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Register a new userDoes your gene need a background check? How genetic background impacts the analysis of mutations, genes, and evolution
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The premise of genetic analysis is that a causal link exists between phenotypic and allelic variation. Yet it has long been documented that mutant phenotypes are not a simple result of a single DNA lesion, but rather are due to interactions of the focal allele with other genes and the environment. Although an experimentally rigorous approach, focusing on individual mutations and isogenic control strains, has facilitated amazing progress within genetics and related fields, a glimpse back suggests that a vast complexity has been omitted from our current understanding of allelic effects. Armed with traditional genetic analyses and the foundational knowledge they have provided, we argue that the time and tools are ripe to return to the under-explored aspects of gene function and embrace the context-dependent nature of genetic effects. We assert that a broad understanding of genetic effects and the evolutionary dynamics of alleles requires identifying how mutational outcomes depend upon the wild-type genetic background. Furthermore, we discuss how best to exploit genetic background effects to broaden genetic research programs.
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The phenotypic consequences of individual mutations are modulated by the wild type genetic background in which they occur.Although such background dependence is widely observed, we do not know whether general patterns across species and traits exist, nor about the mechanisms underlying it. We also lack knowledge on how mutations interact with genetic background to influence gene expression, and how this in turn mediates mutant phenotypes. Furthermore, how genetic background influences patterns of epistasis remains unclear. To investigate the genetic basis and genomic consequences of genetic background dependence of the scallopedE3 allele on the Drosophila melanogaster wing, we generated multiple novel genome level datasets from a mapping by introgression experiment and a tagged RNA gene expression dataset. In addition we used whole genome re-sequencing of the parental lines two commonly used laboratory strains to predict polymorphic transcription factor binding sites for SD. We integrated these data with previously published genomic datasets from expression microarrays and a modifier mutation screen. By searching for genes showing a congruent signal across multiple datasets, we were able to identify a robust set of candidate loci contributing to the background dependent effects of mutations in sd. We also show that the majority of background-dependent modifiers previously reported are caused by higher-order epistasis, not quantitative non-complementation. These findings provide a useful foundation for more detailed investigations of genetic background dependence in this system, and this approach is likely to prove useful in exploring the genetic basis of other traits as well.
In unicellular organisms such as bacteria the same acquired mutations beneficial in one environment can be restrictive in another. However, evolving Escherichia coli populations demonstrate remarkable flexibility in adaptation. The mechanisms sustaining genetic flexibility remain unclear. In E. coli the transcriptional regulation of gene expression involves both dedicated regulators binding specific DNA sites with high affinity and also global regulators - abundant DNA architectural proteins of the bacterial chromoid binding multiple low affinity sites and thus modulating the superhelical density of DNA. The first form of transcriptional regulation is dominantly pairwise and specific, representing digitial control, while the second form is (in strength and distribution) continuous, representing analog control. Here we look at the properties of effective networks derived from significant gene expression changes under variation of the two forms of control and find that upon limitations of one type of control (caused e.g. by mutation of a global DNA architectural factor) the other type can compensate for compromised regulation. Mutations of global regulators significantly enhance the digital control; in the presence of global DNA architectural proteins regulation is mostly of the analog type, coupling spatially neighboring genomic loci; together our data suggest that two logically distinct types of control are balancing each other. By revealing two distinct logical types of control, our approach provides basic insights into both the organizational principles of transcriptional regulation and the mechanisms buffering genetic flexibility. We anticipate that the general concept of distinguishing logical types of control will apply to many complex biological networks.
The leaves of the Coriandrum sativum plant, known as cilantro or coriander, are widely used in many cuisines around the world. However, far from being a benign culinary herb, cilantro can be polarizing---many people love it while others claim that it tastes or smells foul, often like soap or dirt. This soapy or pungent aroma is largely attributed to several aldehydes present in cilantro. Cilantro preference is suspected to have a genetic component, yet to date nothing is known about specific mechanisms. Here we present the results of a genome-wide association study among 14,604 participants of European ancestry who reported whether cilantro tasted soapy, with replication in a distinct set of 11,851 participants who declared whether they liked cilantro. We find a single nucleotide polymorphism (SNP) significantly associated with soapy-taste detection that is confirmed in the cilantro preference group. This SNP, rs72921001, (p=6.4e-9, odds ratio 0.81 per A allele) lies within a cluster of olfactory receptor genes on chromosome 11. Among these olfactory receptor genes is OR6A2, which has a high binding specificity for several of the aldehydes that give cilantro its characteristic odor. We also estimate the heritability of cilantro soapy-taste detection in our cohort, showing that the heritability tagged by common SNPs is low, about 0.087. These results confirm that there is a genetic component to cilantro taste perception and suggest that cilantro dislike may stem from genetic variants in olfactory receptors. We propose that OR6A2 may be the olfactory receptor that contributes to the detection of a soapy smell from cilantro in European populations.
We report on a theoretical study of point mutations effects on charge transfer properties in the DNA sequence of the tumor-suppressor p53 gene. On the basis of effective single-strand or double-strand tight-binding models which simulate hole propagation along the DNA, a statistical analysis of charge transmission modulations associated with all possible point mutations is performed. We find that in contrast to non-cancerous mutations, mutation hotspots tend to result in significantly weaker {em changes of transmission properties}. This suggests that charge transport could play a significant role for DNA-repairing deficiency yielding carcinogenesis.
In this paper it is shown that within a Combined Genetic Code Table, realized through a combination of Watson-Crick Table and Codon Path Cube it exists, without an exception, a strict distinction between two classes of enzymes aminoacyl-tRNA synthetases, corresponding two classes of amino acids and belonging codons. By this, the distinction itself is followed by a strict balance of atom number within two subclasses of class I as well as two subclasses of class II of amino acids.
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