Mutations in ASPM (abnormal spindle-like microcephaly associated) cause primary microcephaly in humans, a disorder characterized by a major reduction in brain size in the apparent absence of nonneurological anomalies. The function of the Aspm protein in neural progenitor cell expansion, as well as its localization to the mitotic spindle and midbody, suggest that it regulates brain development by a cell division-related mechanism. Furthermore, evidence that positive selection affected ASPM during primate evolution has led to suggestions that such a function changed during primate evolution. Here, we report that in Aspm mutant mice, truncated Aspm proteins similar to those causing microcephaly in humans fail to localize to the midbody during M-phase and cause mild microcephaly. A human ASPM transgene rescues this phenotype but, interestingly, does not cause a gain of function. Strikingly, truncated Aspm proteins also cause a massive loss of germ cells, resulting in a severe reduction in testis and ovary size accompanied by reduced fertility. These germline effects, too, are fully rescued by the human ASPM transgene, indicating that ASPM is functionally similar in mice and humans. Our findings broaden the spectrum of phenotypic effects of ASPM mutations and raise the possibility that positive selection of ASPM during primate evolution reflects its function in the germline.evolution | cerebral cortex | fertility | neural stem cells | germ cells

The idea of introducing genetic modifications into wild populations of insects to stop them from spreading diseases is more than 40 years old. Synthetic disease refractory genes have been successfully generated for mosquito vectors of dengue fever and human malaria. Equally important is the development of population transformation systems to drive and maintain disease refractory genes at high frequency in populations. We demonstrate an underdominant population transformation system in Drosophila melanogaster that has the property of being both spatially self-limiting and reversible to the original genetic state. Both population transformation and its reversal can be largely achieved within as few as 5 generations. The described genetic construct {Ud} is composed of two genes; (1) a UAS-RpL14.dsRNA targeting RNAi to a haploinsufficient gene RpL14 and (2) an RNAi insensitive RpL14 rescue. In this proof-of-principle system the UAS-RpL14.dsRNA knock-down gene is placed under the control of an Actin5c-GAL4 driver located on a different chromosome to the {Ud} insert. This configuration would not be effective in wild populations without incorporating the Actin5c-GAL4 driver as part of the {Ud} construct (or replacing the UAS promoter with an appropriate direct promoter). It is however anticipated that the approach that underlies this underdominant system could potentially be applied to a number of species.

Genome-wide scans for positive selection in humans provide a promising approach to establish links between genetic variants and adaptive phenotypes. From this approach, lists of hundreds of candidate genomic regions for positive selection have been assembled. These candidate regions are expected to contain variants that contribute to adaptive phenotypes, but few of these regions have been associated with phenotypic effects. Here we present evidence that a derived nonsynonymous substitution (370A) in EDAR, a gene involved in ectodermal development, was driven to high frequency in East Asia by positive selection prior to 10,000 years ago. With an in vitro transfection assay, we demonstrate that 370A enhances NF-κB activity. Our results suggest that 370A is a positively selected functional genetic variant that underlies an adaptive human phenotype.

BackgroundSpecies with heteromorphic sex chromosomes face the challenge of large-scale imbalance in gene dose. Microarray-based studies in several independent male heterogametic XX/XY systems suggest that dosage compensation mechanisms are in place to mitigate the detrimental effects of gene dose differences. However, recent genomic research on female heterogametic ZZ/ZW systems has generated surprising results. In two bird species and one lepidopteran no evidence for a global dosage compensating mechanism has been found. The recent advent of massively parallel RNA sequencing now opens up the possibility to gauge the generality of this observation with a broader phylogenetic sampling. It further allows assessing the validity of microarray-based inference on dosage compensation with a novel technology.ResultsWe here expemplify this approach using massively parallel sequencing on barcoded individuals of a bird species, the European crow (Corvus corone), where previously no genetic resources were available. Testing for Z-linkage with quantitative PCR (qPCR,) we first establish that orthology with distantly related species (chicken, zebra finch) can be used as a good predictor for chromosomal affiliation of a gene. We then use a digital measure of gene expression (RNA-seq) on brain transcriptome and confirm a global lack of dosage compensation on the Z chromosome. RNA-seq estimates of male-to-female (m:f) expression difference on the Z compare well to previous microarray-based estimates in birds and lepidopterans. The data further lends support that an up-regulation of female Z-linked genes conveys partial compensation and suggest a relationship between sex-bias and absolute expression level of a gene. Correlation of sex-biased gene expression on the Z chromosome across all three bird species further suggests that the degree of compensation has been partly conserved across 100 million years of avian evolution.ConclusionsThis work demonstrates that the study of dosage compensation has become amenable to species where previously no genetic resources were available. Massively parallele transcriptome sequencing allows re-assessing the degree of dosage compensation with a novel tool in well-studies species and, in addition, gain valuable insights into the generality of mechanisms across independent taxonomic group for both the XX/XY and ZZ/ZW system.

