between what some of our most interesting and productive models imply about evolution, and what our textbooks say. The MS theory of causal forces urges us to choose between the opposing pressures of mutation and selection. By contrast, within the 2-step view, we can understand evolution differently, as both an expression of internal tendencies of variation and, at the same time, a response to conditions mediated by differential reproduction.Nevertheless, it would be a mistake to conclude that is has no particular significance. The evolutionary 2-step shares many of the implications of the “mutationist” view that appealed to the founders of genetics , but wasThe author declares that he has no competing interests.The author notes that, in response to comments from my colleague David McCandlish, I have made a minor change of wording in one sentence, and I have deleted a rhetorical question that had a misleading implication (regarding the reasons that Orr quotes Bateson’s statement on the sizes of changes in evolution).Reviewer’s report 1Alex Kondrashov, University of MichiganIt is hard for me to provide a useful review for this manuscript, because it consists, almost exclusively, of rather general reasoning, instead of precise, falsifiable statements. I do not see much value in almost-philosophical consideration of “Modern Synthesis” and “neo-Darwinism”, whatever these expressions might mean. I fully agree with the original claim of the author, made in 1999, that fixations of effectively neutral alleles may result in something new and that limitations imposed by availability of mutations on the outcomes of adaptive evolution are crucial . Statements of this kind were made many times , but heAuthor’s response:Kondrashov’s position is that professional scientists already agree on the implications of selection, mutation and drift, and have no need of the kind of “discussions of basic principles” found in my article. In other words, to the extent that my article explains implications of theoretical evolutionary genetics, and interprets results in terms of abstract causal processes, Kondrashov does not object, but finds it trivial, on the grounds that everyone knows this already. Where others might see complex schemes, difficult concepts, and problematic choices, Kondrashov sees the same basic principles underlying everything. Thus, he sees no novelty in my 1999 paper, but only the same principles underlying many prior sources.The aspiration to derive a common understanding of causation from basic, universally accepted principles may be a laudable ideal, but as a description of reality, this view is indefensible. The reality of scientific practice is that selection, mutation and drift are not basic principles with universally agreed implications, but complex concepts freighted with history and metaphor, whose implications are disputed and problematic. For instance, if one simply consults the contemporary Oxford Encyclopedia of Evolution, the topic article[provides multiple conflicting descriptions of natural selection, including as a “theory” entangled with Darwinian assumptions . Evidence that the implications of such concepts are not a matter of universal agreement is given in my article, e.g., cases in which evolutionary biologists make mistakes due to the influence of an “opposing pressures” argument that goes back to Fisher and Haldane. I listed several principles of causation that follow under origin-fixation conditions, and stated that these principles will not be found in any textbook .c articleprovides Thus, while Kondrashov may find my comments about evolutionary causes rather obvious, I doubt that they will be so obvious to everyone, and clearly they have not been obvious in the recent history of our field.Reviewer’s report 2Eugene Koonin, National Center for Biotechnology InformationIn my opinion, this is a truly excellent article that presents an exceptionally clear and well-written account of constructive neutral evolution, its underlying mechanisms and implications. A fully convincing case is made for the major role of CNE in evolution and ‘creative’ role of mutational biases. I particularly like the simple entropic argument for the virtual inevitability of the emergence of ‘complexity’ (or simply mess) via CNE. I have no objection to any of the statements in this article. I would only like to add that the contribution of mutations to evolution does not stop at biases. It is clear now that a variety of mechanisms exist for directing mutations to specific targets that are relevant for adaptation under the given conditions. This results in a plethora of Lamarckian and pseudo-Lamarckian processes that substantially contribute to evolution .Author’s response:As Koonin helpfully notes, the concept of "mutation bias" (which merely implicates non-uniformity) is distinct from the idea of non-uniformities in variation that arise from programmed responses to conditions, and thus evoke the ideas of Lamarck.While my article may have convinced some of the “major role of CNE in evolution”, I was aiming only to explain it more fully. CNE is an abstract schema for generating neutral models, and a conceptual tool for exploring ideas about causation and explanation. In the former guise, it suggests some interesting models that are largely ignored, except in the case of gene duplication (due to the independent efforts of Lynch and colleagues). The adaptationist program tends to ensure that, to the extent that neutral models are apt, their distinctive conditions and dynamics are incorporated into the next generation of adaptive models. My hope is not that CNE will win a greater share of the complexity market, but that it will cause us to re-think how we frame evolutionary questions (and answers).Reviewer’s report 3Johann Peter Gogarten, University of ConnecticutI first read about Constructive Neutral Evolution (CNE) in Arlin Stoltzfus's 1999 paper "On the possibility of constructive neutral evolution"  – I had Both of these topics, CNE and the conflict between proponents of the modern synthesis and the mutationists, are reviewed in the current