Genetic variants regulating expression levels and isoform diversity during embryogenesis

Abstract

The effects of genetic variation on transcriptional and post-transcriptional regulation are systematically mapped across multiple stages of embryogenesis in eighty inbred Drosophila lines, identifying thousands of quantitative trait loci affecting approximately 17% of expressed genes, often with heteroalleic interactions. Eileen Furlong, Ewan Birney and colleagues systematically map the effects of genetic variation on transcriptional and post-transcriptional regulation across multiple stages of development in 80 inbred Drosophila lines. They identify quantitative trait loci (QTLs) regulating approximately 17% of expressed genes, including developmental-stage-specific and shared QTLs, with about one-third of these showing some embryonic-stage-specific effects. They also identify QTLs that affect post-transcriptional 3′ RNA processing and motifs linked to transcript isoform diversity and changes in the lengths of 3′ untranslated regions. Embryonic development is driven by tightly regulated patterns of gene expression, despite extensive genetic variation among individuals. Studies of expression quantitative trait loci1,2,3,4 (eQTL) indicate that genetic variation frequently alters gene expression in cell-culture models and differentiated tissues5,6. 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 isolates7, identifying thousands of developmental-stage-specific and shared QTL. Given the small blocks of linkage disequilibrium in Drosophila7,8,9, 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.

Cite this article

Cannavò, E., Koelling, N., Harnett, D. et al. Genetic variants regulating expression levels and isoform diversity during embryogenesis. Nature 541, 402–406 (2017). https://doi.org/10.1038/nature20802

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