Abstract.-The number of ovarioles of the Drosophila melanogaster ovary is a trait thought to be associated with female fecundity, and therefore is expected to be under strong natural selection. This hypothesis may be tested by examining patterns of genetic and environmental variation for ovariole number in natural populations, and by determining the association between ovariole number and fitness in isogenic lines derived from a natural population. We measured ovariole number, and competitive fitness and its components, for 48 homozygous chromosome 3 substitution lines in a standard inbred background; and body size in a sample of 15 chromosome 3 substitution lines. We found significant segregating genetic variation for ovariole number, with a broad-sense heritability (EP) of 0.403 and correspondingly high coefficients of genetic variation (CV a = 20.8) and residual variation (CV R = 25.3). Estimates of quantitativegenetic parameters for body size (EP = 0.191, CV a = 2.15, and CV R = 3.87) are similar to those previously reported for this trait. Although the isogenic chromosome 3 substitution lines varied significantly for components of fitness, there was no significant linear or quadratic association of ovariole number and body size with fitness. There was, however, highly significant sex X genotypeinteractionfor fitness amongthese lines. This specialcase of genotype X environment interaction for fitness may contribute to the maintenance of genetic variation for fitness in natural populations.Key words.e-Drosophila melanogaster, ovariole, variation.Received April 14, 1996. Accepted March 13, 1997.Understanding the nature of the evolutionary processes leading to the maintenance of quantitative genetic variation within populations and the divergence of trait means between populations and species remains one of the leading unanswered questions in evolutionary biology today. Several mechanisms could, in theory, maintain variation for quantitative traits: mutation-drift balance of selectively neutral alleles (Lynch and Hill 1986), overdominance (Robertson 1956), mutation-selection balance (Barton and Turelli 1989), antagonistic pleiotropy (Rose and Charlesworth 1981), and environmental heterogeneity (Gillespie and Turelli 1989). Different categories of quantitative traits (e.g., morphological and life history) are characterized by different magnitudes of, and proportional contributions of, additive genetic variation and environmental variation (Houle 1992;Falconer and Mackay 1996). This implies that the evolutionary mechanisms maintaining variation and the nature of genetic variation are likely to be different for morphological and lifehistory traits. However, progress in evaluating which mechanisms are responsible for maintaining genetic variation for any quantitative trait has been hindered by tests that rely on relative magnitudes of segregating genetic and mutational variance, genetic correlations between traits, inbreeding depression, the genomic mutation rate and average selection against new mutations (Crow an...

Loss-of-function mutations in ORGANELLE RNA RECOGNITION MOTIF PROTEIN6 (ORRM6) result in the near absence of RNA editing of psbF-C77 and the reduction in accD-C794 editing in Arabidopsis (Arabidopsis thaliana). The orrm6 mutants have decreased levels of photosystem II (PSII) proteins, especially PsbF, lower PSII activity, pale green pigmentation, smaller leaf and plant sizes, and retarded growth. Stable expression of ORRM6 rescues the orrm6 editing defects and mutant phenotype. Unlike ORRM1, the other known ORRM plastid editing factor, ORRM6, does not contain RNA editing interacting protein/multiple organellar RNA editing factor (RIP/MORF) boxes, which are required for ORRM1 to interact with site-specific pentatricopeptide repeat protein editing factors. ORRM6 interacts with RIP1/MORF8, RIP2/MORF2, and RIP9/MORF9, known components of RNA editosomes. While some plastid RRM proteins are involved in other forms of RNA processing and translation, the primary function of ORRM6 is evidently to mediate psbF-C77 editing, like the essential site-specific pentatricopeptide repeat protein LOW PSII ACCUMULATION66. Stable expression in the orrm6 mutants of a nucleus-encoded, plastid-targeted PsbF protein from a psbF gene carrying a T at nucleotide 77 significantly increases leaf and plant sizes, chlorophyll content, and PSII activity. These transformants demonstrate that plastid RNA editing can be bypassed through the expression of nucleus-encoded, edited forms of plastid genes.

We examined the genetic architecture of four fitness-related traits (reproductive success, ovariole number, body size and early fecundity) in a panel of 98 Oregon-R x 2b3 recombinant inbred lines (RILs). Highly significant genetic variation was observed in this population for female, but not male, reproductive success. The cross-sex genetic correlation for reproductive success was 0.20, which is not significantly different from zero. There was significant genetic variation segregating in this cross for ovariole number, but not for body size or early fecundity. The RILs were genotyped for cytological insertion sites of roo transposable elements, yielding 76 informative markers with an average spacing of 3.2 cM. Quantitative trait loci (QTL) affecting female reproductive success and ovariole number were mapped using a composite interval mapping procedure. QTL for female reproductive success were located at the tip of the X chromosome between markers at cytological locations 1B and 3E; and on the left arm of chromosome 2 in the 30D-38A cytological region. Ovariole number QTL mapped to cytological intervals 62D-69D and 98A-98E, both on the third chromosome. The regions harbouring QTL for female reproductive success and ovariole number were also identified as QTL for longevity in previous studies with these lines.