manuscript. The manuscript then discusses the concept of forces acting on gene frequencies and provides a clear discussion of bias in the introduction of variants, which is better understood as a two step proposal-and-acceptance process. I particularly liked the demonstration that mutation biased evolution need not be neutral evolution. My only suggestion for improvement concerns the initial description of selection in the mutationist framework as "a stochastic filter (a sieve or pruning hook) that modulates the chance of survival of spontaneously arising mutants, some of which get lucky". A little bit more details and explanation will make it easier for the reader to parse this rather dense description.i in the denominator on the right hand side of the equation should be μj.And in equation 1 the μAuthor’s response:I have made the suggested correction in Eqn 1. In regard to understanding the mutationist concept of selection as a sieve, it may be helpful to note that this was offered  to contrast the Darwinian notion that variation supplies only raw materials for a creative force of selection that shapes a mass of variations, the way that a human hand would be said to shape a sand-sculpture— the character of individual grains of sand is unimportant in this process, both because the grains are small relative to the whole, and because they are never moved individually. The key aspects of the mutationist conception are that (1) the issue is framed in terms of the ultimate fate of distinctive individual mutants, (2) the role of “selection” is to modulate this fate, and (3) this modulation is stochastic, i.e., beneficial variants are not guaranteed of success, nor are unfavorable  ones guaranteed of failure. Statements from Morgan and others that document this view may be found in[ found in.This Perl script will compute a graph showing the inversion paths between all (scrambled and unscrambled) configurations of a segmented gene .Click here for file


Choices not only reflect our preference, but they also affect our behavior. The phenomenon of choice-induced preference change has been of interest to cognitive dissonance researchers in social psychology, and more recently, it has attracted the attention of researchers in economics and neuroscience. Preference modulation after the mere act of making a choice has been repeatedly demonstrated over the last 50 years by an experimental paradigm called the “free-choice paradigm.” However, Chen and Risen  pointed  Individuals not only behave according to their preference , but their choice behavior also affects their preference . This process of choice-induced preference change is traditionally explained by cognitive dissonance theory  even without any change in true preference  because the participants’ choice during the choice task has additional information about their preference, which can bias measured preference change , and then rates the same items again an hour later (second rating task). If we randomly pick two items  and those whose rating is likely to decrease . Thus, the free-choice paradigm could be measuring systematic preference change  even in the complete absence of a change in true preference.According to Chen and Risen , the argIt should be noted that in the free-choice paradigm, preference change after a difficult choice between two items with similar preference was typically compared with preference change after an easy choice between one liked and one disliked item. Studies typically show a spreading of alternatives that is larger after a difficult choice compared to an easy choice, which is consistent with the prediction by cognitive dissonance theory . However, this is also what is expected by the methodological artifact because easy choices provide much less “additional” information about a participant’s true preference compared to difficult choices , then chose items among pairs (choice), and finally rated the items again (second rating). Each item was assigned a “true preference score.” Importantly, we assumed that true preference remains stable across the three phases, and therefore the spreading of alternatives found in our simulation study can never be attributed to the effect of choice or cognitive dissonance on true preference. In the first rating phase, we added random noise to the true preference score to generate a “temporal preference” score and paired the items that are closely matched. That is, we paired the items that receive the same ratings on a 10-point scale  was repeated 10,000 times, and the averaged results are plotted in Figure This hypothetical experiment  than choosing an unattractive item or rejecting an attractive item. In other words, our simulation showed that the pattern of ostensible preference change produced by the artifact exactly matches the pattern predicted by cognitive dissonance theory . On the other hand, random noise in the second rating task works to mask the difference in the true preference inherent in chosen and rejected items . As a result, the magnitude of the random noise in rating is expected to have an inverted-U shaped effect on the spreading of alternatives . The second parameter is the magnitude of the random noise in the choice phase. This parameter basically reduces the difference between chosen and rejected items, as true preference would have less influence on choice with larger random noise  were categorized as “chosen” or “rejected” on the basis of a choice between each of the two items and another item, not by direct comparison . That is, items a and item b were each paired with another item (h or l), and participants made choices between a and h, and b and l. Items h and l were selected from a set of items based on the first rating; reported preference for h was higher than a, and reported preference for l was lower than b (h > a = b > l in the first preference rating). Therefore, participants were likely to choose h over a, and b over l. Then, preference change between the first and second rating were compared between the rejected item a and the chosen item b. Importantly, if one of choices in the a-h and b-l pairings was