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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 1  |  Issue : 1  |  Page : 14-23

Genotype, environment, and evolutionary mechanism of diseases


1 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine; Department of Pathology, Wayne State University School of Medicine; Karmanos Cancer Institute, Detroit, USA
2 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit; Division of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, USA
3 Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

Date of Web Publication14-Apr-2016

Correspondence Address:
Henry H. Q. Heng
3226 Scott Hall, 540 E. Canfield, Detroit, MI 48201
USA
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Source of Support: None, Conflict of Interest: None


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  Abstract 

Large-scale genomic projects have unexpectedly challenged the current approach of focusing on genes in disease studies. As common gene mutations are difficult to identify for common/complex diseases, and the diagnostic distinction of gene profile between “normal” and “patient” becomes increasingly blurry, the power of gene-focused studies in medicine is actually decreasing. More attention is now being focused on gene–environment interaction. However, such a transition is still within the framework of using molecular descriptions of specific genes for understanding diseases, which is challenging in the clinic, where nonlinear relationships are dominant. In this article, we define diseases as genotype/environment-induced variants that are not compatible with a current environment. This explains (1) why the genotype is not simply the gene mutation profile, but comprised of multiple levels of genetic/nongenetic (including epigenetic) variations, as environmental dynamics require all sorts of system modifications; (2) why many disease conditions represent a trade-off of cellular adaptation, in addition to inherited or environment-induced bio-errors; and (3) why costly variants function as the “insurance policy” for adapting to the unpredictability of environments. This leads to the general mechanism of the majority of diseases: genotype–environment interaction generates variations, which are either essential for future crises or useful for current cellular function. Unfortunately, as a trade-off, these variants also contribute to diseases. This general mechanism can unify diverse specific molecular mechanisms, and suggests that the goal of eliminating all diseases is not only impossible, but also comes with the potential negative consequence of reducing the heterogeneity essential for human survival.

Keywords: Evolutionary mechanism of diseases, fuzzy inheritance, genotype, heterogeneity, phenotype, system inheritance


How to cite this article:
Heng HH, Regan S, Ye CJ. Genotype, environment, and evolutionary mechanism of diseases. Environ Dis 2016;1:14-23

How to cite this URL:
Heng HH, Regan S, Ye CJ. Genotype, environment, and evolutionary mechanism of diseases. Environ Dis [serial online] 2016 [cited 2018 Jul 23];1:14-23. Available from: http://www.environmentmed.org/text.asp?2016/1/1/14/180332


  Introduction Top


Since the first identification of a gene mutation responsible for human disease by positional cloning,[1] the mechanistic research of diseases has shifted to an understanding based on molecular genetics. In particular, illustrating how gene mutations cause disease become mainstream research.[2],[3] The rationale is simple: If genes are mainly responsible for phenotypic traits, and various gene mutations are the molecular basis for diseases, then the identification of these gene mutations is of ultimate importance, as it will certainly lead to effective diagnosis and treatment. One strong point of support for favoring genetic studies in disease comes from the infectious diseases research community; since the 1980s, there has been a growing recognition that for virtually all infectious diseases, human genetic susceptibility or differential resistance plays an important role.[4] To push this rationale further, the Human Genome Project (sequencing phase) was also achieved,[5] leading to various large-scale-omics and the excitement of system biology.[6],[7],[8],[9],[10] The hope was that by cataloguing the entire sets of genes/proteins/pathways, we could identify all abnormal genetic parts, and therefore understand the molecular mechanism of most diseases.

