Montage of false-colored confocal projections of Drosophila brains labeled with a photoreceptor axonal marker highlights the roles of Eya and Jak/Stat genes in retinal axon guidance. In this issue, Hoi et al. report a novel requirement for Jak/Stat components in axon guidance and synergy with the retinal determination gene, Eya, in this process. Genetic perturbations, clockwise from top left: Eya (knockdown in magenta, overexpression in orange); Hop knockdown (red); Stat knockdown (green); Socs36E knockdown (cyan); and Socs44A knockdown (yellow). Image courtesy of Charlene Hoi.

Check out the July issue of GENETICS by looking at the highlights or the full table of contents!

This Month’s Centennial Articles

Alfred Sturtevant and George Beadle untangle inversions, pp. 1001-1003

R. Scott Hawley and Barry Ganetzky

R. Scott Hawley and Barry Ganetzky introduce Sturtevant and Beadle’s 1936 Classic that explained why inversion heterozygosity in the Drosophila X chromsome produces an odd set of meiotic anomalies. This work stands as a paradigm for the genetic analysis of chromosome behavior in Drosophila.

Na Li and Matthew Stephens on modeling linkage disequilibrium, pp.1005-1006

Yun S. Song

Associate Editor Yun S. Song introduces Li and Stephens’ 2003 Classic “Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data.” This influential work led to a paradigm shift in modeling genetic relatedness with large-scale data.

Back to the future: mutant hunts are still the way to go, pp. 1007-1010

Fred Winston and Douglas Koshland

Fred Winston and Douglas Koshland predict that the future of genetics will be dominated by what has worked so stupendously well in the past: the mutant hunt. They describe how an explosion of new technologies has eliminated long-standing hurdles to key elements of mutant hunts in a broader range of organisms.

Weaving a tapestry from threads spun by geneticists: the series Perspectives on Genetics, 1987-2008, pp. 1011-1022

William F. Dove

William F. Dove reflects on the lessons of the first 21 years of the Perspectives series in GENETICS, Dedicated to presenting vignettes of the history of genetics, the series created a veritable tapestry of stories of the science, as told by geneticists themselves.


Determinants of genetic diversity of spontaneous drug resistance in bacteria, pp. 1369-1380

Alejandro Couce, Alexandro Rodríguez-Rojas, and Jesús Blázquez

A microbial population’s capacity to cope with second-line antibiotics can depend on its genetic diversity at resistance loci. How this diversity accumulates before antibiotic treatment is poorly understood. Combining theory and experiments, Couce et al. find that diversity is extremely sensitive to variations in the fitness effects of resistance. Indeed, a slight fitness advantage of the mutant over the wild-type is enough to keep diversity low and independent of population size. These insights will assist the fight against multi-drug resistant microbes, as well as efforts to predict cancer evolution.

Buffering of genetic regulatory networks in Drosophila melanogaster, pp. 1177-1190

Justin M. Fear, Luis G. León-Novelo, Alison M. Morse, Alison R. Gerken, Kjong Van Lehmann, John Tower, Sergey V. Nuzhdin, and Lauren M. McIntyre

A strong consensus is emerging from gene regulation analyses in model organisms: cis and trans effects are compensatory. This phy- logenetically ubiquitous pattern is frequently postulated to be the result of co-evolution. But within species, cis and trans effects cannot co-evolve as they are not co-transmitted. Fear et al. propose that the compensatory nature of cis and trans effects explains widespread observations of gene regulatory network (GRN) robustness. This provides a bridge between molecular models of GRN and genome-wide models of regulatory variation where both point to large scale robustness.

Epistasis and the dynamics of reversion in molecular evolution, pp. 1335-1351

David M. McCandlish, Premal Shah, and Joshua B. Plotkin

Evolutionary geneticists have speculated that the longer a mutation has been fixed in a population, the more difficult it is to revert – i.e. to be replaced by its ancestral allele. Indeed, recent empirical and simulation studies suggest that this phenomenon of entrenchment is ubiquitous in protein evolution. McCandlish et al. provide a rigorous mathematical exploration of reversions, demonstrating that reversion rates will always decrease with time when the effects of mutations depend upon the genetic background.

