Behavior-specific changes in transcriptional modules lead to distinct and predictable neurogenomic states [Genetics]

Behavior-specific changes in transcriptional modules lead to distinct and predictable neurogenomic states [Genetics]: Using brain transcriptomic profiles from 853 individual honey bees exhibiting 48 distinct behavioral phenotypes in naturalistic contexts, we report that behavior-specific neurogenomic states can be inferred from the coordinated action of transcription factors (TFs) and their predicted target genes. Unsupervised hierarchical clustering of these transcriptomic profiles showed three clusters that correspond to three ecologically important behavioral categories: aggression, maturation, and foraging. To explore the genetic influences potentially regulating these behavior-specific neurogenomic states, we reconstructed a brain transcriptional regulatory network (TRN) model. This brain TRN quantitatively predicts with high accuracy gene expression changes of more than 2,000 genes involved in behavior, even for behavioral phenotypes on which it was not trained, suggesting that there is a core set of TFs that regulates behavior-specific gene expression in the bee brain, and other TFs more specific to particular categories. TFs playing key roles in the TRN include well-known regulators of neural and behavioral plasticity, e.g., Creb, as well as TFs better known in other biological contexts, e.g., NF-κB (immunity). Our results reveal three insights concerning the relationship between genes and behavior. First, distinct behaviors are subserved by distinct neurogenomic states in the brain. Second, the neurogenomic states underlying different behaviors rely upon both shared and distinct transcriptional modules. Third, despite the complexity of the brain, simple linear relationships between TFs and their putative target genes are a surprisingly prominent feature of the networks underlying behavior.

Digital gene expression for non-model organisms [METHOD]

Digital gene expression for non-model organisms [METHOD]:

Next-generation sequencing technologies offer new approaches for global measurements of gene expression but are mostly limited to organisms for which a high-quality assembled reference genome sequence is available. We present a method for gene expression profiling called EDGE, or EcoP15I-tagged Digital Gene Expression, based on ultra-high-throughput sequencing of 27-bp cDNA fragments that uniquely tag the corresponding gene, thereby allowing direct quantification of transcript abundance. We show that EDGE is capable of assaying for expression in >99% of genes in the genome and achieves saturation after 6–8 million reads. EDGE exhibits very little technical noise, reveals a large (10⁶) dynamic range of gene expression, and is particularly suited for quantification of transcript abundance in non-model organisms where a high-quality annotated genome is not available. In a direct comparison with RNA-seq, both methods provide similar assessments of relative transcript abundance, but EDGE does better at detecting gene expression differences for poorly expressed genes and does not exhibit transcript length bias. Applying EDGE to laboratory mice, we show that a loss-of-function mutation in the melanocortin 1 receptor (Mc1r), recognized as a Mendelian determinant of yellow hair color in many different mammals, also causes reduced expression of genes involved in the interferon response. To illustrate the application of EDGE to a non-model organism, we examine skin biopsy samples from a cheetah (Acinonyx jubatus) and identify genes likely to control differences in the color of spotted versus non-spotted regions.

Evolutionary divergence of intrinsic and trans-regulated nucleosome positioning sequences reveals plastic rules for chromatin organization [RESEARCH]

Evolutionary divergence of intrinsic and trans-regulated nucleosome positioning sequences reveals plastic rules for chromatin organization [RESEARCH]:

The packaging of eukaryotic genomes into nuclesomes plays critical roles in chromatin organization and gene regulation. Studies in Saccharomyces cerevisiae indicate that nucleosome occupancy is partially encoded by intrinsic antinucleosomal DNA sequences, such as poly(A) sequences, as well as by binding sites for trans-acting factors that can evict nucleosomes, such as Reb1 and the Rsc3/30 complex. Here, we use genome-wide nucleosome occupancy maps in 13 Ascomycota fungi to discover large-scale evolutionary reprogramming of both intrinsic and trans determinants of chromatin structure. We find that poly(G)s act as intrinsic antinucleosomal sequences, comparable to the known function of poly(A)s, but that the abundance of poly(G)s has diverged greatly between species, obscuring their antinucleosomal effect in low-poly(G) species such as S. cerevisiae. We also develop a computational method that uses nucleosome occupancy maps for discovering trans-acting general regulatory factor (GRF) binding sites. Our approach reveals that the specific sequences bound by GRFs have diverged substantially across evolution, corresponding to a number of major evolutionary transitions in the repertoire of GRFs. We experimentally validate a proposed evolutionary transition from Cbf1 as a major GRF in pre-whole-genome duplication (WGD) yeasts to Reb1 in post-WGD yeasts. We further show that the mating type switch-activating protein Sap1 is a GRF in S. pombe, demonstrating the general applicability of our approach. Our results reveal that the underlying mechanisms that determine in vivo chromatin organization have diverged and that comparative genomics can help discover new determinants of chromatin organization.