Surprisingly, however, despite the fact that there is a handful of well-known clinical success stories based on gene identification, large-scale postgenomic research has been disappointing in delivering results to medicine;[11] furthermore, increased massive-omics data have unexpectedly challenged the very rationale of searching for gene mutations to improve our understanding of the human diseases,[12] which was supposed to offer effective and target-specific treatment.[13] First, the cloning of disease-specific genes has not so far directly helped patients in the majority of cases. One notable example is the cystic fibrosis story. Over two decades have passed since the gene related to this disease was cloned. However, the resulting treatment has been disappointing.[14] Second, for the diagnosis of many common diseases, the identified genetic markers provide only limited diagnostic value. When 101 genetic markers (single nucleotide polymorphisms that are associated with genetic risk score) were used in clinical research based on more than 19,000 individuals, with a follow-up of over 12 years, the predicting power of these markers was not significantly associated with the incidence of total cardiovascular disease.[15] Ironically, the combinational prediction power of these hard-to-identify markers is less than a simple question can bring: Have your family members had heart disease (based on self-reported family history)? Third: The reality of genetic research is that even the identification of common genetic markers is much more difficult than we previously thought.[8],[16],[17],[18],[19] Many large-scale whole genome scanning projects only reveal limited common markers, and when all significant markers are put together, they can only explain a small portion of genetic contributions.[20] On the other hand, for most common and complex diseases, many more statistically significant genetic loci (thousands of them) are continuously discovered, which makes individual prediction based on identified variants much less useful. One example is the cancer genome sequencing project. Not only is the mutation profile a long-tail pattern of distribution, with most driver mutations displaying low penetrance in patient populations, but also nearly all drivers are moving targets, such that “drivers” and “passengers” are constantly changing due to the dynamic evolutionary process! This situation has led to a heated discussion about the issue of the missing heritability as well as future strategies.[20],[21] It further raises doubt toward the genetic determinism that is based on the power of gene-centric concepts, a continuous discussion of the issue of “nature versus nurture.”

To explain these big surprises, which are hard to interpret based on the theoretical framework of traditional gene theory, many ideas are up in the air, including collecting more samples, developing even more powerful computational programs, focusing on nongenetic (such as epigenetic) factors, and monitoring the network with a group of genes.[9] Another renewed trend is to study gene–environment interaction. It seems logical to make use of the dynamic environmental influence on genes to explain the reduced power of individual genes in the attempt to understand diseases.

While it is in the right direction to study how environments contribute to disease, in practice, it is rather challenging to link specific environments to diseases, especially in quantitative fashion. For example, except for some strong and consistent factors, such as smoking and bacterial/viral infection, the linkage between many other environmental factors and cancer is modest or weak based on population studies. The majority of researchers are still focused on individual genes, and by creating a specific and often extreme experimental environment, the importance of gene mutation in diseases can be artificially illustrated. These seemingly convincing linkages between specific animal models and environmental factors often can make headlines for the general public, but their limitation is obvious. There are limited efforts being made to directly compare how much a given gene mutation or environmental factor can contribute to a specific disease in a specific model and its role in the reality of the disease. To change the landscape of studying gene–environment interaction, we need to correctly understand how an individual organism, as well as an individual cell, passes genetic information, and what the genotype–phenotype relationship really is, especially within the context of evolutionary selection. In particular, what is the common basis for diseases, and why is it that by and large, the environment is more important than genetic profiles for the majority of the human population? The understanding of these questions will not only reconcile many seemingly conflicting observations, but will also shine new light on the research of how gene/genome/environment interactions contribute to human disease. It will further help us to determine how to use this knowledge to improve diagnosis and treatment methods, and more importantly, for the prevention of most common and complex diseases or illnesses.

On the occasion of launching a new scientific journal that is dedicated to the topic of the environment and diseases, it is better to consider some seemingly simple, but often ignored, and in fact, quite challenging questions. In particular, it is both essential and timely to rethink these questions in the context of the genome theory of somatic evolution, and in the face of the massive data from various omics, as these are not easily explained by the traditional genetic framework.[10],[19],[22],[23],[24]


  What Is Disease? Top


The term disease broadly refers to an impairment of the normal physiological function of a tissue/organ, organ system, or of the body and mind, in the context of genetic or developmental errors and unfavorable environmental factors (i.e., infection, poisons, and nutritional deficiency or imbalance). Disease is often associated with specific physiological responses and/or pathological changes caused by stress.[8],[13],[16],[24] It is now acknowledged by many that it is rather difficult to define diseases, and similarly, to define the opposite of disease (that is, health), as these concepts are both dynamic and fuzzy. It is additionally worth noting that whether people consider or believe themselves to be ill or “abnormal” varies with social class, gender, ethnic group, proximity to support from family members,[25] age, personal tolerating ranges, and living environments. The definition of disease can also change with advances in science or social standards, including new diagnostic tools. Furthermore, the definition of disease becomes more challenging when considering most common and complex diseases. In contrast to defining infectious diseases, where the causative factors and symptoms are highly specific and characteristic, many common and complex diseases are associated with various conditions, and the symptoms are highly diverse as well.