not as expected, the four items were excluded from the analysis .The third strategy  have the same preference rating in the first rating task (h = a = b = l). If participants picked h over a, and b over l, the second preference ratings for rejected items (a and l) are likely to decrease while ratings for chosen items (b and h) are likely to increase. Thus, although no choice was made between a and b, we can still predict that the second rating for b is likely to be higher than a . Just like the differential level of artificial spreading of alternatives for easy and difficult choice conditions seen in our simulation  were . The closer the reported preferences between a and h, and b and l, the more additional information choices can reveal, and thus the larger the spread of alternatives by the artifact. This seems to fit with their findings that spreading of alternatives generally decreases as the difference (D) in reported preference between a and h, and b and l increases, thus suggesting that the implicit choice method is susceptible to the artifact.Unfortunately, although the information about relative preference between a as rejected and item b as chosen). Because there is no selection bias in this case, the artifact should not produce preference. In other words, the findings from the implicit choice method are considered to be valid only for the results from this robustness check analysis. Alós-Ferrer et al. (vice versa).It should be noted, however, that they also conducted an additional analysis that they called a “robustness check.” In this analysis, they included all items regardless of the participant’s actual choices by treating them as if all of choices were as expected from the first rating . The behavioral experiments conducted by Chen and Risen (Q(3) = 0.618, p = 0.89. Importantly, the integrated effect size is statistically significant, but small in magnitude based on the conventional criterion . This effect size is also substantially smaller than that reported in the recent meta-analysis, d = 0.61, 95% CI = (0.55, 0.66; Kenworthy et al., It is worth noting that the magnitude of the effect is substantially smaller than that reported in previous studies when researchers appropriately used these methodologies to address Chen and Risen’s  critiquend Risen  exhibitend Risen  and Sharnd Risen  utilizednd Risen . This innd Risen . Accordind Risen  to compund Risen . The effn Cohen, , d = 0.2So far there are three ways of addressing the criticism, and each has produced evidence that choice-induced preference change truly exists. However, the effect size is considerably smaller than what had been previously shown. It is also important to note that not all studies using these methods provided sufficient evidence. As stated above, the Rate-Rate-Choose condition is probably not a good way to control the effect of information revealed by choice especially when testing for long-lasting preference change. Furthermore, although Alós-Ferrer et al.  tried toIt is important to note that Chen and Risen’s  argumentTherefore, at least some of results of past studies using the traditional free-choice paradigm are in question. In addition to the original study by Brehm , investiThe effect of explicit memory about past choice has been investigated by comparing normal control participants with amnesic patients (Study 1 in Lieberman et al., Using the free-choice paradigm, many social psychological studies have investigated the effect of moderating factors on choice-induced preference change as a measure of dissonance reduction. The studies typically compare preference changes between two or more conditions with different experimental manipulations (e.g., choice importance, choice reversibility, etc.; e.g., Brehm, The same argument applies to past studies comparing preference change between two groups of individuals with different personalities (e.g., Gordon and Glass, Three fMRI studies previously investigated which brain regions during the choice task (Jarcho et al., Past studies have also examined across-participant correlation between choice-induced preference change and other variables (e.g., Gawronski et al., As reviewed above, the extent to which the criticism by Chen and Risen  affects Recently, Kenworthy et al.  conducteFinally, it should be noted that although a number of past studies did not address the criticism by Chen and Risen  as stateChen and Risen  pointed The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Implicit in this formulation is that a system that drives appetitive pursuit toward needed resources is essential for survival. Dopamine is the go-and-get-it neurotransmitter. In it's association with addiction and compulsive behavior— a “hijacked reward system”— dopamine has become neuroscience's version of Freud's id, driving appetitive pursuit without regard to consequences.If dopamine were a politician, it might have an image problem. The organizing metaphor for dopamine function is modulatory. That is, dopamine adjusts these functions, which begs the question to what end? The impulse behind this research topic is that the “root” function of dopamine is not to drive reward behavior, but rather to adjust reward oriented behavior in order to achieve adaptive behavioral flexibility. That is, dopamine evolved to adapt reward pursuit, not blindly drive it like a catecholaminergic id. From this perspective, compulsive pathology arises from the loss of dopamine's capacities to adapt appetitive behavior to the environment. Instead of thinking of dopamine as a “reward neurotransmitter,” we might just as well consider it a “flexibility neurotransmitter.” This is not merely semantic but can reframe the questions we ask, how experiments are designed and how data are interpreted. However, conceptual frameworks for thinking about dopamine and behavioral flexibility are not as well developed as those that emphasize dopamine and reward.However, some evidence suggests that dopamine is not essential for basic reward related behaviors. Even with diminished dopamine transmission, animals still like food, still eat, and can still learn about