Understanding how polygenic traits evolve under selection is an unsolved problem, because challenges exist for identifying genes underlying a complex trait and understanding how multilocus selection operates in the genome. Here we study polygenic response to selection using artificial selection experiments. Inbred strains from seven independent long-term selection experiments for extreme mouse body weight ("high" lines weigh 42-77 g versus 16-40 g in "control" lines) were genotyped at 527,572 SNPs to identify loci controlling body weight. We identified 67 parallel selected regions (PSRs) where high lines share variants rarely found among the controls. By comparing allele frequencies in one selection experiment against its unselected control, we found classical selective sweeps centered on the PSRs. We present evidence supporting two G protein-coupled receptors GPR133 and Prlhr as positional candidates controlling body weight. Artificial selection may mimic natural selection in the wild: compared to control loci, we detected reduced heterozygosity in PSRs in unusually large wild mice on islands. Many PSRs overlap loci associated with human height variation, possibly through evolutionary conserved functional pathways. Our data suggest that parallel selection on complex traits may evoke parallel responses at many genes involved in diverse but relevant pathways.

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Whereas all mammals have one glutamate dehydrogenase gene (GLUD1), humans and apes carry an additional gene (GLUD2), which encodes an enzyme with distinct biochemical properties. We inserted a bacterial artificial chromosome containing the human GLUD2 gene into mice and analyzed the resulting changes in the transcriptome and metabolome during postnatal brain development. Effects were most pronounced early postnatally, and predominantly genes involved in neuronal development were affected. Remarkably, the effects in the transgenic mice partially parallel the transcriptome and metabolome differences seen between humans and macaques analyzed. Notably, the introduction of GLUD2 did not affect glutamate levels in mice, consistent with observations in the primates. Instead, the metabolic effects of GLUD2 center on the tricarboxylic acid cycle, suggesting that GLUD2 affects carbon flux during early brain development, possibly supporting lipid biosynthesis.human evolution | GLUD2 | brain metabolism G lutamate dehydrogenase (GDH) is a metabolic enzyme catalyzing the conversion of glutamate to α-ketoglutarate and ammonia (1). Whereas the ammonia is metabolized via the urea cycle, the α-ketoglutarate enters the tricarboxylic acid (TCA) cycle in mitochondria. Besides its metabolic role, glutamate also functions as a major excitatory neurotransmitter (2, 3).Whereas most organisms contain one copy of the GLUD gene encoding the GDH enzyme, humans and apes have two: GLUD1 and an additional gene, GLUD2, which originated by retroposition of the GLUD1 transcript after the split from apes and old world monkeys (4). Sequence analysis suggests that it is highly unlikely that GLUD2 would have contained an intact ORF and a K a /K s <1 throughout the evolution of apes without being functional (5). Moreover, positive selection has affected GLUD2 (4), including changes in amino acid residues that make it less sensitive to low pH and GTP inhibition, and resulting in a requirement for high ADP levels for allosteric activation (4, 6, 7). GLUD2 mRNA expression levels in tissues are lower than those of GLUD1, but similarly distributed across tissues. However, whereas the ancestral version of the GLUD enzyme occurs both in mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria (8, 9).Changes in GLUD2 properties have been suggested to reflect functional adaptation to the metabolism of the neurotransmitter glutamate in the brain (4, 10), and the fact that GLUD2 has been positively selected and maintained during ape and human evolution suggests that it may have physiological effects important for the function of ape and human brains. However, the connection between the emergence of the GLUD2 gene in the ancestors of apes and humans and changes in brain function remains elusive. To date, the only direct insights into GLUD2 function come from a rare GLUD2 mutation linked to the onset of Parkinson's disease (11) and from glioma cells carrying a mutated isocitrate dehydrogenase 1 gene (IDH1) where GLUD2 expression reverses the ...

Divergence of gene expression is known to contribute to the differentiation and separation of populations and species, although the dynamics of this process in early stages of population divergence remains unclear. We analyzed gene expression differences in three organs (brain, liver, and testis) between two natural populations of Mus musculus domesticus that have been separated for at most 3000 years. We used two different microarray platforms to corroborate the results at a large scale and identified hundreds of genes with significant expression differences between the populations. We find that although the three tissues have similar number of differentially expressed genes, brain and liver have more tissue–specific genes than testis. Most genes show changes in a single tissue only, even when expressed in all tissues, supporting the notion that tissue–specific enhancers act as separable targets of evolution. In terms of functional categories, in brain and to a smaller extent in liver, we find transcription factors and their targets to be particularly variable between populations, similar to previous findings in primates. Testis, however, has a different set of differently expressed genes, both with respect to functional categories and overall correlation with the other tissues, the latter indicating that gene expression divergence of potential importance might be present in other datasets where no differences in fraction of differentially expressed genes were reported. Our results show that a significant amount of gene expression divergence quickly accumulates between allopatric populations.