Based on the appreciation of the ultimate importance of genetic heterogeneity to human species' adaptation and survival, we would like to define disease as genetic–environment interaction-generated variable phenotypes, which display functional disadvantages, discomfort, and/or harmfulness, when they are less fit in the current environment (note, nevertheless, that some potential benefits could be achieved in very different environments). With this more neutral tone of definition, some new perspectives have become obvious to us.

First, many disease conditions or variable phenotypes exist as a package deal, with both potential and current advantages and disadvantages, even though some are more obvious than others in a given environment. For example, an unstable mind can be associated with both creativity and mental problems; the dynamics of the immune system can either lead to cancer or autoimmune diseases or both.

Second, many disease conditions represent the trade-off or price to pay for the very survival of the cell or organism.[8],[24],[26] When the additional dimensions of human culture/behavior are included, many factors, from smoking, alcohol addiction, and drug abuse, to indoor tanning with a ultraviolet bed, may lead to health problems. Fundamentally, cells need adenosine triphosphate for cellular function, but they also have to accept the consequences of bio-wastes generated from energy production, some of which can damage tissue or lead to cancer. Genetic variation is needed for cellular adaptation, but altered genomes also increase the risk of cancer; an adventurous lifestyle is associated with both excitement and increased risk. Even some seemingly minor factors could have profound negative impacts. For example, some unhealthy foods/beverages are convenient and sometimes addictive, but also harmful to long-term health status.

Third, it is difficult to even realize that, while representative of unfortunate circumstances for some individual patients, having many genetic variations in the human population is essential to ensuring the necessary degree of heterogeneity or robustness (regardless of the good or harm to some individuals in current conditions), which could ultimately contribute to the existence of humanity. In other words, a certain level of genetic heterogeneity is the insurance policy of potential adaptation that humanity has to have, despite its costs to some individuals' luck, as most of the potential benefits are unknown in current environmental conditions. In a sense, an individual who displays a less fit phenotype in current environments is, in fact, paying the price for being variable, which is important for human diversity. Thus, science should not consider the option of eliminating all disease-related variants. It is impossible, as well as dangerous. Putting all these together, to define disease, we need to understand the genotype, the past/current/future environments within both somatic and organismal evolutionary contexts, and individual and population (including societal) perspectives.


  How Should We Define Genotype? Top


Based on the concept that phenotype is equal to genotype plus environment, disease phenotype can be defined by the following relationship:

Disease phenotype = Disease genotype + environments (1)
or = Predisposition genotype + environments (2)
or = Normal genotype + environments (3)

It used to be simple to define genotype based on Mendelian genetics.[8] The characterization of disease genes has been the central focus of molecular genetic studies for decades. Category (1) suits typical Mendelian single gene diseases, where the environment mainly affects the disease phenotype severity. Most common and complex diseases belong to categories (2) and (3). There are many examples of category (2) in hereditary and familial cancers, for example. Perhaps category (3) represents most cases of human diseases, where environmental conditions seem to play a dominant role. Many sporadic cases of various diseases belong to this category. Since the postgenomics era, however, the characterization of genotype has inadvertently become more complicated. Genotype is clearly not just equal to gene mutations. Furthermore, most diseases are not just caused by a combination of multiple gene mutations. Now, despite the efforts that have been made to identify multiple genes/genetic loci using large-scale methods such as whole genome scanning and sequencing, it is challenging to pinpoint the common genes responsible for a given complex disease. Such a situation has even challenged the definition of inheritance.[8],[19],[20] During the search for disease genes as well as the missing heritability, four interesting observations have emerged.