rewards. Dopamine is not at the root of these functions; rather, it is activation of D2 receptors facilitates flexible behavioral responding and appears necessary for restoring sensitivity to changes in outcome value; that is, necessary for updating value associated with actions and subsequent behavior. Similar to Nelson, Barker found, conversely, that antagonism of D1 facilitated flexibility. These studies, together, suggest that D1 may facilitate exploitation of prior learning while D2 may promote behavioral flexibility. Klanker et al. (The papers in this research topic highlight several themes relevant to viewing dopamine as a neurotransmitter that has evolved to promote flexibility in the service of appetitive pursuit. Fundamental to behavioral flexibility is the ability to strike the right balance between exploiting acquired knowledge and exploring to update one's knowledge, the so-called explore-exploit dilemma, which dopamine may regulate (Beeler et al., r et al.  systematr et al.  report aOf course, the dopamine system is not monolithic. Although we may abstract general themes, as above, other papers in this topic remind us that dopamine contributes to a mosaic of functions. In a review of its role in prefrontal function, Floresco  challengBaudonnat et al.  take a sfear to signaling safety, once the animal learns to avoid the aversive stimulus, engaging dopamine incentive learning.Associated primarily with signaling positive, rewarding outcomes, what role does dopamine play in altering behavior in response to deleterious outcomes? Oleson and Cheer  review rFinally, returning to pathology in the dopamine system, Cepeda and Levine (Chen et al., id of neurotransmitters, dopamine emerges more as the brain's chief comptroller in energy allocation (Beeler et al., The traditional view of dopamine as the “reward neurotransmitter” has, in recent years, been gradually evolving. Through the work of many, dopamine is increasingly framed in neuroeconomic, decision-making terms (e.g., Gan et al.,


Foreign body granuloma is a reaction to either a biodegradable substance or inert material. In a breast cancer patient who had undergone an excision or mastectomy with axillary clearance, a foreign body granuloma in the axilla may be misinterpreted as an axillary lymph node. We report our experience with a case of cotton-ball granuloma of the axilla in a breast cancer patient, which mimics a lymph node radiologically from the CT scan, mammogram and ultrasonography. Following biopsy and excision, the mass was diagnosed histologically as a foreign body granuloma. Lymphadenopathy is a common clinical finding and can usually be explained by concurrent infection. However, in a known carcinoma patient, it needs to be investigated as the possibility of recurrence or metastases. Although very rare, foreign body granuloma in various parts of the body can be confused as a tumour , 2, 3 duThis paper highlights a case of an axillary mass where a foreign body granuloma, following reaction to cotton material, was thought to be a recurring axillary lymphadenopathy in a patient with previous history of breast carcinoma, who had undergone previous wide local excision and axillary clearance.Madam RS is a 62-year-old female who presented to the hospital for investigation of a non-palpable right axillary mass that was noted incidentally on computed tomography (CT). She had a history of right breast carcinoma and has had a right wide local excision and axillary lymph nodes clearance done in a private centre six months earlier. She was not on any hormone replacement therapy and there was no family history of carcinoma. She attained menarche at nine years old and a hysterectomy had been done seven years earlier for uterine fibroid.She was otherwise well and was referred to the authors’ institute for adjuvant chemotherapy and radiotherapy following her surgery. Upon completion of her treatment, a contrast-enhanced CT scan of the thorax, abdomen and pelvis revealed a well-defined soft tissue density mass measuring 1.7 cm in the right axillary region . There wA mammogram done one month later showed an irregular high density mass in the right axillary region . No otheThe biopsy specimens were inadequate for proper diagnostic interpretation by the pathologist. However, with the gross finding of “cotton-like” material during the biopsy, the patient was scheduled for an exploration of the right axilla one month later. At surgery, a mass with a fibrotic capsule was found in the axilla adjacent to the site of previous surgery and revealed a ball of cotton fibre within . FurtherA foreign body granuloma is a reaction to immunologically inert material that can be exogenous, like suture material, gauze, talc, silicon or fragment of a tile –5, or enInert material is usually asymptomatic or found as a suspicious mass either symptomatically or as an incidental finding on imaging. Foreign body granulomas have been reported to mimic neoplasms in the body. In breast surgery, although uncommon, foreign body granulomas from surgical material have presented as neoplasia-like findings which can cause diagnostic controversy particularly in a patient with known history of breast carcinoma , 5, 6. OThe authors’ literature review found only two cases of foreign body granuloma in the axilla that mimicked a mass. Adams et al.  reportedSonographically a foreign body granuloma usually appears as a well-defined hypoechoic mass with/without posterior acoustic shadowing, and may mimic a lymph node if found in the axilla –3, 5, 6.As shown in this case with all the imaging modalities, radiologists can confuse an axillary foreign body granuloma as a suspicious mass, carcinoma or lymphadenopathy. In this case, the presence of a solitary “recurring lymph node” in a patient who had undergone axillary clearance also suggests that the mass cannot simply be explained as a lymph node. Although foreign body granuloma is rare, it is worth considering in the differential diagnosis. Only by doing a biopsy and, if necessary, a surgical excision, can the diagnosis of a foreign body granuloma be confirmed histologically.


