Snap, phenotype, genotype and fitness - Gene Expression
Environmental factors do not change the genotype of an animal directly, Exploring the genotype-phenotype relationship of livestock to explain .. power to detect genetic variants associated with the trait of interest (quote). This uniqueness is a result of the interaction between our genetic make-up, inherited factors and coined the terms 'genotype' and 'phenotype' in ( identical) twins to investigate the genotype/phenotype relationship. overly simplistic theories of genotype±phenotype Two issues are at stake: how direct the relation der, for example, the following quote by Pinker ().
In this paper the authors aim to fix that problem. To explore genetic interactions in hybrids, and how they effect gene expression, they selected the genus Antirrhinum as their model. They observe the effect of taking genes from a set of species and placing them in the genetic background of another.
Just as they focus on a specific genus of organism, so they also focus on a specific set of genes and the molecular and developmental genetic phenomenon associated with those genes. Variance in gene expression simply defines the concrete difference in levels of protein product.
Insertion of transposons can abolish gene expression, resulting in removal or alteration of function. What is that function? I added the labels. B and F approach wild type, but the other outcomes are more mixed. Note the genotypes in the small print. Table 1 measures the expression levels of the gene product for the various genotype: The process is not reversed.
Finally, the heterozygote states does result in reduced dosage of the gene product. Though the phenotypes might be closer to wild type than the mutant, the molecular expression of the gene is substantially changed. This is one of the issues which is always important to remember: On a molecular level there is incomplete dominance. On the level of exterior morphology there is more perceived dominance.
This is not even addressing the issue of pleiotropy, where the same gene may have dominant and recessive expression on two different traits simultaneously in inverted directions i.
Figure 1 shows the different allelic expression levels in hybrids of Antirrhinum species. But what about the impact of the combinations on phenotype? Note that the wild-type, C, lies on a plateau while the double heterozygote, E, is on the slope. Triangles pointing upwards indicate species showing notch phenotype. C Enlargement of rectangle in B. As I note above the mapping between the manifestation of genetic variation on the molecular level and on the gross morphological level may be subtle.
Figure 4 has the two genes under consideration forming a plane through the x and z-axes, while gross morphology is illustrated on y-axis. So the interval 0 to 1 in phenotype space is a good gauge as to the deviation of the morphology from wild type.
The letters in panel A are representations of the letters in the first and second figures within this post. G represents the double homozygote mutant.
The idea of dominance and recessiveness already indicate that not all genetic variation is created equal, and that there are non-linearities in the interaction of genetic variation and phenetic variation. Panel B seems to be similar to L. The circles in panel B represent conventional hybrids between A.
There is variation in gene expression levels within these hybrids, but note that they reside on the phenotypic plateau. In contrast, the triangles show double heterozygotes: The heterozygote combinations are for a variety of species, as indicated in the figure text.
Note that they explore more of the phenotype type space, as evident in panel C, which is just an zoom of the rectangle in panel B. Additionally, wild type hybrids move in the gene expression dimension, but not in the phenotype space.
So next they looked at the impact of a particular species CYC and RAD genes against the majus genetic background in the doubly heterozygote state. Figure 5 shows the results of such a cross: The result of these studies show that alleles from A.
This is because of underlying gene expression differences across species. The development of the MPO in provided the first formal ontology for the description of mammalian phenotypes. The combination of a well-formed ontology and the manual curation to the ontology carried out by Mouse Genome Informatics MGI curators has meant that the mouse is still probably the best phenotypically annotated vertebrate. Several strategies for mapping of MPO to human phenotype terms have been developed.
Problems with disambiguation of gene names, conceptual dissonance between the terminologies and semantic inconsistency within MPO show some of the drawbacks with this approach. Nevertheless, the possibility of mapping a large number of terminologies via UMLS in a single mapping is very powerful. This approach can be used as a way of identifying equivalent terms in different terminologies for both intra- and cross-species data integration.