Widespread signatures of recent selection linked to nucleosome positioning in the human lineage [RESEARCH]

Widespread signatures of recent selection linked to nucleosome positioning in the human lineage [RESEARCH]:

In this study we investigated the strengths and modes of selection associated with nucleosome positioning in the human lineage through the comparison of interspecies and intraspecies rates of divergence. We identify significant evidence for both positive and negative selection linked to human nucleosome positioning for the first time, implicating a widespread and important role for DNA sequence in the location of well-positioned nucleosomes. Selection appears to be acting on particular base substitutions to maintain optimum GC compositions in core and linker regions, with, e.g., unexpectedly elevated rates of C->T substitutions during recent human evolution at linker regions 60–90 bp from the nucleosome dyad but significant depletion of the same substitutions within nucleosome core regions. These patterns are strikingly consistent with the known relationships between genomic sequence composition and nucleosome assembly. By stratifying nucleosomes according to the GC content of their genomic neighborhood, we also show that the strength and direction of selection detected is dictated by local GC content. Intriguingly these signatures of selection are not restricted to nucleosomes in close proximity to exons, suggesting the correct positioning of nucleosomes is not only important in and around coding regions. This analysis provides strong evidence that the genomic sequences associated with nucleosomes are not evolving neutrally, and suggests that underlying DNA sequence is an important factor in nucleosome positioning. Recent signatures of selection linked to genomic features as ubiquitous as the nucleosome have important implications for human genome evolution and disease.

What fraction of the human genome is functional? [REVIEW]

What fraction of the human genome is functional? [REVIEW]:

Many evolutionary studies over the past decade have estimated α_sel, the proportion of all nucleotides in the human genome that are subject to purifying selection because of their biological function. Most of these studies have estimated the nucleotide substitution rates from genome sequence alignments across many diverse mammals. Some α_sel estimates will be affected by the heterogeneity of substitution rates in neutral sequence across the genome. Most will also be inaccurate if change in the functional sequence repertoire occurs rapidly relative to the separation of lineages that are being compared. Evidence gathered from both evolutionary and experimental analyses now indicate that rates of "turnover" of functional, predominantly noncoding, sequence are, indeed, high. They are sufficiently high that an estimated 50% of mouse constrained noncoding sequence is predicted not to be shared with rat, a closely related rodent. The rapidity of turnover results in, at least, a twofold underestimate of α_sel by analyses that measure constraint across the eutherian phylogeny. Approaches that take account of turnover estimate that the steady-state value of α_sel lies between 10% and 15%. Experimental studies corroborate the predicted rates of loss and gain of noncoding functional sites. These studies show the limitations inherent in the use of deep sequence conservation for identifying functional sequence. Experimental investigations focusing on lineage-specific, noncoding, and functional sequence are now essential if we are to appreciate the complete functional repertoire of the human genome.

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution:

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

Nature Communications 2, 519 (2011). doi:10.1038/ncomms1525

Authors: Shai Carmi, George M. Church & Erez Y. Levanon

De Novo Genesis of Enhancers in Vertebrates

De Novo Genesis of Enhancers in Vertebrates:
by Michael P. Eichenlaub, Laurence Ettwiller


Evolutionary innovation relies partially on changes in gene regulation. While a growing body of evidence demonstrates that such innovation is generated by functional changes or translocation of regulatory elements via mobile genetic elements, the de novo generation of enhancers from non-regulatory/non-mobile sequences has, to our knowledge, not previously been demonstrated. Here we show evidence for the de novo genesis of enhancers in vertebrates. For this, we took advantage of the massive gene loss following the last whole genome duplication in teleosts to systematically identify regions that have lost their coding capacity but retain sequence conservation with mammals. We found that these regions show enhancer activity while the orthologous coding regions have no regulatory activity. These results demonstrate that these enhancers have been de novo generated in fish. By revealing that minor changes in non-regulatory sequences are sufficient to generate new enhancers, our study highlights an important playground for creating new regulatory variability and evolutionary innovation.