The theory of speciation is dominated by adaptationist thinking, with less attention to mechanisms that do not affect species adaptation. Degeneracy – the imperfect specificity of interactions between diverse elements of biological systems and their environments – is key to the adaptability of populations. A mathematical model was explored in which population and resource were distributed one-dimensionally according to trait value. Resource consumption was degenerate – neither strictly location-specific nor location-independent. As a result, the competition for resources among the elements of the population was non-local. Two modeling approaches, a modified differential-integral Verhulstian equation and a cellular automata model, showed similar results: narrower degeneracy led to divergent dynamics with suppression of intermediate forms, whereas broader degeneracy led to suppression of diversifying forms, resulting in population stasis with increasing phenotypic homogeneity. Such behaviors did not increase overall adaptation because they continued after the model populations achieved maximal resource consumption rates, suggesting that degeneracy-driven distributed competition for resources rather than selective pressure toward more efficient resource exploitation was the driving force. The solutions were stable in the presence of limited environmental stochastic variability or heritable phenotypic variability. A conclusion was made that both dynamic diversification and static homogeneity of populations may be outcomes of the same process – distributed competition for resource not affecting the overall adaptation – with the difference between them defined by the spread of trait degeneracy in a given environment. Thus, biological degeneracy is a driving force of both speciation and stasis in biology, which, by themselves, are not necessarily adaptive in nature. Although selection-driven heritable phenotypic divergence is the key mechanism of adaptive evolution, prolonged evolutionary stasis is common in populations remaining in stable or near-stable environments -8. EvoluIn addition to stabilizing selection, the theory of canalization suggests that “the constancy of the wild-type must be taken as evidence of the buffering of the genotype against minor variations not only in the environment in which the animals developed but also in its genetic make-up” . In otheBoth stabilizing selection and trait canalization are adaptive mechanisms. However, alternative explanations are also possible. For example, canalization may be a result of constraints that are imposed by the developmental process, which are controlled by a network of interacting transcriptional regulators . In thisAlthough prolonged stasis and rapid differentiation are diametrically opposed in their effects on population diversity (the former narrows and the latter broadens the heterogeneity of phenotypic characters), the underlying mechanisms of these two processes are not necessarily conflicting. Moreover, there is a possibility that common mechanisms contribute to these opposing processes, which must be viewed together as periods of “punctuated stasis” rather than independent evolutionary processes. One important mechanistic commonality in prolonged stasis and rapid diversification is the apparent suppression of certain trait values.In the evolutionary divergence of new species, intermediate, or transitional, forms are suppressed and, ultimately, excluded. Darwin reflected “… that species come to be tolerably well-defined objects, and do not at any one period present an inextricable chaos of varying and intermediate links …” . HoweverA similar concern applies to static populations. As discussed above, static populations converge toward trait homogeneity. As a result, outlying trait values – analogous to transitional forms in divergent evolution – are rare. Whether through stabilizing selection, trait canalization, or due to constraints imposed by complex network interactions, stasis is defined by removal of diversifying trait values. Thus, there appears to be a commonality between, on the one hand, diversification of traits in divergent evolution and, on the other hand, homogeneity of traits in evolutionary stasis. In both cases, certain trait values are suppressed, and the suppressed values are those that substantially deviate from the population mean – either from the mean trait values in the newly formed groups in the divergent dynamics (the intermediate forms) or from the mean trait value of the static population  of certain forms. Darwin focused on elimination of intermediate forms through competition in his argument that “the range of inhabitants of any country by no means exclusively depends on insensibly changing physical conditions, but in a large part on the presence of other species … with which it comes into competition; … each species on the confines of its range, where it exists in lessened numbers, will, during fluctuations in the number of its enemies or of its prey, or in the nature of the seasons, be extremely liable to utter extermination; and thus its geographical range will come to be still more sharply defined.” He then convincingly illustrated his point with an example of artificial selection of three varieties of sheep: the mountain, hill, and plain breeds (see pages 136–137 in ). This eThere are at least two immediate questions that need to be addressed regarding these considerations. One, how exactly do two units  with different trait values come into competition? Competition among individuals carrying the same trait values is intuitively understandable, because the same trait value is equivalent to a requirement for the same resources, such as food, space, or mates. However, two individuals with different trait values will presumably be dependent on two