Abstract
Annotating the genotype-phenotype relationship, and developing a proper quantitative description of the relationship, requires understanding the impact of natural genomic variation on gene expression. We apply a sequence-level model of gap gene expression in the early development of Drosophila to analyze single nucleotide polymorphisms (SNPs) in a panel of natural sequenced D. melanogaster lines. Using a thermodynamic modeling framework, we provide both analytical and computational descriptions of how single-nucleotide variants affect gene expression. The analysis reveals that the sequence variants increase (decrease) gene expression if located within binding sites of repressors (activators). We show that the sign of SNP influence (activation or repression) may change in time and space and elucidate the origin of this change in specific examples. The thermodynamic modeling approach predicts non-local and non-linear effects arising from SNPs, and combinations of SNPs, in individual fly genotypes. Simulation of individual fly genotypes using our model reveals that this non-linearity reduces to almost additive inputs from multiple SNPs. Further, we see signatures of the action of purifying selection in the gap gene regulatory regions. To infer the specific targets of purifying selection, we analyze the patterns of polymorphism in the data at two phenotypic levels: the strengths of binding and expression. We find that combinations of SNPs show evidence of being under selective pressure, while individual SNPs do not. The model predicts that SNPs appear to accumulate in the genotypes of the natural population in a way biased towards small increases in activating action on the expression pattern. Taken together, these results provide a systems-level view of how genetic variation translates to the level of gene regulatory networks via combinatorial SNP effects.
Highlights
The analysis of molecular phenotypes is expected to bridge the gap between genotypic and phenotypic variation, thereby facilitating both basic and health research [1, 2]
We study polymorphism observed in regulatory regions of the gap genes hb, Kr, gt, and kni in the study population of 213 Drosophila lines, in the context of our model of gene expression
The set of experimentally observed single nucleotide polymorphisms (SNPs) in these transcription factor binding sites (TFBSs) consists of a total of 90 SNPs at 139 unique bindings sites (Fig 1A; S2 Table). 34 of these SNPs fall into multiple TFBSs due to overlap, resulting in a total of 149 observed combinations of SNP and TFBS (S2 Table)
Summary
The analysis of molecular phenotypes is expected to bridge the gap between genotypic and phenotypic variation, thereby facilitating both basic and health research [1, 2]. As opposed to GWAS, which is focused on capturing associations, an advantage of this alternative approach is that we can infer specific mechanisms, or causal relations, linking variation in the regulatory DNA to its effect on gene expression patterns [3]. We apply this approach in the context of the gap gene network involved in early development of Drosophila melanogaster. The regulatory role can vary, as in the case of Hunchback (Hb) that bifunctionally regulates even-skipped (eve) stripe 7 expression through two separate “shadow enhancers”, activating one of them and repressing the other [7]
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