To a great extent the almost exclusive use of lexical matching for knowledge extraction and cross-species phenotype bridging in phenotype analysis was determined by the lack, untilof a widely applicable HPO [ 25 ].
Such an ontology could be used in direct annotation or computational markup and data extraction from documents and on-line resources such as OMIM. However, the harmonization of these vocabularies is an ongoing task and until recently it has not been possible to integrate or co-analyze annotation date from these sources.
Additional formal nomenclatures are being developed, notably for dysmorphology [ 44 ]. The issues are not simply those of establishing straight mappings, though that is difficult enough, but where there are large evolutionary distances between species, bridging to the most closely related phenotypes.
For example, cardiac defects such as the tetralogy of Fallot are closely related in human and mouse, but while the syndrome is impossible in fish due to the different anatomical structure of the fish heart, other cardiac morphological defects may well be the consequence of dysregulation of the same morphogenetic processes in all three organisms.
It is useful to include such related defects in the analysis. This requires a way to provide rich, explicit and consistent descriptions, so that automated systems are able to process and distinguish the meaning of their terms and use them to infer new information.
The problems with the use of lexical matching and lack of a formal ontology for human phenotypes have now been resolved with the much needed development of the HPO [ 25 ]. We now have phenotype ontologies for the mouse, yeast, worm and fly, all of which are available from the Open Biological and Biomedical Ontology OBO foundry http: In recent years an approach has been developed to circumvent the species specificity of the phenotype ontologies using matching of logical definitions for classes within each ontology rather than text.
The definitions utilize species-agnostic ontologies such as GO to provide a common semantic level at which they can be integrated into a single framework [ 4849 ] and a post-composition strategy termed Entity—Quality EQ. Rather than using a precomposed ontology such as HPO, phenotypes may be described using the EQ formalism [ 49 ]. In the EQ method, a phenotype is characterized by an affected Entity from an anatomy or process ontology and a Quality [from the Phenotype and Trait Ontology PATO ] that specifies how the entity is affected [ 48 ].
The affected entity can either be a biological function or process as specified in GO, or an anatomical entity. The Zfin database uses the EQ method exclusively to capture phenodeviance [ 50 ], but these statements may be used as logical definitions for classes within a phenotype ontology. Once their classes are formally defined, phenotype ontologies may be linked through common or related cross-product definitions and striking concordances may be discovered between the phenotypes of different species.
This method was successfully exploited by Washington et al. They showed that, based on the subsumption of classes in the ontologies and the frequency of annotation, they could detect other alleles of the same gene, other members of a signaling pathway, and orthologous genes and pathway members across species through the similarity of the phenotypes, demonstrating a proof of principle for the EQ approach.
More recently, a whole-phenome approach to comparative phenomics was developed exploiting the full semantic content of ontologies [ 54 ]. The method requires the formalization of anatomy and phenotype ontologies so that they can be integrated using the parthood relation followed by the generation of a single, unified and logically consistent representation of phenotype data for multiple species annotated to the species-specific phenotype ontologies within a single semantically coherent framework, amenable to automated reasoning [ 55 ].
The ontology contains more than classes and more than a million axioms, including classes for 86 complex phenotype annotations drawn from the model organism databases and OMIM.
What Influences Phenotype? | Sciencing
A great advantage is that the ontology can be regenerated to include new phenotype annotations and future developments of all of the constituent ontologies, and a tool to query the data has been made available on http: This method is the first to be able to allow automated reasoning over all of the phenotype ontologies and the gathered ontologies involved in the logical class definitions. It permits a simultaneous survey and computation over all of the phenotype data available from the main model organism and human databases.
The network can be used to successfully identify orthologous genes through related phenotypes, and genes involved in the same pathway as well as genes giving rise to the same disease. It is clear that the manual annotation of MGD represents a gold standard for literature annotation to a precomposed phenotype ontology. In contrast, the heterogeneity and in some case sparseness of annotation in OMIM is problematical. First, the documentation of phenotype information in scientific databases and publications needs to be further standardized.
