Analysis of allele-specific expression reveals cis-regulatory changes associated with a recent mating system shift and floral adaptation in Capsella
Kim A Steige , Johan Reimegård , Daniel Koenig , Douglas G Scofield , Tanja Slotte
Cis-regulatory changes have long been suggested to contribute to organismal adaptation. While cis-regulatory changes can now be identified on a transcriptome-wide scale, in most cases the adaptive significance and mechanistic basis of rapid cis-regulatory divergence remains unclear. Here, we have characterized cis-regulatory changes associated with recent adaptive floral evolution in the selfing plant Capsella rubella, which diverged from the outcrosser Capsella grandiflora less than 200 kya. We assessed allele-specific expression (ASE) in leaves and flower buds at a total of 18,452 genes in three interspecific F1 C. grandiflora x C. rubella hybrids. After accounting for technical variation and read-mapping biases using genomic reads, we estimate that an average of 44% of these genes show evidence of ASE, however only 6% show strong allelic expression biases. Flower buds, but not leaves, show an enrichment of genes with ASE in genomic regions responsible for phenotypic divergence between C. rubella and C. grandiflora. We further detected an excess of heterozygous transposable element (TE) insertions in the vicinity of genes with ASE, and TE insertions targeted by uniquely mapping 24-nt small RNAs were associated with reduced allelic expression of nearby genes. Our results suggest that cis-regulatory changes have been important for recent adaptive floral evolution in Capsella and that differences in TE dynamics between selfing and outcrossing species could be an important mechanism underlying rapid regulatory divergence.
Adaptive evolution of anti-viral siRNAi genes in bumblebees
Sophie Helbing , Michael Lattorff
The high density of frequently interacting and closely related individuals in social insects enhance pathogen transmission and establishment within colonies. Group-mediated behavior supporting immune defenses tend to decrease selection acting on immune genes. Along with low effective population sizes this will result in relaxed constraint and rapid evolution of genes of the immune system. Here we show that sociality is the main driver of selection in antiviral siRNAi genes in social bumblebees compared to their socially parasitic cuckoo bumblebees that lack a worker caste. RNAi genes show frequent positive selection at the codon level additionally supported by the occurrence of parallel evolution and their evolutionary rate is linked to their pathway specific position with genes directly interacting with viruses showing the highest rates of molecular evolution. We suggest that indeed higher pathogen load in social insects drive adaptive evolution of immune genes, if not compensated by behavior.
Mycobacterial infection induces a specific human innate immune response
John D Blischak , Ludovic Tailleux , Amy Mitrano , Luis B Barreiro , Yoav Gilad
The innate immune system provides the first response to pathogen infection and orchestrates the activation of the adaptive immune system. Though a large component of the innate immune response is common to all infections, pathogen-specific responses have been documented as well. The innate immune response is thought to be especially critical for fighting infection with Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB). While TB can be deadly, only 5-10% of individuals infected with MTB develop active disease. The risk for disease susceptibility is, at least partly, heritable. Studies of inter-individual variation in the innate immune response to MTB infection may therefore shed light on the genetic basis for variation in susceptibility to TB. Yet, to date, we still do not know which properties of the innate immune response are specific to MTB infection and which represent a general response to pathogen infection. To begin addressing this gap, we infected macrophages with eight different bacteria, including different MTB strains and related mycobacteria, and studied the transcriptional response to infection. Although the ensued gene regulatory responses were largely consistent across the bacterial infection treatments, we were able to identify a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. Genetic variants that are associated with regulatory differences in these genes should be considered candidate loci for explaining inter-individual susceptibility TB.
Abundant contribution of short tandem repeats to gene expression variation in humans
Melissa Gymrek , Thomas Willems , Haoyang Zeng , Barak Markus , Mark J Daly , Alkes L Price , Jonathan Pritchard , Yaniv Erlich
Expression quantitative trait loci (eQTLs) are a key tool to dissect cellular processes mediating complex diseases. However, little is known about the role of repetitive elements as eQTLs. We report a genome-wide survey of the contribution of Short Tandem Repeats (STRs), one of the most polymorphic and abundant repeat classes, to gene expression in humans. Our survey identified 2,060 significant expression STRs (eSTRs). These eSTRs were replicable in orthogonal populations and expression assays. We used variance partitioning to disentangle the contribution of eSTRs from linked SNPs and indels and found that eSTRs contribute 10%-15% of the cis-heritability mediated by all common variants. Functional genomic analyses showed that eSTRs are enriched in conserved regions, co-localize with regulatory elements, and are predicted to modulate histone modifications. Our results show that eSTRs provide a novel set of regulatory variants and highlight the contribution of repeats to the genetic architecture of quantitative human traits.