First, the importance of epigenetic impact on disease has received increased attention.[27],[28] Since the epigenetic system is more sensitive to environmental stressors than gene mutations, it is logical to use this layer of inheritance to study the stress response and its impact on metabolism or other biological features. Interesting examples include established epigenetic linkage between early life exposure/experience and adult health decades later, as well as explanations of trans-generational inheritance through epigenetic mechanisms. It is clear to us that for diseases that involve micro-cellular evolution, the epigenetic mechanism will play an important role. Since studies of epigenetics are well-discussed in current literature,[29],[30],[31] it will not be the focus of our discussion.

Second, it is gradually being realized that genome-level alterations are overwhelmingly present in different normal and aged tissues, especially in tissues with disease phenotypes. In fact, these striking observations were made decades ago,[32] but were not given enough attention.[8],[33] Based on the precision of the genetic concept, these observations do not make sense, and it was assumed that all these “outliers” would be eliminated and were thus unimportant.[34] That is also the reason why, since we have focused on the characterization of genome-level alterations in cancer evolution, few have paid attention.[35],[36],[37],[38] This situation began to change following the important realization that the genome context or karyotype itself represents a new type of genetic coding: The system inheritance.[19],[39] If the gene only codes for “part inheritance,” but not the “system inheritance” or the blueprint of how genes interact, these altered karyotypes are fundamentally important.[8],[39] Recently, the aneuploidy/polyploidy status of normal tissue has been “rediscovered” by molecular analyses.[40] Increased reports have illustrated the importance of aneuploidy in yeast.[41] Furthermore, cytogenetic analysis has revealed genome chaos,[35],[36],[42] which has also been confirmed by cancer genome sequencing; indeed, a number of new terms have been used to describe this phenomenon, such as chromothripsis, chromoplexy, chromosome catastrophes, and structural mutations.[43],[44],[45],[46],[47],[48] It is important to point out that various molecular cytogenetic analyses have again led to the characterization of genome-level alterations in diseases. A few groups, including ours, have pushed the concept of using increased nonclonal chromosome aberrations (NCCAs) to monitor genome instability in cancer and other diseases or illnesses.[10],[19],[36] Meanwhile, illustrating the importance of somatic mosaicism in human diseases has led to many exciting discoveries.[33],[49],[50],[51] Together, these observations challenge the precision of the genetic information at various genomic levels.[8],[29],[39],[52]

Third, the high degree of multiple levels of genetic and nongenetic heterogeneity supports the new concept of fuzzy inheritance. One major discovery of various genome sequencing and omics projects has been the unexpected extent of genetic heterogeneity. In fact, even prior to the arrival of massive amounts of data, this point had been realized by some groups.[39],[53] This high degree of genetic diversity cannot be simply explained by genetic errors, especially because NCCAs can be commonly detected from normal individuals. Based on the systematic comparison of how cells pass karyotypes, we realized that in cancer, when the genome is unstable, it is impossible for the same karyotype to be precisely passed, even from mother cells to daughter cells. Interestingly, the newly formed cell population displays similar degrees of heterogeneity, despite the fact that specific chromosomal aberrations are not inherited. Furthermore, the altered genome displays a new pattern of transcriptome, which explains the mechanistic link between genome alteration and evolutionary potential.[54],[55] Importantly, the linkage between cellular adaptation advantages and genome alteration was established, which states that increased genome alteration is not simply a mistake, but the evolutionary choice of the bio-system under stress.[8],[24],[26] Since the environment is constantly changing with little predictability, the genotype must have a certain extent of plasticity. Based on the evidence/concepts described above, we have come to the conclusion that genetic information, by and large, is not that precise in evaluating phenotype, as we previously thought. We have thus named the less precise genetic inheritance as “fuzzy inheritance.” Specifically, fuzzy inheritance defines a specific range of potential genetic changes, but not a specific, fixed change. This concept needs to be applied to the gene and epigene levels of bio-information to explain the heterogeneity at these levels, especially in normal tissues.