While species-specific phenotype ontologies are being applied in several model organism databases, it is a major challenge to unify these phenotype ontologies across species. The EQ approach based on the PATO ontology has been successfully applied to several model organism databases as well as to formally define classes in species-specific phenotype ontologies. Moreover, PATO has been demonstrated to support cross-species integration and comparison.
It would be desirable to further align phenotype ontologies across species based on the PATO framework, to improve mappings between species-specific anatomy ontologies and to develop new phenotype ontologies based on the PATO framework so that ontologies immediately connect to the existing web of cross-species phenotype knowledge. The second area requiring further development is the establishment of an infrastructure for the representation, processing and analysis of phenotype information.
Large-scale reasoning over phenotypic information enables highly expressive queries across multiple domains, but is limited by the complexity of phenotype descriptions.
Modularization approaches, efficient reasoning and reasoning servers may help to allow access to phenotype information [ 55 ]. Further extensions include semantic web service frameworks [ 56 ] and general tools to create, edit and analyze information about phenotypes without requiring knowledge about the structure of the underlying ontologies. Finally, reference databases and resources in biomedicine need to link to and contribute to the unifying web of knowledge that is enabled by formal, ontology-based phenotype descriptions.
In particular, ontology-based phenotype descriptions for diseases, as represented in databases such as OMIM or Orphanet, need to be consistently linked to ontologies, and the phenotypes associated with diseases completed and corrected where errors are detected. These are important aspects of human disease and are in some cases available for model organisms but not captured in current curation practices as we lack a formal model for disease.
Approaches toward developing such a model are being proposed currently [ 5758 ] and it is clear that such developments will improve the richness and accuracy of phenotype—disease descriptions with concomitant improvement in the power of informatics to detect similarities between related diseases and subtypes within apparently uniform conditions.
Key Points Phenotype studies in model organisms are successful in revealing genotype—phenotype relations and the molecular mechanisms underlying human disease. Challenges for analyzing phenotype data include incomplete and noisy information in databases describing model organisms and human diseases.
Approaches toward integrating phenotypes across species include ontology-based approaches and the direct comparison of phenotypes. Biomedical ontologies and automated reasoning are a means to integrate phenotypes across species. The combination of ontology- and similarity-based approaches has been shown to successfully suggest novel genes for rare and orphan diseases.
Schofield is Senior Lecturer in Anatomy. His expertise is in mammalian genetics and bioinformatics. He works on the control of mammalian pre-natal growth and the development of biomedical ontologies to relate human disease to mouse models.
Sundberg's research focuses on the biology and pathobiology of hair and skin using the mouse as a model system, and the role of papillomaviruses in the genesis of skin cancers and related diseases. Genotype could be applied to classes of organisms with a specific pair of genes or small set of pairs or to the specific pairs of genes themselves matching the connotation of type as an abstraction away from the full set of observed characteristics.
In Mendelian experiments phenotypes-as-classes demarcated by a small set of traits could be used to identify genotypes-as-classes.
Then, once the genotype as pair s of genes was mapped to a locus on the chromosome, the direction could be reversed: A range of phenotypes may be shown to correspond to the same genotype—expressivity. A phenotype that is associated with a certain genotype may be observed for only a fraction of individuals in or with that genotype—penetrance. With respect to expressivity and penetrance, researchers try to link the observed variation to conditions occurring during development, stochastic developmental noise, or differences remaining at loci not under study, and to decide where in the range of the trait, say, melanin pigmentation, to demarcate one phenotype from another.
Incomplete dominance means the occurrence of an intermediate phenotype e. Incomplete dominance removed some of the ambiguities in using phenotypes to distinguish genotypes, but the combination of the four phenomena and linkage for multiple loci meant that Mendelian researchers had to distinguish among multiple hypotheses about the genotypes consistent with observed patterns of traits in the offspring of crosses.
