Developing a global understanding of the PRC and NuRD complexes in stem cell differentiation and in disease

The effects of genetic variation on gene expression dynamics during development —Lehner lab (2014)

Mirko Francesconi and Ben Lehner 

The development of a multicellular organism and physiological responses require massive coordinated changes in gene expression across several cell and tissue types1–3. Polymorphic regions of the genome that influence gene expression levels have been identified by expression quantitative trait locus (eQTL) mapping in many species4–6, including loci that have cell-dependent7,8, tissue-dependent9 and age-dependent10 effects. However, there has been no comprehen- sive characterization of how polymorphisms influence the complex dynamic patterns of gene expression that occur during development and in physiology. Here we describe an efficient experimental design to infer gene expression dynamics from single expression profiles in different genotypes, and apply it to characterize the effect of local (cis) and distant (trans) genetic variation on gene expression at high tem- poral resolution throughout a 12-hour period of the development of Caenorhabditis elegans. Taking dynamic variation into account iden- tifies .50% more cis-eQTLs, including more than 900 that alter the dynamics of expression during this period. Local sequence poly- morphisms extensively affect the timing, rate, magnitude and shape of expression changes. Indeed, many local sequence variants both increase and decrease gene expression, depending on the time-point profiled. Expression dynamics during this 12-hour period are also influenced extensively in trans by distal loci. In particular, several trans loci influence genes with quite diverse dynamic expression pat- terns, but they do so primarily during a common time interval. Trans loci can therefore act as modifiers of expression during a particular period of development. This study provides the first characterization, to our knowledge, of the effect of local and distant genetic variation on the dynamics of gene expression throughout an extensive time period. Moreover, the approach developed here should facilitate the genetic dissection of other dynamic processes, including potentially develop- ment, physiology and disease progression in humans. 

Nature  505: 208-211   doi: 10.1038/nature12772

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