different qualities of the resource. Using the well-known Lamarckian example, two giraffes with similar neck lengths will compete for foliage at the same altitude above the ground, whereas two giraffes with different neck lengths will consume foliage at different altitudes and thus should not compete. Therefore, inter- and intra-specific competition leading to suppression of transitional and diversifying forms, respectively Figure , needs aWe propose that the phenomenon known as trait degeneracy centrally contributes to suppression of transitional and diversifying forms in diverging and static populations, respectively. Moreover, we argue that these two modes of suppression are manifestations of the same mechanism. Gerald Edelman, whose pioneering ideas have inspired this entire field of research , has defpopulation of functional responses manifested by an individual. Of critical importance, the individual ranges of degeneracy can overlap, suggesting that the degenerate – not exactly similar and not completely different functionally – units will compete for the resource in the overlapping regions. Realistic degenerate populations are much larger than the simplified case shown in Figure Degeneracy is an intermediate state between diversity and redundancy. In degeneracy, diversity is present, but each of the diverse elements is not perfectly unique and is partially similar to other elements of the group. Redundancy is also present, but, unlike completely redundant groups, the elements are not exact copies of each other and partially differ. Degeneracy may also be defined as functional micro-diversity of individual elements in a group or population so that structurally unique elements of repertoires function similarly to other elements. In biological populations, genotypes are diverse, but phenotypes, through their functional flexibility, are degenerate . A simplDegeneracy is a fundamental feature of biological systems, which is centrally important for their reliability and adaptability and, according to Edelman, “both necessary for, and an inevitable outcome of, natural selection” -35,39. DThe central role of degeneracy is directly supported by Mason’s reasoning on the “Cambrian explosion” . ReferriPreviously, we have pointed out that, in addition to these obvious benefits of trait degeneracy for populations, it adds one more feature, distributed competition for resources ,32-35. TTo estimate the possible effects of degeneracy on populations, consider a simple one-dimensional population in which individuals are characterized by a single trait. The population is diverse, with individuals differing in, and definitively characterized by, their specific trait values. The trait defines the ability to consume a diverse resource, which can also be plotted on the same scale of values. For example, a plant foliage resource is distributed above the ground—short, medium, and tall grasses, short, medium, and tall bushes, and short, medium, and tall trees. Correspondingly, herbivorous animal populations are distributed on the same scale, from small rodents to giraffes. Such distributions do not have to be merely spatial. For example, one can plot a distribution of small prey  according to how fast they escape from predators . The predators will then be distributed according to their average speed in chasing prey. In a similar fashion, one could distribute all antigens and their corresponding antigen-specific recognizers (antibodies or T cell receptors).Realistically, any distribution of resource has limits. In the foliage distribution example, there are obvious limits to how short or tall plants can be. Consider a simple rectangular resource distribution within a certain range and a population that is also evenly distributed on the same axis according to the trait values Figure . In the Starting with the same initial population, different dynamics would be expected depending on the type of degeneracy. Consider a population in which the range of trait degeneracy is substantially narrower than the distribution of resource . However, in the absence of non-local, degeneracy-driven competition, local competition would occur only among the individuals with identical trait values , and the growth of peripheral subpopulations would ultimately catch up with that of the central subpopulations. These considerations suggest that the frequently observed static trait homogeneity -8 may beS of a single characteristic, or trait, of cellular automata  containing a resource that these organisms require for survival and propagation. Reflecting the finite amount of resource in this Verhulstian model, the carrying capacity K is distributed in S according to K(s), where individual locations s ∈ S. Organisms are also distributed in the same space according to N(s). In this generalized model, S may be (but does not need to be) a geometric space. S may represent non-geometric traits, such as antigenic properties of immunogens, a particular quality of food, or the receptor-binding characteristic of a ligand. S may also represent physical space in which case K(s) could be a distribution of vegetation (food for herbivores) along a river bank or at various altitudes on a mountain. In a specific case, K may represent the amount of livable physical space for the organisms at a given location s. The only characteristic of organisms and of resource units in this model is their individual location.The model is a one-dimensional “universe” represented by space N, where t is time, at any location s0 will be independent of any other location in S, and the dynamics of the overall population of organisms will be characterized by a series of mutually independent logistic growth curves, each at a separate s:In a trivial version of this model with strict specificity of resource consumption, the relationship