Background levels of mutation, including mutations in non-germ cells during the lifetime, ensure that even genotypes-as-classes consisting of clones or of identical or monozygotic twins are not made up of strictly identical members. Nevertheless, with suitable organisms and for certain traits, and under the inbreeding and control of conditions typical of Mendelian experiments, the painstaking work of inferring genotypes as pairs of genes from phenotypes could bear fruit. There were many traits for which the continuous variation could not be subdivided into discrete phenotypes, let alone linked to genotypes, especially for traits in agriculture of economic interest such as yield of plant and animal varieties or breeds.
By the end of the s Ronald Fisher and Sewall Wright had begun to address the need to reconcile the discreteness of genotypes with continuous variation in many observable traits.
In the mathematical models of a field that came to be known as quantitative genetics, differences between unobserved theoretical genotypes in the sense of pairs of genes at each of a large number of loci contribute to differences in the trait, modulated by degrees of correspondingly theoretical dominance and epistasis. Under the reasonable assumption that more of the genes are shared among relatives than in the population as a whole, data on a given trait as it varies across genealogically defined lines or groups of specified relatedness could be analyzed so as to provide predictions of changes in the average value of the trait in the population under selective breeding.
Of course, the trait values and thus the predictions depended on the conditions in which the organisms developed, but in the laboratory and, to varying degrees, in agricultural breeding, conditions could be replicated. For the breeder, the focus of the quantitative genetic data analysis on differences in the trait makes practical sense; it is not necessary to know the mechanisms through which the traits developed as organisms reacted to conditions.
In other words, the meanings of genotype, phenotype, and their distinction again make sense as an abstraction through practices of control over biological materials and conditions in agricultural and laboratory breeding and the allied use of models and analysis of data.
It should also be noted that, in agricultural breeding, the lines or other genealogically defined groups became called genotypes as well. Genotypes in this sense are classes of individuals related by genealogy from a common ancestor or set of ancestors. The relatedness takes a variety of forms—not only pure inbred or cloned lines, but also offspring of a given pair of parents or a set of ancestors or an open pollinated plant variety in which the genes vary within replicable bounds among the generations of individuals in the class.
The corresponding phenotype is then the range of values of the trait or set of traits as they are observed to vary for the genealogically defined line or group in the given location s or situation s.
Quantitative genetics extended to humans does not involve controlled breeding, but does rely on relatedness that differs between, say, monozygotic and dizygotic i. Even though a twin pair is not conventionally referred to as a genotype, human quantitative genetics has followed the same idea for data analysis as used in agricultural breeding.
Data on the variation for a trait in a specific group or population could be analyzed so as to estimate the parameters in the model that would generate the observed changes in the average value of the trait over time. Thinking about evolution in the terms of quantitative genetics meant that it was no longer necessary, contra Johannsen Notice, again the separate theoretical genotypes and their contributions, this time to selection coefficients, remain unobserved; the focus of the data analysis could be on differences in the trait, not the mechanisms of trait development.
The complexity of developmental mechanisms, which involve interactions with the environment, was collapsed in the models into the selection coefficients modulated by parameters for dominance between alleles i. A parallel development, initiated again by Fisher and Wright, as well as by J. Haldane, involved mathematical models of theoretical genotypes at one or a few loci each contributing to the parameters for surviving and leaving offspring.
In this field, which came to be known as Population Genetics, estimation of selection coefficients of genotypes inferred from distinct phenotypes was possible, albeit more readily when the populations were subject to artificial selection in the laboratory than when frequencies or changes over time were observed in the wild which was studied in the new field of ecological genetics.
Just as in quantitative genetics, the focus in population genetics was on difference in traits; complexities of development in its ecological context were typically collapsed into the parameters of the models.
