Genetic variants regulating expression levels and isoform diversity during embryogenesis

Abstract

Embryonic development is driven by tightly regulated patterns of gene expression, despite extensive genetic variation among individuals. Studies of expression quantitative trait loci (eQTL) indicate that genetic variation frequently alters gene expression in cell-culture models and differentiated tissues. However, the extent and types of genetic variation impacting embryonic gene expression, and their interactions with developmental programs, remain largely unknown. Here we assessed the effect of genetic variation on transcriptional (expression levels) and post-transcriptional (3' RNA processing) regulation across multiple stages of metazoan development, using 80 inbred Drosophila wild isolates, identifying thousands of developmental-stage-specific and shared QTL. Given the small blocks of linkage disequilibrium in Drosophila, we obtain near base-pair resolution, resolving causal mutations in developmental enhancers, validated transcription-factor-binding sites and RNA motifs. This fine-grain mapping uncovered extensive allelic interactions within enhancers that have opposite effects, thereby buffering their impact on enhancer activity. QTL affecting 3' RNA processing identify new functional motifs leading to transcript isoform diversity and changes in the lengths of 3' untranslated regions. These results highlight how developmental stage influences the effects of genetic variation and uncover multiple mechanisms that regulate and buffer expression variation during embryogenesis.

Common genetic variation drives molecular heterogeneity in human iPSCs

“…Our study substantially extends on previous work6,7 by demonstrating widespread functional consequences of genetic variation for many molecular and cellular phenotypes in human pluripotent stem cell lines, including in the efficiency with which iPS cells differentiate41–43. This is potentially a consequence of variation in core components of the regulatory networks controlling cellular differentiation and responses to external environmental stimuli, as observed previously in hematopoietic cells and mouse and fly embryos44–46.…”

Genetic association of molecular traits: A help to identify causative variants in complex diseases

“…57 One can anticipate that development-stage-specific eQTLs also exist in humans, as it has been reported in Drosophila. 58 Altogether, these studies revealed important recurrent features of the thousands of eQTLs found in different tissues. Thus, almost 60%-80% of genes have at least one eQTL, 64 mostly cis-acting usually within 1 Mb of the transcription start site (TSS).…”

“…Sex and age effects have also been identified . One can anticipate that development‐stage‐specific eQTLs also exist in humans, as it has been reported in Drosophila …”

Natural diversity facilitates the discovery of conserved chemotherapeutic response mechanisms

“…Additionally, responses to tunicamycin were mapped using the Drosophila Genetic Reference Panel [30] to a large number of loci but none of these loci were shown to play a direct role in the variable drug response [40]. In a global approach, a large-scale expression study of 80 inbred D. melanogaster strains from the Drosophila Genetic Reference Panel found 2,000 genes with variable expression that can be explained by genetic differences in the panel, referred to expression quantitative trait loci or eQTL [41]. Interestingly, significant differences in mRNA expression of approximately 20 glutathione S-transferases (GSTs) and cytochrome P450 genes, which have roles in xenobiotic responses, were observed among these strains, suggesting that natural variability to metabolize xenobiotics likely exists among these strains [41].…”

“…In a global approach, a large-scale expression study of 80 inbred D. melanogaster strains from the Drosophila Genetic Reference Panel found 2,000 genes with variable expression that can be explained by genetic differences in the panel, referred to expression quantitative trait loci or eQTL [41]. Interestingly, significant differences in mRNA expression of approximately 20 glutathione S-transferases (GSTs) and cytochrome P450 genes, which have roles in xenobiotic responses, were observed among these strains, suggesting that natural variability to metabolize xenobiotics likely exists among these strains [41]. As another example, European populations of D. melanogaster harbor a deletion in the 3’ UTR of the metallothionein A ( MtnA ) gene that results in a four-fold increase in MtnA expression [42].…”