between units and resource is defined by their individual locations. If the location of a unit is the same as the location of resource, the unit will attempt consumption of that resource. If their locations differ, consumption of resource is impossible. Thus, population dynamics r is the Malthusian growth rate. Since the units are characterized solely by their location, r is location-independent and universal for all locations and thus is a characteristic of the system rather than of subpopulations at various s. The more general case of location-dependent r(s) is not considered here.where s′ consumes resource degenerately across S, so that the maximal resource consumption will still occur at s′, yet consumption is also possible at other locations s according to the degeneracy function f , a unimodal kernel function, which is non-negative, piecewise continuous, even , integrable, and normalized; that is, ∫S f (s)ds = 1. In the specific implementations of the model discussed below, the Gaussian function was chosen to approximate degeneracy, that is, σ defines the “degeneracy range” and is referred to as such below.The purpose of our model, however, is to analyze the effect of degenerate resource consumption on population dynamics. In this more complex version, a unit located at s′ in the absence of units at any other location, the carrying capacity will increase due to such degenerate resource consumption and will become Ks' = ∫ f K(s)ds. For simplicity of notation, the integration here and below is taken over S unless otherwise indicated. As stated above, the individuals in the population are characterized by a single trait, which is their preferred location for resource consumption and defines their own location in S. With this consideration, the units do not differ in their ability to consume resource degenerately, meaning that the degeneracy function does not depend on the absolute values of s and s′ and will be a characteristic of the system as a whole. This consideration leads to an important simplification: the degeneracy function is universal for all units in the system, is location-independent, and depends only on the distance between the organism and resource, f (s–s′) . The more general case of location-dependent f  is not considered here. In an even more general case, also not considered here, different units at a given location may differ in their degeneracy. The dynamics of such an isolated subpopulation with degenerate resource consumption will then be:For a single subpopulation at S, meaning that more than one subpopulation is present and that any two units located at s′ and s′′ may compete for resource at s due to degenerate resource consumption. Thus, degeneracy leads to a new kind of competition. In addition to competition among similar units, various subpopulations now compete for resource at various locations through degeneracy. The latter phenomenon needs formal description.Realistic populations, however, are distributed in s0 by all units of the population. In order to perform this analysis, we will utilize the notion of “demand,” defined as the amount of limitless resource that would be consumed in the absence of any competition. The demand for resource at s0 by units at s′ will be proportional to f (s0 − s′)N(s′), whereas the overall demand for resource at s0 by the entire population will be proportional to ∫ f(s0 − s′′)N(s′′)ds′′. Due to the stated equality of the competitive abilities of the units, the total carrying capacity at a location s0, K(s0), will be distributed among various consumers according to their demand for that resource. The fraction of de mand for resource at s0 by a subpopulation N (s′) in the overall demand for that resource is s0 that is available to N(s′) is Consider consumption of resource located at th order) integration to find the solution.Finding solutions of this differential-integral equation analytically would require non-trivial approaches. Therefore, we utilized numerical  similar to the resource above, whereas the trait degeneracy range is universal for all automata. The flow of time is cyclical, represented by iteration cycles. Each automaton  is processed at each cycle, with the important caveat that the order of processing is randomized at every cycle. The resource is “consumed” by cellular automata during a cycle, but is restored to the initial state at the beginning of each cycle. During each cycle, each cellular automaton:• expends a constant fraction of previously consumed resource for self-maintenance (“cost of living”);σ defining the degeneracy range around the automaton’s location; if resource is available at the degenerately selected location, a constant unit of resource is consumed (carried over from the resource array to the automaton);• attempts to feed (consume resource) at a location that is randomly selected using a Box-Muller Gaussian random number generator, with • if the balance of accumulated resource (the result of expenditure and consumption above) becomes equal or less than zero, the automaton “dies” and is no longer considered;• if the balance of accumulated resource exceeds an established constant threshold, the automaton “self-propagates,” creating a copy of itself.This implementation is similar to the previously reported approach ,31.