An important feature of development is the formation of patterns that are proportional to the overall size of the embryo. But how such proportionality, or scaling, is achieved mechanistically remains poorly understood. Furthermore, it is currently unclear whether organisms utilize similar or distinct mechanisms to achieve scaling within a species and between species. Here we investigate within-species scaling mechanisms for anterior-posterior (A-P) patterning in Drosophila melanogaster, focusing specifically on the properties of the Bicoid (Bcd) morphogen gradient. Using embryos from lines artificially selected for large and small egg volume, we show that large embryos have higher nuclear Bcd concentrations in the anterior than small embryos. This anterior difference leads to scaling properties of the Bcd gradient profiles: in broad regions of the large and small embryos along the A-P axis, normalizing their positions to embryo length reduces the differences in both the nuclear Bcd concentrations and Bcd-encoded positional information. We further trace the origin of Bcd gradient scaling by showing directly that large embryos have more maternally deposited bcd mRNA than small embryos. Our results suggest a simple model for how within-species Bcd gradient scaling can be achieved. In this model, the Bcd production rate, which is dependent on the total number of bcd mRNA molecules in the anterior, is scaled with embryo volume.
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Justin Crocker's reading list...
Tuesday, June 7, 2011
Scaling of the Bicoid morphogen gradient by a volume-dependent production rate [RESEARCH ARTICLES]
Friday, June 3, 2011
Distinct Functional Constraints Partition Sequence Conservation in a cis-Regulatory Element
by Antoine Barrière, Kacy L. Gordon, Ilya Ruvinsky
Different functional constraints contribute to different evolutionary rates across genomes. To understand why some sequences evolve faster than others in a single cis-regulatory locus, we investigated function and evolutionary dynamics of the promoter of the Caenorhabditis elegans unc-47 gene. We found that this promoter consists of two distinct domains. The proximal promoter is conserved and is largely sufficient to direct appropriate spatial expression. The distal promoter displays little if any conservation between several closely related nematodes. Despite this divergence, sequences from all species confer robustness of expression, arguing that this function does not require substantial sequence conservation. We showed that even unrelated sequences have the ability to promote robust expression. A prominent feature shared by all of these robustness-promoting sequences is an AT-enriched nucleotide composition consistent with nucleosome depletion. Because general sequence composition can be maintained despite sequence turnover, our results explain how different functional constraints can lead to vastly disparate rates of sequence divergence within a promoter.
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HIGH-DIMENSIONAL VARIANCE PARTITIONING REVEALS THE MODULAR GENETIC BASIS OF ADAPTIVE DIVERGENCE IN GENE EXPRESSION DURING REPRODUCTIVE CHARACTER DISPLACEMENT
ABSTRACT
Although adaptive change is usually associated with complex changes in phenotype, few genetic investigations have been conducted of adaptations that involve sets of high dimensional traits. Microarrays have supplied high-dimensional descriptions of gene expression, and phenotypic change resulting from adaptation often results in large-scale changes in gene expression. We demonstrate how genetic analysis of large-scale changes in gene expression generated during adaptation can be accomplished by determining by high-dimensional variance partitioning within classical genetic experimental designs. A microarray experiment conducted on a panel of recombinant inbred lines (RILs) generated from two populations of Drosophila serrata that have diverged in response to natural selection, revealed genetic divergence in 10.6% of 3762 gene products examined. Over 97% of the genetic divergence in transcript abundance was explained by only 12 genetic modules. The two most important modules, explaining 50% of the genetic variance in transcript abundance, were genetically correlated with the morphological traits that are known to be under selection. The expression of three candidate genes from these two important genetic modules was assessed in an independent experiment using qRT-PCR on 430 individuals from the panel of RILs, and confirmed the genetic association between transcript abundance and morphological traits under selection.
Cryptic genetic variation promotes rapid evolutionary adaptation in an
RNA enzyme
Cryptic genetic variation promotes rapid evolutionary adaptation in an
RNA enzyme
Nature 474, 7349 (2011). doi:10.1038/nature10083
Authors: Eric J. Hayden, Evandro Ferrada & Andreas Wagner
Cryptic variation is caused by the robustness of phenotypes to mutations. Cryptic variation has no effect on phenotypes in a given genetic
or environmental background, but it can have effects after mutations or environmental
change. Because evolutionary adaptation by natural
selection requires phenotypic variation, phenotypically revealed cryptic genetic
variation may facilitate evolutionary adaptation. This
is possible if the cryptic variation happens to be pre-adapted, or “exapted”, to a new environment, and is thus advantageous once revealed.
