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.

Species 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.

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.

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.