Entire genome transcription across evolutionary time exposes non-coding DNA to de novo gene emergence
Rafik Neme , Diethard Tautz
Even in the best studied Mammalian genomes, less than 5% of the total genome length is annotated as exonic. However, deep sequencing analysis in humans has shown that around 40% of the genome may be covered by poly-adenylated non-coding transcripts occurring at low levels. Their functional significance is unclear, and there has been a dispute whether they should be considered as noise of the transcriptional machinery. We propose that if such transcripts show some evolutionary stability they will serve as substrates for de novo gene evolution, i.e. gene emergence out of non-coding DNA. Here, we characterize the phylogenetic turnover of low-level poly-adenylated transcripts in a comprehensive sampling of populations, sub-species and species of the genus Mus, spanning a phylogenetic distance of about 10 Myr. We find evidence for more evolutionary stable gains of transcription than losses among closely related taxa, balanced by a loss of older transcripts across the whole phylogeny. We show that adding taxa increases the genomic transcript coverage and that no major transcript-free islands exist over time. This suggests that the entire genome can be transcribed into poly-adenylated RNA when viewed at an evolutionary time scale. Thus, any part of the “non-coding” genome can become subject to evolutionary functionalization via de novo gene evolution.
RNAseq in the mosquito maxillary palp: a little antennal RNA goes a long way
David C. Rinker , Xiaofan Zhou , Ronald Jason Pitts , Antonis Rokas , LJ Zwiebel
A comparative transcriptomic study of mosquito olfactory tissues recently published in BMC Genomics (Hodges et al., 2014) reported several novel findings that have broad implications for the field of insect olfaction. In this brief commentary, we outline why the conclusions of Hodges et al. are problematic under the current models of insect olfaction and then contrast their findings with those of other RNAseq based studies of mosquito olfactory tissues. We also generated a new RNAseq data set from the maxillary palp of Anopheles gambiae in an effort to replicate the novel results of Hodges et al. but were unable to reproduce their results. Instead, our new RNAseq data support the more straightforward explanation that the novel findings of Hodges et al. were a consequence of contamination by antennal RNA. In summary, we find strong evidence to suggest that the conclusions of Hodges et al were spurious, and that at least some of their RNAseq data sets were irrevocably compromised by cross-contamination between samples.
Exploring functional variation affecting ceRNA regulation in humans
Mulin Jun Li , Jiexing Wu , Peng Jiang , Wei Li , Yun Zhu , Daniel Fernandez , Russell J. H. Ryan , Yiwen Chen , Junwen Wang , Jun S. Liu , X. Shirley Liu
MicroRNA (miRNA) sponges have been shown to function as competing endogenous RNAs (ceRNAs) to regulate the expression of other miRNA targets in the network by sequestering available miRNAs. As the first systematic investigation of the genome-wide genetic effect on ceRNA regulation, we applied multivariate response regression and identified widespread genetic variations that are associated with ceRNA competition using 462 Geuvadis RNA-seq data in multiple human populations. We showed that SNPs in gene 3’UTRs at the miRNA seed binding regions can simultaneously regulate gene expression changes in both cis and trans by the ceRNA mechanism. We termed these loci as endogenous miRNA sponge expression quantitative trait loci or “emsQTLs”, and found that a large number of them were unexplored in conventional eQTL mapping. We identified many emsQTLs are undergoing recent positive selection in different human populations. Using GWAS results, we found that emsQTLs are significantly enriched in traits/diseases associated loci. Functional prediction and prioritization extend our understanding on causality of emsQTL allele in disease pathways. We illustrated that emsQTL can synchronously regulate the expression of tumor suppressor and oncogene through ceRNA competition in angiogenesis. Together these results provide a distinct catalog and characterization of functional noncoding regulatory variants that control ceRNA crosstalk.