It is also important to consider the factors of both change and constraint in evolutionary force. It seems that higher levels of genetic organization can serve as a constraint for lower-level parts. For example, the genome can function as a constraint for gene mutations. Since the key is to maintain a certain degree of heterogeneity with the potential for adaptation, good or bad effects will be determined by the future. Tissue/organ/system homeostasis can function as a constraint on the genome. Ultimately, the balance of necessary dynamics and constraint for a given species is achieved by the separation of germline and somatic cells. According to the genome theory, at the somatic cell level, fuzzy inheritance-mediated alterations are important for cellular adaptation, which is encouraged by selection. By evaluating the literature, it is clear that fuzzy inheritance is overwhelmingly detectable from various bio-processes. For example, at the chromosomal level, all aneuploidy, defective mitotic figures (DMF), sticky chromosomes, and giant nuclei, as well as a large array of chaotic genomes and their dynamic changes, contribute to fuzziness.[56],[57],[58],[59],[60],[61],[62],[63] At the RNA level, the diverse profiles among individual cells are also associated with the fuzziness from sperm to cancer cells.[64] There are many examples in between.[8],[56],[63] Meanwhile, to maintain the species' identity, the function of sexual reproduction serves as a gatekeeper to eliminate all accumulated alterations at the somatic level.[65],[66],[67]

Fourth, what is the normal genotype anyway? Personal genome projects have revealed a big surprise: Most “normal” individuals display a high level of gene mutations.[68] Recent cancer genome projects have further confirmed this.[8] In some types of normal tissue, the mutation rate is quite high.[69] When combined with copy number variations, genome alterations, and somatic mosaicism, and especially when single cell profiling is included, the degree of genetic and nongenetic changes is beyond our imagination.[49],[56],[70] Based on this evidence, it is starting to make sense why the environment plays a major role in human diseases, as most of the evolutionary potential will be fulfilled by environmental interaction-mediated evolution. It appears that gene mutation itself does not necessarily contribute to diseases, since many gene mutations are without detrimental impact during the cellular evolutionary process, wherein the genome package, rather than individual genes, is selected upon. Moreover, most gene mutation is de novo, and gene mutations (both germline and somatic mutations) come and go, due to both the repair system and internal fuzziness of genetic information. As long as the genome is maintained, the range of genetic change is inherited, and this represents the best evolutionary strategy. This idea strongly supports the concept of fuzzy inheritance.

Fifth, there is yet another layer of complexity regarding the genotype. Now, the human microbiome is considered by some as part of human hologenomes.[71] Despite the fact that microbiome research represents an exciting frontier and is long overdue,[72] caution is needed to understand its quantitative contribution in the real world rather than in experimental models. Such concern is based on the following observations/considerations: (1) It is easier to demonstrate its impact in model systems than in patients and (2) for complex systems, many factors can be linked to their features, but it is usually hard to identify one among many associated factors as the magic bullet. For example, bacterial population dynamics can be linked to many factors that can be linked to disease as well. (3) After many decades of molecular characterizations, many popular ideas, as well as “that is it” moments, have come and gone like fashion. Therefore, a critical evaluation of the feasibility of using the microbiome in predicting diseases in the clinic (not just based on linear experimental models) is needed. It is important to investigate, for example, to what extent specific micro-organisms contribute to the evolutionary selection of hosts. Who controls who and in what degree? (Specifically, is the human genome selecting the microbiome, or the other way around, or is selection based on the interaction package? Microbiomes of animals/plants can be considered a living environment which can impact many features of the hosts, but why are these types of environments so different from others?) Does the host–microbiome interaction-mediated degree of heterogeneity matter the most, rather than any specific interaction? Should the microbiome be considered as an environmental component, no matter how many types and numbers of them there are? (Similarly, should the number/type of animals/plants surrounding humans be included as part of the hologenome?) When compared to the multiple types and levels of genome heterogeneity (which so far have been largely ignored), which type of impact is more significant?

Altogether, it is clear that the environment can actually alter the genotype itself, possibly through regulating the plasticity of the genotype or even directly modifying the genome by adding/integrating genetic parts. In the case of the extreme example of macro-cellular cancer evolution, the environment clearly can change the fuzzy inheritance.


  How Do We Define Environment? Top


Environment is a rather general term in the discussion of diseases. It can refer to geography, season/weather, food, natural and artificial exposures, living conditions, social interaction, and micro-cellular conditions. Despite the fact that environment is a seemingly simple concept, its impact on health is rather complicated, and some important hidden links among different types of environments have been slowly revealed.

