Pleiotropic fitness effects across sexes and ages in the Drosophila genome and transcriptome.

Selection varies between categories of individuals, with far-reaching ramifications: Sex-specific selection can impede or accelerate adaptation, and differences in selection between young and old individuals are ultimately responsible for senescence. Here, we measure early- and late-life fitness in adults of both sexes from the Drosophila genetic reference panel and perform quantitative genetic and transcriptomic analyses. Fitness was heritable, showed positive pleiotropy across sexes and age classes, and appeared to be influenced by very large numbers of loci with small effects plus a smaller number with moderate effects. Most loci affected male and female fitness in the same direction; relatively few candidate sexually antagonistic loci were found, though these were enriched on the X chromosome as predicted by theory. The expression level of many genes showed an opposite correlation with fitness in males and females, consistent with unresolved sexual conflict over transcription. The load of deleterious mutations correlated negatively with fitness across genotypes, and we found some evidence for the mutation accumulation (but not the antagonistic pleiotropy) theory of aging.

Sibling rivalry versus mother's curse: can kin competition facilitate a response to selection on male mitochondria?

Assuming that fathers never transmit mitochondrial DNA (mtDNA) to their offspring, mitochondrial mutations that affect male fitness are invisible to direct selection on males, leading to an accumulation of male-harming alleles in the mitochondrial genome (mother's curse). However, male phenotypes encoded by mtDNA can still undergo adaptation via kin selection provided that males interact with females carrying related mtDNA, such as their sisters. Here, using experiments with Drosophila melanogaster carrying standardized nuclear DNA but distinct mitochondrial DNA, we test whether the mitochondrial haplotype carried by interacting pairs of larvae affects survival to adulthood, as well as the fitness of the adults. Although mtDNA had no detectable direct or indirect genetic effect on larva-to-adult survival, the fitness of male and female adults was significantly affected by their own mtDNA and the mtDNA carried by their social partner in the larval stage. Thus, mtDNA mutations that alter the effect of male larvae on nearby female larvae (which often carry the same mutation, due to kinship) could theoretically respond to kin selection. We discuss the implications of our findings for the evolution of mitochondria and other maternally inherited endosymbionts.

Fitness consequences of the selfish supergene Segregation Distorter.

Segregation distorters are selfish genetic elements that subvert Mendelian inheritance, often by destroying gametes that do not carry the distorter. Simple theoretical models predict that distorter alleles will either spread to fixation or stabilize at some high intermediate frequency. However, many distorters have substantially lower allele frequencies than predicted by simple models, suggesting that key sources of selection remain to be discovered. Here, we measured the fitness of Drosophila melanogaster adults and juveniles carrying zero, one or two copies of three different variants of the naturally occurring supergene Segregation Distorter (SD), in order to investigate why SD alleles remain relatively rare within populations despite being preferentially inherited. First, we show that the three SD variants differ in the severity and dominance of the fitness costs they impose on individuals carrying them. Second, SD-carrying parents produced less fit offspring in some crosses, independent of offspring genotype, indicating that SD alleles can have nongenetic, transgenerational costs in addition to their direct costs. Third, we found that SD carriers sometimes produce a biased offspring sex ratio, perhaps due to off-target effects of SD on the sex chromosomes. Finally, we used a theoretical model to investigate how sex ratio and transgenerational effects alter the population genetics of distorter alleles; accounting for these additional costs helps to explain why real-world segregation distorter alleles are rarer than predicted.

Mother's curse and indirect genetic effects: Do males matter to mitochondrial genome evolution?

Maternal inheritance of mitochondrial DNA (mtDNA) was originally thought to prevent any response to selection on male phenotypic variation attributable to mtDNA, resulting in a male-biased mtDNA mutation load ("mother's curse"). However, the theory underpinning this claim implicitly assumes that a male's mtDNA has no effect on the fitness of females he comes into contact with. If such "mitochondrially encoded indirect genetics effects" (mtIGEs) do in fact exist, and there is relatedness between the mitochondrial genomes of interacting males and females, male mtDNA-encoded traits can undergo adaptation after all. We tested this possibility using strains of Drosophila melanogaster that differ in their mtDNA. Our experiments indicate that female fitness is influenced by the mtDNA carried by males that the females encounter, which could plausibly allow the mitochondrial genome to evolve via kin selection. We argue that mtIGEs are probably common, and that this might ameliorate or exacerbate mother's curse.

JNK signaling is needed to tolerate chromosomal instability.

Chromosomal instability (CIN), as a common feature of tumors, represents a potential therapeutic target if ways can be found to specifically cause apoptosis in unstably dividing cells. We have previously shown that if signaling through the JNK pathway is reduced, apoptosis is triggered in models of chromosomal instability induced by loss of the spindle checkpoint. Here we identify components upstream and downstream of JNK that are able to mediate this effect, and test the involvement of p53 and DNA damage in causing apoptosis when JNK signaling is reduced in CIN cells. We show that cell cycle progression timing has a strong effect on the apoptosis seen when JNK signaling is reduced in genetically unstable cells: a shortened G 2 phase enhances the apoptosis, while lengthening G 2 rescues the JNK-deficient CIN cell death phenotype. Our findings suggest that chromosomal instability represents a significant stress to dividing cells, and that without JNK signaling, cells undergo apoptosis because they lack a timely and effective response to DNA damage.

A screen for selective killing of cells with chromosomal instability induced by a spindle checkpoint defect.

BACKGROUND: The spindle assembly checkpoint is crucial for the maintenance of a stable chromosome number. Defects in the checkpoint lead to Chromosomal INstability (CIN), which is linked to the progression of tumors with poor clinical outcomes such as drug resistance and metastasis. As CIN is not found in normal cells, it offers a cancer-specific target for therapy, which may be particularly valuable because CIN is common in advanced tumours that are resistant to conventional therapy. PRINCIPAL FINDINGS: Here we identify genes that are required for the viability of cells with a CIN phenotype. We have used RNAi knockdown of the spindle assembly checkpoint to induce CIN in Drosophila and then screened the set of kinase and phosphatase genes by RNAi knockdown to identify those that induce apoptosis only in the CIN cells. Genes identified include those involved in JNK signaling pathways and mitotic cytoskeletal regulation. CONCLUSIONS/SIGNIFICANCE: The screen demonstrates that it is feasible to selectively kill cells with CIN induced by spindle checkpoint defects. It has identified candidates that are currently being pursued as cancer therapy targets (e.g. Nek2: NIMA related kinase 2), confirming that the screen is able to identify promising drug targets of clinical significance. In addition, several other candidates were identified that have no previous connection with mitosis or apoptosis. Further screening and detailed characterization of the candidates could potentially lead to the therapies that specifically target advanced cancers that exhibit CIN.