Long-term memory in Drosophila is influenced by histone deacetylase HDAC4 interacting with SUMO-conjugating enzyme Ubc9, pp. 1249-1264

Silvia Schwartz, Mauro Truglio, Maxwell J. Scott, and Helen L. Fitzsimons

Haploinsufficiency of the histone deacetylase HDAC4 results in intellectual disability in humans and reduction of HDAC4 impairs memory in animal models. However, increasing evidence suggests HDAC4 has essential non-nuclear roles beyond transcriptional regulation. Schwartz et al. performed an enhancer screen in Drosophila and identified 26 genes that interacted genetically with HDAC4. These included genes that regulate axon and/or dendritic growth through rearrangement of the actin cytoskeleton, and genes that regulate SUMOylation, an important process in memory formation. Moreover, they showed that the SUMO-conjugating enzyme Ubc9 interacts with HDAC4 during memory formation.

Heterozygote advantage is a common outcome of adaptation in Saccharomyces cerevisiae, pp. 1401-1413

Diamantis Sellis, Daniel J. Kvitek, Barbara Dunn, Gavin Sherlock, and Dmitri A. Petrov

Adaptation in diploids has been predicted theoretically to follow different dynamics than adaptation in haploids. Adaptive mutations in diploids are expected to exhibit heterozygous advantage allowing directional selection to generate and maintain abundant genetic variation rather than to remove it. However, despite the broad implications for our understanding of adaptation, empirical evidence for heterozygote advantage in adapting populations has been lacking. Sellis et al. experimentally test this prediction and find strong evidence in its favor.

Genomic conflicts that cause pollen mortality and raise reproductive barriers in Arabidopsis thaliana, pp. 1353-1367

Matthieu Simon, Stéphanie Durand, Natacha Pluta, Nicolas Gobron Lucy Botran, Anthony Ricou, Christine Camilleri, and Françoise Budar

In plants, an important component of postzygotic reproductive isolation is hybrid sterility. Simon et al. dissect the complex genetic architecture of Arabidopsis thaliana intraspecific hybrid male sterility. They find that hybrid sterility results from the combination and genetic linkage of pollen killer (PK) loci and gametophytic cytoplasmic male-sterility (CMS) loci. These results suggest that genomic conflicts underlying the evolution of PK and CMS create reproductive barriers between distant strains within a species, which may eventually lead to speciation.

Increased proportion of variance explained and prediction accuracy of survival of breast cancer patients with use of whole-genome multiomic profiles, pp. 1425-1438

Ana I. Vazquez, Yogasudha Veturi, Michael Behring, Sadeep Shrestha, Matias Kirst, Marcio F R. Resende, Jr., and Gustavo de los Campos

Multi-omic information can be used to illuminate disease processes and develop risk assessments. Vazquez et al. describe a statistical framework for predicting disease risk by integrating multi-layer high-dimensional omics with clinical covariates. They use data from The Cancer Genome Atlas to develop models for breast cancer survival. Whole-genome gene expression profiles were more predictive of survival than any of the commonly used clinical covariates, including cancer subtype and stage.

Synaptonemal complex proteins of budding yeast define reciprocal roles in muts-mediated crossover formation, pp. 1091-1103

Karen Voelkel-Meiman, Shun-Yun Cheng, Savannah J. Morehouse, and Amy J. MacQueen

The meiosis-specific, proteinaceous synaptonemal complex (SC) structure is a widely conserved feature of meiotic chromosomes undergoing recombination, and the vast majority of genetic data indicate a role for the SC in promoting crossovers. Voelkel-Meiman et al. describe an unanticipated result, finding that budding yeast mutants missing a specific subset of SC structural proteins display more crossover events, instead of the decrease that is characteristic of previously described SC-deficient mutants.

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