For example, the eyes of fruit flies, normally red, are sometimes white. Geneticists identified the location on the chromosomes that corresponds to the white-eye mutation Morgan and later investigated the pigment-formation metabolic pathway and the enzymes proteins that modulate biochemical interactions involved as fruit fly eyes develop the normal or mutant color e. Research since World War II that came to be known as molecular genetics or molecular biology went on to identify DNA as the chemical basis of genes and the mechanisms of DNA replication, mutation, transcription to RNA, and translation to polypeptides components of proteins.
Researchers probed the feedback networks that regulate these mechanisms, first in viruses and bacteria, then in complex, multicellular organisms; mapped and modified the specific DNA sequence of organisms; compared sequences among taxonomic groups i.
Such research, which now occupies the center of biology, renders it plausible to many researchers and commentators that development of traits will eventually be understood in terms of a composite of the influences on the organism over time of identified DNA variants see entry on gene.
Philosophical Issues Brought into Play by Attention to Control of Biological Materials and Conditions Johannsen, as noted earlier and conveyed in the contrast between the method of figure 2 and the theory of figure 1provided no method to divide a natural varying population into phenotypes as classes of organisms, let alone to use these classes to identify genotypes as classes within such populations.
What would be required then in order to apply his terms and distinction in the study of heredity for natural varying populations? A number of pathways can be delineated: As a sociological, not a logical matter, success in engineering may underwrite theoretical generalizing and both may, in turn, make more plausible any assumed extension to naturally varying populations. Together with further experiments, these pathways may eventually lead to success in re-integration.
It could be imagined that the processes exposed in controlled conditions would eventually explain heredity in naturally varying populations. However, there is no guarantee that the original experimental basis for the genotype-phenotype distinction or subsequent developments must lead to effective engineering, theoretical generalization, or likening that clarifies. Indeed, as a sociological not logical matter, pursuing such steps may distract attention from the project of re-integration.
Section 5 reviews what would be entailed in reintegration, doing so in order to problematize the status of the original experimentally based distinction as a basis for the study of heredity for natural varying populations. The rest of section 4 points to several areas of philosophical discussions brought into play and extended by experiments followed by the pathways and steps above.
As noted earlier section 2attention is also warranted to the ways that an area of biology, such as the study of heredity, becomes experimental in the first place. Experiments in biology may lead to the engineering of new phenomena or objects, such as knockout mice i.
To continue the knockout example: In other words, the demonstration of genes in knockout lines that have defined effects could be a textbook case of something represented—the DNA sequence as gene—warranting the status real given the reliable effect of its absence.
Yet antirealists could point to what has not yet been observed given the special experimental conditions of Mendelian research and subsequent molecular biology see entry on scientific realism. Such an objection notwithstanding, if there is a method that is productive of results, there will be scientists who apply it even if the results do not address questions that once motivated their line of inquiry as evident, for example, when, as noted earlier, the study of heredity came to focus on differences not similarity and development.
How is any such pragmatism to be viewed? Or is it a pragmatism highlighted more in sociology than philosophy of science, in which the researcher or the interpreter of science considers how difficult it is in practice to modify what has been established as knowledge Latour ?
It should be noted, however, that this form of abstraction centers on objects that are concrete, not therefore conforming to the contrast abstract versus concrete see entry on abstract objects. The interrelated issues concerning pragmatism, scientific realism, and abstraction become even more pertinent when the theory and models that inform experiments, such as the genotype-phenotype distinction in Mendelian research, are extended to less-controlled situations, such as agricultural breeding trials, and to analysis of data derived from them.
As noted earlier, quantitative genetics relies on models of contributions from unobserved, theoretical genotypes. Analyses of data using those models allow breeders to decide which traits to enhance through selection even though they have no evidence independent of the data to confirm the assumption in their models about theoretical genotypes and their contributions Lloyd Yet, as publications, careers, release of varieties, software packages, and so on get built on such a foundation, it becomes ever more difficult in practical terms for researchers to promote alternatives that do not rest on the unobserved and unconfirmed entities and properties.