The number of ovarioles of the Drosophila melanogaster ovary is a trait thought to be associated with female fecundity, and therefore is expected to be under strong natural selection. This hypothesis may be tested by examining patterns of genetic and environmental variation for ovariole number in natural populations, and by determining the association between ovariole number and fitness in isogenic lines derived from a natural population. We measured ovariole number, and competitive fitness and its components, for 48 homozygous chromosome 3 substitution lines in a standard inbred background; and body size in a sample of 15 chromosome 3 substitution lines. We found significant segregating genetic variation for ovariole number, with a broad-sense heritability (EP) of 0.403 and correspondingly high coefficients of genetic variation (CV a = 20.8) and residual variation (CV R = 25.3). Estimates of quantitativegenetic parameters for body size (EP = 0.191, CV a = 2.15, and CV R = 3.87) are similar to those previously reported for this trait. Although the isogenic chromosome 3 substitution lines varied significantly for components of fitness, there was no significant linear or quadratic association of ovariole number and body size with fitness. There was, however, highly significant sex X genotypeinteractionfor fitness amongthese lines. This specialcase of genotype X environment interaction for fitness may contribute to the maintenance of genetic variation for fitness in natural populations.

Aberrant expression of the Forkhead box transcription factor, FOXQ1, is a prevalent mechanism of epithelial-mesenchymal transition (EMT) and metastasis in multiple carcinoma types. However, it remains unknown how FOXQ1 regulates gene expression. Here, we report that FOXQ1 initiates EMT by recruiting the MLL/KMT2 histone methyltransferase complex as a transcriptional coactivator. We first establish that FOXQ1 promoter recognition precedes MLL complex assembly and histone-3 lysine-4 trimethylation within the promoter regions of critical genes in the EMT program. Mechanistically, we identify that the Forkhead box in FOXQ1 functions as a transactivation domain directly binding the MLL core complex subunit RbBP5 without interrupting FOXQ1 DNA binding activity. Moreover, genetic disruption of the FOXQ1-RbBP5 interaction or pharmacologic targeting of KMT2/MLL recruitment inhibits FOXQ1-dependent gene expression, EMT, and in vivo tumor progression. Our study suggests that targeting the FOXQ1-MLL epigenetic axis could be a promising strategy to combat triple-negative breast cancer metastatic progression.

Norovirus is the leading cause of acute gastroenteritis worldwide with a yearly reported 700 million cases driving a $60 billion global socioeconomic burden. With no United States Food and Drug Administration approved therapeutics and the chance for severe chronic infection and life-threatening complications, researchers have identified the protease as a potential target. However, drug development has focused on the norovirus GI.1 strain despite its accounting for less than 5% of all outbreaks. Our lab aims to change focus for norovirus drug design from GI.1 to the highly infective GII.4, responsible for more than 50% of all outbreaks worldwide. With the first published crystal structure of the norovirus GII.4 protease, we have identified several significant differences in the structure and active site that have hindered development of a potent inhibitor targeting the norovirus GII.4 protease. With these new insights, we have begun designing compounds that demonstrate increased inhibition of the clinically most relevant norovirus GII.4 strain.

The nature of genetic variation for Drosophila longevity in a population of recombinant inbred lines was investigated by estimating quantitative genetic parameters and mapping quantitative trait loci (QTL) for adult life span in five environments: standard culture conditions, high and low temperature, and heat-shock and starvation stress. There was highly significant genetic variation for life span within each sex and environment. In the analysis of variance of life span pooled over sexes and environments, however, the significant genetic variation appeared in the genotype × sex and genotype × environment interaction terms. The genetic correlation of longevity across the sexes and environments was not significantly different from zero in these lines. We estimated map positions and effects of QTL affecting life span by linkage to highly polymorphic roo transposable element markers, using a multiple-trait composite interval mapping procedure. A minimum of 17 QTL were detected; all were sex and/or environment-specific. Ten of the QTL had sexually antagonistic or antagonistic pleiotropic effects in different environments. These data provide support for the pleiotropy theory of senescence and the hypothesis that variation for longevity might be maintained by opposing selection pressures in males and females and variable environments. Further work is necessary to assess the generality of these results, using different strains, to determine heterozygous effects and to map the life span QTL to the level of genetic loci.

In land plants, plastid and mitochondrial RNAs are subject to post-transcriptional C-to-U RNA editing. T-DNA insertions in the ORGANELLE RNA RECOGNITION MOTIF PROTEIN6 gene resulted in reduced photosystem II (PSII) activity and smaller plant and leaf sizes. Exon coverage analysis of the ORRM6 gene showed that orrm6-1 and orrm6-2 are loss-of-function mutants. Compared to other ORRM proteins, ORRM6 affects a relative small number of RNA editing sites. Sanger sequencing of reverse transcription-PCR products of plastid transcripts revealed 2 plastid RNA editing sites that are substantially affected in the orrm6 mutants: psbF-C77 and accD-C794. The psbF gene encodes the β subunit of cytochrome b, an essential component of PSII. The accD gene encodes the β subunit of acetyl-CoA carboxylase, a protein required in plastid fatty acid biosynthesis. Whole-transcriptome RNA-seq demonstrated that editing at psbF-C77 is nearly absent and the editing extent at accD-C794 was significantly reduced. Gene set enrichment pathway analysis showed that expression of multiple gene sets involved in photosynthesis, especially photosynthetic electron transport, is significantly upregulated in both orrm6 mutants. The upregulation could be a mechanism to compensate for the reduced PSII electron transport rate in the orrm6 mutants. These results further demonstrated that Organelle RNA Recognition Motif protein ORRM6 is required in editing of specific RNAs in the Arabidopsis (Arabidopsis thaliana) plastid.