Animal Transcription Networks as Highly Connected, Quantitative Continua

Animal Transcription Networks as Highly Connected, Quantitative Continua: Mark D. Biggin. To understand how transcription factors function, it is essential to determine the range of genes that they each bind and regulate in vivo. Here I review evidence that most animal transcription fa....

Deciphering Gene Expression Patterns

Deciphering Gene Expression Patterns: Norbert Perrimon. Large-scale studies in various model systems including Drosophila, fish, and the mouse have documented the exquisite temporal and spatial expression patterns of thousands of genes during de....

Preventing Dangerous Nonsense: Selection for Robustness to Transcriptional Error in Human Genes

Preventing Dangerous Nonsense: Selection for Robustness to Transcriptional Error in Human Genes:

by Brian P. Cusack, Peter F. Arndt, Laurent Duret, Hugues Roest Crollius

Nonsense Mediated Decay (NMD) degrades transcripts that contain a premature STOP codon resulting from mistranscription or missplicing. However NMD's surveillance of gene expression varies in efficiency both among and within human genes. Previous work has shown that the intron content of human genes is influenced by missplicing events invisible to NMD. Given the high rate of transcriptional errors in eukaryotes, we hypothesized that natural selection has promoted a dual strategy of “prevention and cure” to alleviate the problem of nonsense transcriptional errors. A prediction of this hypothesis is that NMD's inefficiency should leave a signature of “transcriptional robustness” in human gene sequences that reduces the frequency of nonsense transcriptional errors. For human genes we determined the usage of “fragile” codons, prone to mistranscription into STOP codons, relative to the usage of “robust” codons that do not generate nonsense errors. We observe that single-exon genes have evolved to become robust to mistranscription, because they show a significant tendency to avoid fragile codons relative to robust codons when compared to multi-exon genes. A similar depletion is evident in last exons of multi-exon genes. Histone genes are particularly depleted of fragile codons and thus highly robust to transcriptional errors. Finally, the protein products of single-exon genes show a strong tendency to avoid those amino acids that can only be encoded using fragile codons. Each of these observations can be attributed to NMD deficiency. Thus, in the human genome, wherever the “cure” for nonsense (i.e. NMD) is inefficient, there is increased reliance on the strategy of nonsense “prevention” (i.e. transcriptional robustness). This study shows that human genes are exposed to the deleterious influence of transcriptional errors. Moreover, it suggests that gene expression errors are an underestimated phenomenon, in molecular evolution in general and in selection for genomic robustness in particular.

[Report] The Dynamic Architecture of Hox Gene Clusters

[Report] The Dynamic Architecture of Hox Gene Clusters: Sequential activation of Hox genes correlates with a transition of negative to positive three-dimensional chromosome structure.

Authors: Daan Noordermeer, Marion Leleu, Erik Splinter, Jacques Rougemont, Wouter De Laat, Denis Duboule

Regulatory elements required for the activation and repression of the protocadherin-{alpha} gene cluster [Neuroscience]

Regulatory elements required for the activation and repression of the protocadherin-{alpha} gene cluster [Neuroscience]: The mouse protocadherin (Pcdh) -α, -β, and -γ gene clusters encode more than 50 protein isoforms, the combinatorial expression of which generates vast single-cell diversity in the brain. At present, the mechanisms by which this diversity is expressed are not understood. Here we show that two transcriptional enhancer elements, HS5-1 and HS7, play a critical role in Pcdhα gene expression in mice. We show that the HS5-1 element functions as an enhancer in neurons and a silencer in nonneuronal cells. The enhancer activity correlates with the binding of zinc finger DNA binding protein CTCF to the target promoters, and the silencer activity requires the binding of the REST/NRSF repressor complex in nonneuronal cells. Thus, the HS5-1 element functions as a neuron-specific enhancer and nonneuronal cell repressor. In contrast, the HS7 element functions as a Pcdhα cluster-wide transcription enhancer element. These studies reveal a complex organization of regulatory elements required for generating single cell Pcdh diversity.

Joint morphology in the insect leg: evolutionary history inferred from Notch loss-of-function phenotypes in Drosophila [RESEARCH REPORT]

Joint morphology in the insect leg: evolutionary history inferred from Notch loss-of-function phenotypes in Drosophila [RESEARCH REPORT]: Reiko Tajiri, Kazuyo Misaki, Shigenobu Yonemura, and Shigeo Hayashi

Joints permit efficient locomotion, especially among animals with a rigid skeleton. Joint morphologies vary in the body of individual animals, and the shapes of homologous joints often differ across species. The diverse locomotive behaviors of animals are based, in part, on the developmental and evolutionary history of joint morphogenesis. We showed previously that strictly coordinated cell-differentiation and cell-movement events within the epidermis sculpt the interlocking ball-and-socket joints in the adult Drosophila tarsus (distal leg). Here, we show that the tarsal joints of various insect species can be classified into three types: ball-and-socket, side-by-side and uniform. The last two probably result from joint formation without the cell-differentiation step, the cell-movement step, or both. Similar morphological variations were observed in Drosophila legs when Notch function was temporarily blocked during joint formation, implying that the independent acquisition of cell differentiation and cell movement underlay the elaboration of tarsal joint morphologies during insect evolution. These results provide a framework for understanding how the seemingly complex morphology of the interlocking joint could have developed during evolution by the addition of simple developmental modules: cell differentiation and cell movement.

Copy-Number Variation: The Balance between Gene Dosage and Expression in Drosophila melanogaster

Copy-Number Variation: The Balance between Gene Dosage and Expression in Drosophila melanogaster:

Copy-number variants (CNVs) reshape gene structure, modulate gene expression, and contribute to significant phenotypic variation. Previous studies have revealed CNV patterns in natural populations of Drosophila melanogaster and suggested that selection and mutational bias shape genomic patterns of CNV. Although previous CNV studies focused on heterogeneous strains, here, we established a number of second-chromosome substitution lines to uncover CNV characteristics when homozygous. The percentage of genes harboring CNVs is higher than found in previous studies. More CNVs are detected in homozygous than heterozygous substitution strains, suggesting the comparative genomic hybridization arrays underestimate CNV owing to heterozygous masking. We incorporated previous gene expression data collected from some of the same substitution lines to investigate relationships between CNV gene dosage and expression. Most genes present in CNVs show no evidence of increased or diminished transcription, and the fraction of such dosage-insensitive CNVs is greater in heterozygotes. More than 70% of the dosage-sensitive CNVs are recessive with undetectable effects on transcription in heterozygotes. A deficiency of singletons in recessive dosage-sensitive CNVs supports the hypothesis that most CNVs are subject to negative selection. On the other hand, relaxed purifying selection might account for the higher number of protein–protein interactions in dosage-insensitive CNVs than in dosage-sensitive CNVs. Dosage-sensitive CNVs that are upregulated and downregulated coincide with copy-number increases and decreases. Our results help clarify the relation between CNV dosage and gene expression in the D. melanogaster genome.