σ representing the degeneracy range; the value of σ was the same for all locations s and did not change with time; and a rectangular static resource (carrying capacity) distribution was analyzed. All implementations of the model have been validated by testing the case of degeneracy σ=0, with the results showing the trivial solution – a series of identical independent logistic growth curves as predicted in Figure To preserve the focused scope of this study, several specific limitations were imposed: only a Gaussian degeneracy function was considered, with σ=60 is shown in Figure σ=120, as shown in Figure σ=60 is shown in Figure σ=120, as shown in Figure Initial simulations considered the cases of narrow and broad degeneracy values  of such a distribution denoted as “mutability.” Due to mutability, an initial population represented by one or a few individuals spreads with time across the spectrum of trait values Figure . This veWe investigated a model of degenerate resource consumption in diverse populations placed in a stable homogenous environment. Analytical and cellular automata implementations of the model have been tested. The results suggest that degeneracy of a heritable phenotypic character – a preference for a particular kind of resource – leads to distributed competition for resource. This degeneracy-driven distributed competition facilitates either divergent dynamics or homogenous stasis, depending on the relative dispersions of trait degeneracy and resource distribution. The solutions are stable in the presence of limited environmental stochastic variability or heritable phenotypic variability. Importantly, the observed behaviors – either heritable phenotypic divergence or stasis – did not change the overall adaptation of the population in that they did not affect the total population size or the overall efficiency of resource consumption.Such a role of degeneracy in population dynamics was not initially predicted in the early works that were concerned with the contributions of degeneracy to reliability in stable environments and adaptability to novel environments ,29. In tThere are several implications to these findings. One, these results add specifics and significantly expand Darwin’s explanations to the difficult question, “why do species exist?” By considering the contribution of degeneracy-driven competition, we add important details to Darwin’s argument for the role of intra- and inter-population rivalry in suppression and, ultimately, exclusion of intermediate forms. Two, our results suggest that the same mechanism plays a key role not only in the emergence of diversification, but also in maintaining population stasis. In both cases, an environmental change is not required, and the population behavior – either divergence or stasis – is defined solely by degeneracy in relation to the overall environment. Three, these findings suggest that observed rapid (in evolutionary terms) transitions between prolonged evolutionary stasis and rapid diversification -8,10,11 An important limitation is that only asexual reproduction has been modeled, as the “offspring” are exact copies  but notspecies” ); this aspecies”  discuss The model has other limitations, and additional work is needed to more fully understand the nature of degeneracy-driven dynamics in populations. A one-dimensional – considering only a single heritable phenotypic trait – model has been considered here. Realistic degenerate units are multi-dimensional and characterized by numerous traits; these traits may also interact in a pair-wise or more complex fashion. The results of this work are purely theoretical and computational, and will need to be confirmed with experimental and observational evidence. Experimenting with degeneracy may be challenging, as general practical approaches have not yet been elaborated, and quantitative measures of degeneracy are yet to be defined. Various resource distributions, static and dynamic or uniform and non-uniform, need to be assessed for their effects on population changes in order to better approximate real-world resources. Populations with mixed, heritably retained degeneracy ranges  need to be tested to better approximate real-world populations. As a theoretical exercise and in preparation for the degeneracy-driven technologies of the future , it woulThe results of this model-based study suggest that the two major modes of evolutionary process, dynamic diversification and static homogeneity, may both be driven, in a stable environment, solely by degenerate competition for resource. The results also suggest that the elimination of transitional forms in divergent evolution and the preservation of heritable trait heterogeneity in phenotypic stasis are not driven by adaptive forces but are both the result of the same mechanism stemming from the degeneracy of heritable phenotypic traits. The observed competitive suppression and, ultimately, competitive exclusion define whether a population splits into two or more subgroups or, alternatively, preserves its integrity while becoming more homogenous. The relative dispersion of degeneracy versus the dispersion of resource distribution defines whether the population undergoes diversification or stasis. If the degeneracy of resource consumption is comparable with the range of resource distribution, the population will remain static, and the competitive pressure stemming from degeneracy will increase trait heterogeneity. If the dispersion of degenerate resource consumption is substantially smaller than the range of resource distribution, the population will diversify into several groups, with transitional forms suppressed due to the same degeneracy-driven competitive pressure. As such, static homogeneity and dynamic diversification are two outcomes of the same process, with the difference between them defined by the dispersion of trait degeneracy in a given environment.The authors declare that they have no competing interests.All authors have made substantial intellectual contributions to this study. NA, MSA, and FA contributed to formulation of the model, analysis and interpretation of the results, and preparation of the manuscript. NA and SPA implemented the model in software. SPA conceived of the study, formulated the model, and analyzed and interpreted the results. All authors read and approved the final manuscript.