  1. For many common and complex diseases, the environmental impact dominates. In contrast, genomic data alone are insufficient for predicting most diseases.[8],[16],[37] This observation, however, does not dismiss the important contribution of genetic components, but rather supports the importance of fuzzy inheritance.[8],[52] If we accept the concept of fuzzy inheritance, then for most noninfectious and non-Mendelian diseases, there should not be a one-to-one relationship between gene and disease in the first place. The environmental impact within an evolutionary platform can generate an array of disease phenotypes within the defined range of fuzzy inheritance
  2. The linkage between cellular evolution and all types of environmental impacts is the level of stress with decreased specificity, which increases the evolutionary potential of the cell population. Such potential is beneficial to cellular function through adaptation, but also, paradoxically, is harmful by favoring disease conditions, representing a typical trade-off package. Increased evidence supports the idea that stress is necessary for cellular function, but too much is harmful.[73] The key is the balance of homeostasis.[24],[26] This viewpoint that the overall system stability is more important than some specific molecular pathways also offers explanations to the benefit of a healthy lifestyle (including regular/suitable exercise, good nutrition, stable social relationship, and a reduced-stress environment). Currently, there are interesting studies that link exercise with the regulation of the inflammation-immune axis, micro-environments, and tumorigenicity.[74] At the same time, exercise can also be linked to reduced body fat,[75] reduced daily stress, slowing down aging, and many other factors. We think that the key hidden benefit might be the overall system homeostasis, which can be explained by diverse specific factors. For example, nutritional imbalance will impact the energy level, and lower energy can lead to instability (Heng, unpublished observation).[76] Nutritional status can also be linked to some molecular pathways, again recapitulating the concept that all individual factors can lead to genetic/nongenetic variations, as predicted by the evolutionary mechanism of cancer [77],[78]
  3. The importance of social environments has been ignored, due to the challenge of linking it to a specific molecular causation. A related issue is the study of an individual's mind–body interaction. Recently, more studies have linked disease recovery and survival rate to social environments and psychological factors. Based on the genome theory, these factors can function as system constraints
  4. When discussing the environment–disease relationship, one important aspect is the dynamism of environmental changes. In addition to the association studies that link health explicitly to a “good” or “bad” environment, the duration within this specific environment (including during the developmental stages, which are more sensitive to a given environment) and the transition time/frequencies of shifts back and forth among different environments are also important. Recent studies have illustrated that the stability of the family environment (and not just purely the social economic status) in earlier childhood living conditions has a significant impact on health status in later adult life.[79] Interestingly, each change represents an initial stressful condition, regardless of the direction of switching.[24],[80],[81] Furthermore, during this drastic switching, the average behavior and outliers' behaviors are very different. This idea requires more attention in medicine, as the implication is obvious when using drugs to control symptoms. The most drastic treatment should be avoided for many common and complex diseases that took years to develop, as treatment itself could function as a powerful stress to patients
  5. Due to above complexities, the knowledge derived from various well-defined animal models is rather limited for improving understanding of diseases in the real world, where genetic and nongenetic factors, including environments, are highly heterogeneous.[8] Future research efforts that depend on animal models need to intentionally include this high level of heterogeneity
  6. There is a need to broaden the definition of environments for disease studies. Any environmental stresses should be considered, as long as they can impact cellular evolution, regardless of their involvement in mind–body interaction, microbiomes, and genome heterogeneity itself. Significantly, in general, the genotype–environment interaction is not separable, as they are actually dependent on each other. Many indirect environmental factors can change the system constraint above the genome level, leading to a change of the genotype–environment interactive relationship.



  What Is The Common Mechanism Of Disease? Top


The brief discussions above of genotype/environment/diseases phenotype can lead to a realization of the general mechanism of diseases.