However, this facilitating role for cryptic variation has not been proven,
partly because most pertinent work focuses on complex phenotypes of whole
organisms whose genetic basis is incompletely understood. Here we show that
populations of RNA enzymes with accumulated cryptic variation adapt more rapidly
to a new substrate than a population without cryptic variation. A detailed
analysis of our evolving RNA populations in genotype space shows that cryptic
variation allows a population to explore new genotypes that become adaptive
only in a new environment. Our observations show that cryptic variation contains
new genotypes pre-adapted to a changed environment. Our results highlight
the positive role that robustness and epistasis can have in adaptive evolution.
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High sensitivity to aligner and high rate of false positives in the estimates of positive selection in the 12 Drosophila genomes [RESEARCH]
We investigate the effect of aligner choice on inferences of positive selection using site-specific models of molecular evolution. We find that independently of the choice of aligner, the rate of false positives is unacceptably high. Our study is a whole-genome analysis of all protein-coding genes in 12 Drosophila genomes annotated in either all 12 species (~6690 genes) or in the six melanogaster group species. We compare six popular aligners: PRANK, T-Coffee, ClustalW, ProbCons, AMAP, and MUSCLE, and find that the aligner choice strongly influences the estimates of positive selection. Differences persist when we use (1) different stringency cutoffs, (2) different selection inference models, (3) alignments with or without gaps, and/or additional masking, (4) per-site versus per-gene statistics, (5) closely related melanogaster group species versus more distant 12 Drosophila genomes. Furthermore, we find that these differences are consequential for downstream analyses such as determination of over/under-represented GO terms associated with positive selection. Visual analysis indicates that most sites inferred as positively selected are, in fact, misaligned at the codon level, resulting in false positive rates of 48%–82%. PRANK, which has been reported to outperform other aligners in simulations, performed best in our empirical study as well. Unfortunately, PRANK still had a high, and unacceptable for most applications, false positives rate of 50%–55%. We identify misannotations and indels, many of which appear to be located in disordered protein regions, as primary culprits for the high misalignment-related error levels and discuss possible workaround approaches to this apparently pervasive problem in genome-wide evolutionary analyses.
"Natural genetic variation caused by small insertions and deletions in the human genome [RESEARCH]
Human genetic variation is expected to play a central role in personalized medicine. Yet only a fraction of the natural genetic variation that is harbored by humans has been discovered to date. Here we report almost 2 million small insertions and deletions (INDELs) that range from 1 bp to 10,000 bp in length in the genomes of 79 diverse humans. These variants include 819,363 small INDELs that map to human genes. Small INDELs frequently were found in the coding exons of these genes, and several lines of evidence indicate that such variation is a major determinant of human biological diversity. Microarray-based genotyping experiments revealed several interesting observations regarding the population genetics of small INDEL variation. For example, we found that many of our INDELs had high levels of linkage disequilibrium (LD) with both HapMap SNPs and with high-scoring SNPs from genome-wide association studies. Overall, our study indicates that small INDEL variation is likely to be a key factor underlying inherited traits and diseases in humans.
"Thursday, June 2, 2011
Genetic basis of wing morphogenesis in Drosophila: sexual dimorphism and non-allometric effects of shape variation
The Drosophila wing represents a particularly appropriate model to investigate the developmental control of phenotypic variation. Previous studies which aimed to identify candidate genes for wing morphology demonstrated that the genetic basis of wing shape variation in D. melanogaster is composed of numerous genetic factors causing small, additive effects. In this study, we analyzed wing shape in males and females from 191 lines of D. melanogaster, homozygous for a single P-element insertion, using geometric morphometrics techniques. The analysis allowed us to identify known and novel candidate genes that may contribute to the expression of wing shape in each sex separately and to compare them to candidate genes affecting wing size which have been identified previously using the same lines.
Results:
Our results indicate that more than 63% of induced mutations affected wing shape in one or both sexes, although only 33% showed significant differences in both males and females. The joint analysis of wing size and shape revealed that only 19% of the P-element insertions caused coincident effects on both components of wing form in one or both sexes. Further morphometrical analyses revealed that the intersection between veins showed the smallest displacements in the proximal region of the wing. Finally, we observed that mutations causing general deformations were more common than expected in both sexes whereas the opposite occurred with those generating local changes. For most of the 94 candidate genes identified, this seems to be the first record relating them with wing shape variation.
Conclusions:
Our results support the idea that the genetic architecture of wing shape is complex with many different genes contributing to the trait in a sexually dimorphic manner. This polygenic basis, which is relatively independent from that of wing size, is composed of genes generally involved in development and/or metabolic functions, especially related to the regulation of different cellular processes such as motility, adhesion, communication and signal transduction. This study suggests that understanding the genetic basis of wing shape requires merging the regulation of vein patterning by signalling pathways with processes that occur during wing development at the cellular level."