Indeed, unconceived alternatives, the possibility that Stanford highlights, may well include theories that entail methods that are, for various reasons, impractical. The pragmatic issue of needing a practical method applies in turn to philosophy: When philosophers make distinctions or otherwise point to issues that scientists have left unclear or under-examined, by what means do they envisage influencing the scientists to change their views or practices?
The Genotype/Phenotype Distinction
That question is left open by this entry. The genotype-phenotype distinction has been positioned in this entry in relation to control of biological materials and conditions, thus drawing attention to the challenge of reintegrating what had been de-emphasized through that control.
Yet, no method is provided for philosophers to get the challenge taken up beyond the implication that the description—the framing—would be a helpful starting point. In other words, the entry has positioned the genotype-phenotype distinction in line with the descriptive emphasis in the New Experimentalism on scientific practice, a prescriptive possibility of reintegration, and an open question about the method needed to shift actual practice.
The description versus prescription contrast also comes into play in relation to the different kinds of meaning given to the genotype-phenotype distinction. Should philosophers descriptively trace the shifts in meaning from Johannsen to the current day, or should they prescriptively disambiguate different meanings that may coexist among the work of different groups of researchers or even within a given group see entry on ambiguity?
Descriptively, philosophers could tease out the different, sometimes incommensurable, interests and purposes that make a line of inquiry rational. However, two other possibilities remain, namely, ambiguity in the use of the genotype-phenotype distinction obscures shortcomings in theories and methods and allows the advances in one field e.
Control and Reintegration Sections 2 and 3 described how the original genotype-phenotype distinction was operationalized under special, controlled conditions, namely, the growing and crossing of inbred lines raised under uniform conditions. Section 4 laid out pathways from the experimentally based distinction: Yet biology and philosophy of biology have not emphasized the need to reintegrate what has been abstracted away as a necessary step if the genotype-conception of heredity is to be extended beyond those special conditions Figures 2 and 3 and applied to the study of heredity for natural varying populations Figure 1.
Therefore, to highlight the implications of basing the genotype-phenotype distinction in controlled conditions, this section considers what control and possible reintegration might entail in the different realms reviewed so far.
Such a program had proponents, especially in the first half of the twentieth century, but came to be eclipsed by Mendelian genetics and discounted by historians and philosophers of heredity Sapp The relevant part of the genotype was shown to be pairs of genes located along chromosomes as long as, given the control entailed by Mendelian experiments, the focus lay on differences in traits, not on how an offspring develops to have the trait at all.
Recall, as Johannsen noted, that Mendelian experiments are limited in examining the species-typical aspects of the germ cells and subsequent development. Again, a program for reintegrating what is abstracted away through experimental control can be imagined: From the composite of these influences the organism as a structured whole might emerge. Two emerging features of the study of heredity, however, work against such a reintegration program: Heredity, as mentioned earlier, has become equated with the transmission of and cross-generational patterns in the differences.
That means development became a separate and secondary matter Sapp ; analysis of the dynamics of species-typical development of morphological structure was eclipsed by genetics. It is not strictly correct to assert that Mendelian experiments are unable to examine species-typical traits. For example, all individuals of all species of the fruit-fly genus Drosophila have exactly three simple light receptors, ocelli, arranged in a symmetrical triangle on the midline of the top of their heads.
The simplest assumption is that there is no variation in genotypes in the sense of material constituents that influence this trait and its development is resistant to normal environmental disturbance. However, if the development of the fly is sufficiently disturbed, some flies with two or fewer ocelli are observed. If those with fewer than three ocelli are used as parents for the next generation, they produced more abnormal flies than the parental generation.
Any investigation of how the diverse genotypes result in the development of the typical three-ocelli pattern now has to explain the occurrence of the aberrant pattern as well.