Structural Biochemistry/Function Attribution of Gene & Gene Products

Different Views of Functions of Gene and Gene Products
The concept of function is taken for granted when applying to genes and gene product. People tend to misunderstand, or simplify the concept of function of genes and gene products in terms of different circumstance. Neil S. Greenspan gives us several well organized ways to distinguish the function attribution of gene and gene products in different aspects.
Biochemical function vs. genetic function
Biochemical function: The basis of attribution of biochemical function is merely the behavior of authentic gene product without considering the biological environment. For example, isolating a protein X (which is the “without considering the biological environment”) to detect its particular catalytic activity (which is “the behavior of authentic gene product”). Biochemical function refers to a relatively narrow view of the gene product’s function, as it is determined only by the effect mediated directly by gene product (Greenspan 293).
Genetic function: The basis of attribution of genetic function is the behavior of the whole system (often refer to as cellular or organismal systems) in presence or absence of wild type gene product. For example, when modifying DNA sequence (which is “the presence of absence of wild type gene product”), we could possibly alternate the phenotype of individual cell, or even the whole organism (which is “the behavior of the whole system”). In this example, biological context is required, which is the opposite of biochemical function attribution. Genetic function is a relatively board view of the gene product’s function, as it is determined by looking at the whole system with/without the wild type gene. Genetic function is commonly seen in genetic engineering. For example, when studying behavior of IFN-γ to inflammation, wild-type mice and mice with different concentration of IFN-γ are compared in terms of the level of inflammation. This is a typical example of genetic function attribution, because the experiment needs biological environment, and is comparing the whole systems’ behavior in presence or absence of wild type gene product.
Other senses of function attributed to genes or gene products
Sense1. Function should be the positive contribution to cellular or organismal function. According to this sense, the function attributed to gene or gene products should lead towards survival and reproduction of the associated cell of organism. In another word, this positive function attribution should be parallel to favor evolutionarily adaption.
Sense2. Function should be determined by the net effect of particular gene product on cell or organism. Furthermore, this function attribution is divided into 2 parts: (i) when compare with absence of gene product (ii) when compare with allelic form. This sense is similar with the idea of genetic function. For example, when studying the sickle cell allel at the β-globin locus, we aren’t only look at the heterozygous form, but also the homozygous form, this net effect of combination of sickle cell’s heterozygous form and homozygous form determines the function of gene product encoded by the sickle cell’s allel at the β-globin locus.
Relational nature of molecular function
The classification of function of gene and gene product can be more complicated. Greenspan states that the effects attributable to a given protein or RNA molecule can vary in different cellular contexts. (294) For example, depend on cell type and range of stimuli received by the cell, activation of NF-kB can generate different responses. When people simplified the molecular function, they often make the “fundamental attribution error” when only consider the intrinsic properties without considering cellular environment, because different biological environment might cause completely different effects. This also explain why genetic function is more often used than biochemical function, because it consider the entire systems’ effect rather than the individual gene product’s function when isolated.
The crucial point of molecular function is “the interaction between molecules or between forms of energy and molecules”(Greenspan 295). Therefore, there is a difference between function attributes to isolated gene product and function attributes to gene product in particular context (when interact with other molecules). For example, when modifying gene encoding XR receptor to form a different structure, the hormone or growth factor X no longer works, although the isolated X doesn’t change the structure and the function attributes to isolated X doesn’t change. The function attributes to the whole system (when X interact with XR) change. Therefore, the molecular function also change.
Protein thermodynamics & function
The technique of protein thermodynamics can help us to determine functional contributions of individuals alleles to cellular or oganismal phenotypes. Basically, the technique requires protein-ligand binding, when applying mutagenesis to change ligand recognition. Affinity and free energy will change, from database of properties of different amino acids, protein thermodynamic can assess us to determine the functional or phenotype of interest. The most important advantage of protein thermodynamics is that it allows us to obtain various amino acids at various positions by looking up at the quantitative database.
By using thermodynamic contribution, scientist determined that “thermodynamic contributions of individual amino acids change with single point mutations at other positions in the same polypeptide chain” (Greenspan 295). This idea illustrates that when we change the amino acids of certain gene sequence, although genotype changes, phenotype may not change. Furthermore, Lim and Sauer figured out the in order to keep normal function of certain amino acids, another amino acid is needed in another position. However, this amino acid does not need to be the one in wild-type. For example, in order for methionine at position 36 to function normal, isoleucine needs to occupy position 51, while phenyalanine, which is in wild-type, is not essential. This is a good example to illustrate that there is functional flexibility even if some amino acids are substituted. Protein thermodynamic allows us to determine functional contribution of given structural element by tracking the properties of different amino acids at various positions.
Mathematical functions of gene vs. gene product
Gene and Gene products’ function are often not determined by single factor, thus multiple factors are required. Therefore, the function of gene product can be viewed as a mathematical function of multiple variables. These variables could be temperature, ionic strength, pH and so on.
In terms of the mathematical functions, the function of gene is more complex of the function of gene product, because one gene can generate different gene product by mRNA splicing (which is the abandoned of different introns and recombination of different entrons).

References

1. Greespan, N.S. (2011) Opinion-Attributing functions to genes and gene products. Trends in Biochemical Sciences Vol.36, No.6