First, whether or not a given genetic variation will display increased or decreased fitness depends on the environment. Second, many genetic alterations will not display phenotypic advantages or disadvantages in the current environment until some significant additional stresses are introduced. This explains the large amount of genetic variation observed in seemingly normal individuals. Third, for common and complex diseases, many specific molecular mechanisms can be involved in and contribute to the disease, which makes it challenging to precisely predict clinical outcomes based on limited factors. This point has been forcefully illustrated by cancer research, where the evolutionary mechanism of cancer needs to be explained as the collection of all diverse individual molecular mechanisms. This concept not only unifies a large number of molecular mechanisms,[77],[78],[82] but also links stress-induced genome instability, cellular adaptation, and evolutionary selection to diseases.[24],[26],[63] Interestingly, such a principle is now being applied to other diseases,[24] as all of these phenomena are characteristic of common and complex diseases. Fourth, multiple levels of genetic alterations are not just the result of bio-errors (and in particular, genetic errors), but are achieved through many diverse mechanisms of cellular heterogeneity essential for the adaptation. Specifically, these are achieved through the “stress and fuzzy inheritance interaction.” Fifth, despite the disadvantage for many individuals, genetic variations are fundamentally important for the robustness of human beings, and will not be (and perhaps should not be) completely eliminated.

The general relationship of genotype/environments/diseases can be illustrated as follows:

Disease phenotype = disease genotype (gene + epigene + genome) + environmental interaction within the context of evolutionary selection (including normal physiological changes, i.e., from early development to the aging process, and incidental events that place a high level of stress on the bio-system, such as infection, wound healing, and the imbalance of homeostasis due to immune/metabolic responses). Note that disease genotypes are highly dynamic due to fuzzy inheritance, while the genetic–environmental interaction-generated variants are essential both for cellular adaptation and for the formation of various types of diseases. By applying this principle, we have observed elevated stochastic chromosome aberrations from patients of Gulf War illness and chronic fatigue syndrome (Heng, unpublished observation).[19],[24],[33],[83]

Classifying the genotype into different categories is of importance, especially within the somatic cell evolutionary context, as the choice of monitoring the correct level of genotype depends on micro- or macro-cellular evolutionary phases. For micro-evolution, monitoring gene mutations and epigenetic changes is effective, while studying genome-level alterations is appropriate for macro-cellular evolution. In addition, when both genome- and gene-level alterations are involved, the genome often has a more dominant role.

Since the genome is rather stable during organismal evolution, as it is mainly constrained by the function of sexual reproduction,[8],[65],[66],[67],[84] gene mutations/copy number variations and epigenetic changes become more dynamic than chromosome/genome changes in the germ line. Because environments are constantly changing, and the plasticity of a given genotype is limited, the capability of increasing genetic and nongenetic variation at the somatic level becomes the key for biological adaptation. That is the reason that all types of genetic alterations, and particularly chromosome-level aberrations, can be frequently observed in somatic cells. This is especially significant for understanding genetic variation-mediated diseases. Drastic environmental changes may define or influence which types of diseases dominate in human history (based on the environment and our ability to deal with them). We have suggested that diseases and illnesses will always remain challenges to us, although the disease spectrum will likely be different.[8],[26],[39] For example, with the development of antibiotic agents, the major disease spectrum has shifted from infectious diseases to metabolic diseases, including cancer. The spectrum will further shift to mental diseases.[8] It is likely that in the future, human beings will face increased challenges and will have to deal with different unfit variations unique to future environments. Clearly, the diseases or disadvantageous phenotypes that were present during earlier hunting activities over 2 million years ago differ from those of humans traveling for decades continuously in future spaceships. All these examples of unfitness are defined by the interaction of the environment and the human genetic landscape for different individuals.


  Future Perspective Top


The new trend of studying genomic/environment interaction to illustrate the mechanisms of diseases is truly exciting. The understanding of the disease–genotype–environment relationship will shed light on the understanding of “Nature versus Nurture,” the centuries-long topic of debate. The emergence of molecular genetics has over-emphasized the importance of genotype. The characterization of various disease genes in fixed environments has downplayed the environmental contribution, as many identified genetic alterations can be linked to a certain degree of causation of disease only in such artificial conditions. The idea that “every disease is caused by genetics” has been popular for decades. Now, genetic determinism has faced its biggest challenge, as for most common and complex diseases, the common genetic causes are difficult to identify, the nature of the genetic blueprint is not defined by genes, and genetic information, by nature, is fuzzy.[8],[33],[56],[63]

While it is clear that the overall strategy must be to study the genomic/environmental interaction of disease, this is not an easy task. First, both genetics and the environment are not fixed but highly dynamic. For a long time, the genotype was incorrectly considered as the genetic profile of the germline; an individual's genotype was regarded as having very limited changes in its life time, and genotype diversity among tissues was ignored. Now, as we know that multiple genetic alterations are common for each individual, and that the somatic cell population can accumulate numerous genetic alterations during somatic evolution, a new technical platform is needed to study this highly dynamic process. One priority is to study the difference between germline and somatic cell-mediated inheritance among different tissue types, and the interaction between these processes in the context of disease evolution and organismal evolution. For most genome-wide association studies, for example, the determination of genotype is mainly based on limited somatic cell types. While this can capture the overall instability of somatic cells, it is challenging to link a large number of variants to specific features that are not closely associated with genome instability. Another important example of this concept is the debate about applying gene-editing methodology (such as the clustered regularly interspaced short palindromic repeats) to correct disease genes. The potential risk is the “off-target effect.” When we compared a few cell lines after they had been through the gene-editing procedure, we found that the genome itself had been altered (Heng, unpublished observation)! This observation is striking, as the altered genome could have biological consequences. We have previously linked various molecular specificities to general stress-induced genome instability and its evolutionary potential.[24],[80] It is thus not so surprising that gene editing is linked to genome alterations. On the other hand, however, since there is a separation between germline and somatic cells, and sexual reproduction serves as a filter to purify significant genetic alterations, altered genes within the human population likely will come and go; that is, as long as we do not allow altered genomes to pass through the germlines,[13],[84] gene editing will not lead to a new species, despite the fact that it is likely that the good wishes of editing a bad gene will lead to some unexpected bad phenotypes. Second, if most genetic alterations only contribute to disease moderately, then environmental stress should be more important. This fact will downplay the importance of genetic profiling, despite that fact that it is easier to profile gene mutations for an individual than it is to elucidate the environmental impact using specific molecular terms/mechanisms. In addition, genetic–environmental interaction is a stochastic process, and each run of somatic evolution could be different, especially during the punctuated evolutionary phases that are associated with pathological changes.

Even though it might take a generation or two to change the current gene-centric paradigm, there are some immediate actions that can be taken. To accept the importance of genomic–environment interaction in disease, one has to adapt the evolutionary framework and methodologies to monitor the process of disease progression.[8],[85],[86] In particular, rather than determining the gene mutation profile (which is often continuously changing), one needs to focus on system behavior, such as the overall stability of homeostasis and the evolutionary potential. Recently, increased investigators have actively promoted the concept of considering healthcare a complex adaptive system, which feeds back on itself.[87],[88] Such a concept, combined with evolutionary medicine,[89],[90],[91] will play an important role in future medicine. Of equal importance, methodologies are needed to identify the patterns of somatic cell evolution (punctuated or stepwise), which differ among individual cells and cell populations, within normal physiological conditions or stochastic pathological conditions.[8] Furthermore, new technologies must be developed to deal with the key challenge of the multiple levels of genetic and nongenetic heterogeneity,[10],[29],[92],[93],[94],[95] and especially the domination of aggressive outliers.[8],[96],[97]

Scientific expectations need to be changed as well, as one has to acknowledge both the high degree of uncertainty in biological processes, and that any medical intervention (especially those that are powerful in effect) could also function as a trade-off. Researchers need to try harder to bridge the gap between basic research and the reality of the clinic, and one key strategy is to seriously consider the reality of the environment. Finally, the research community should let the general public know that the most important step in medicine is prevention. Lifestyle changes are the most effective means to this end, rather than trying to fix a gene or pathway. It is difficult to change individual genes for achieving a specific phenotype, as the emergent properties are far beyond individual genes, but it is within our reach to change the patterns of individual/society–environment interaction to prevent, manage, and reduce the burden of managing various diseases.

Financial support and sponsorship

This article is part of a series of studies entitled “The mechanisms of somatic cell and organismal evolution.” This work was partially supported by the start-up fund for Christine J. Ye from the division of hematology/oncology, University of Michigan.

Conflicts of interest

There are no conflicts of interest.

 
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What Is Disease?
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