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This Month’s Centennial Articles

Motoo Kimura and James Crow on the infinitely many alleles model

pp. 1243–1245

Warren J. Ewens

Warren J. Ewens introduces Kimura and Crow’s 1964 GENETICS Classic The number of alleles that can be maintained in a finite population. This paper introduced a model motivated by the recognition that an astronomically large number of alleles is possible at any locus. Many later developments in evolutionary molecular genetics can be traced back to this foundational paper, including the concept of the coalescent.

Lindsley and Sandler et al. on gene dosage and the Drosophila genome

pp. 1247–1249

Mariana F. Wolfner

GENETICS Associate Editor Mariana F. Wolfner introduces the 1972 GENETICS Classic Segmental aneuploidy and the genetic gross structure of the Drosophila genome, arguably, the first Drosophila functional genomics paper. The work of Lindsley and Sandler et al. provided the first genome-wide survey of gene dosage, generated crucial tools and resources, and foreshadowed the collaborative “jamborees” to annotate the fly genome sequence.

An incomplete understanding of human genetic variation

pp. 1251–1254

John Huddleston and Evan E. Eichler

Although an impressive number of human genetic variants have been cataloged, a large fraction of the genetic difference that distinguishes two human genomes is still not understood at the base-pair level. The emphasis has been on more common (>1%) single-nucleotide variation as opposed to less tractable, more complex genetic variants, including indels and structural variants. In this Centennial Commentary, John Huddleston, and Even E. Eichler propose these more complex variants will have a large impact on human phenotypes but require more systematic assessment of genomes at deeper coverage, along with alternative sequencing and mapping technologies.

 A general approximation for the dynamics of quantitative traits

pp. 1523–1548

Katarína Bod’ová, Gašper Tkacik, and Nicholas H. Barton

Can we predict the temporal evolution of a trait without following the dynamics of the underlying allele frequencies? Bod’ová et al. show how the complex stochastic dynamics of a system of many loci with unequal effects can be accurately characterized by just a few quantities, such as the trait mean and average heterozygosity, which respond predictably to changes in evolutionary forces. The method is based on the principle that—subject to constraints on the observed quantities—entropy is maximized.

Chromosome-specific and global effects of aneuploidy in Saccharomyces cerevisiae

pp. 1395–1409

Stacie E. Dodgson, Sharon Kim, Michael Costanzo, Anastasia Baryshnikova, Darcy L. Morse, Chris A. Kaiser, Charles Boone, and Angelika Amon

Chromosome copy number imbalances, or aneuploidy, impose an array of stresses on eukaryotic cells. In this work, synthetic lethal screens identified previously unknown molecular consequences of aneuploidy in Saccharomyces cerevisiae, including defects in cell wall integrity and impaired protein trafficking capacity. Karyotype-specific effects of chromosomal imbalances are shown to have severe effects on processes such as vesicle transport and endocytosis. As tumor cells are highly aneuploid, this screen suggests that targeting both the chromosome-specific and broad consequences of aneuploidy could have novel therapeutic potential.

SUMO pathway modulation of regulatory protein binding at the ribosomal DNA locus in Saccharomyces cerevisiae,

pp. 1377–1394

Jennifer Gillies, Christopher M. Hickey, Dan Su, Zhiping Wu, Junmin Peng, and Mark Hochstrasser

By identifying cellular targets of Ulp2, a yeast SUMO protease, Gillies et al. discovered a role for SUMO-protein modification in ribosomal DNA (rDNA) regulation. The rDNA chromatin-associated proteins Net1, Tof2, and Fob1 were found to be Ulp2 substrates in vivo. All three proteins exhibit reduced rDNA binding in ULP2-deficient cells. This impaired binding is in part mediated by Slx5/Slx8, a heterodimeric SUMO-targeted ubiquitin ligase. Genetic interactions between ulp2 and either loss or overexpression of rDNA regulatory factors were also observed, underscoring the importance of Ulp2 in the proper function of the rDNA locus.

Phenotypic plasticity promotes balanced polymorphism in periodic environments by a genomic storage effect

pp. 1437–1448

Davorka Gulisija, Yuseob Kim, and Joshua B. Plotkin

Balanced polymorphism promotes adaptation in temporally changing environments, but the evolutionary mechanisms that help maintain polymorphism under such conditions remain poorly understood. This study uncovers a novel mechanism that generates balanced polymorphism under periodically varying selection. When two loci interact to determine fitness, recombination can allow alleles to escape more harmful genetic backgrounds and associate in haplotypes that persist until environmental conditions change. Gulisija et al. quantify the strength of this effect across a range of selection pressures, recombination rates, plasticity modifier effect sizes, and environmental periods.

The genetic basis of haploid induction in maize identified with a novel genome-wide association method

pp. 1267–1276

Haixiao Hu, Tobias A. Schrag, Regina Peis, Sandra Unterseer, Wolfgang Schipprack, Shaojiang Chen, Jinsheng Lai, Jianbing Yan, Boddupalli M. Prasanna, Sudha K. Nair, Vijay Chaikam, Valeriu Rotarenco, Olga A. Shatskaya, Alexandra Zavalishina, Stefan Scholten, Chris-Carolin Schön, and Albrecht E. Melchinger

Hu et al. describe a new approach to genome-wide association studies that allows detection of selective sweeps even under almost perfect confounding of population structure and trait expression. They apply this new test to investigate the genetic basis of maize haploid induction (HI), a phenomenon that underlies a revolution in maize breeding during the last decade. The authors identified three candidate genes involved in DNA or amino acid binding within a 3.97 Mb genome segment required for HI.

Multivariate analysis of genotype-phenotype association

pp. 1345–1363

Philipp Mitteroecker, James M. Cheverud, and Mihaela Pavlicev

For multivariate phenotypes represented by large numbers of measurements, studying pairwise associations between all measurements and all alleles is highly inefficient. Mitteroecker et al. present a new approach that seeks combinations of loci that are maximally associated — in terms of effect size — with combinations of phenotypic variables. This identifies phenotypic features under strong genetic control, together with their associated allele effects. Applying this approach to a mouse sample, the authors found the dimensionality of the genotype-phenotype association was surprisingly low, with important consequences for gene identification.

Quantitative single-embryo profile of Drosophila genome activation and the dorsal-ventral patterning network

pp. 1575–1584

Jeremy E. Sandler and Angelike Stathopoulos

One of the first milestones in Drosophila melanogaster development is the Maternal to Zygotic Transition (MZT), when maternal transcripts in the developing egg are degraded and the zygotic genome is activated. Sandler and Stathopoulos perform single-embryo RNA profiling without amplification to precisely measure transcription during the MZT as gene networks are being activated. Transcripts were quantified for 70 genes at ten time points, providing the first data on absolute numbers of transcripts during Drosophila development. This analysis revealed trends in gene networks including coregulation of target genes and specific temporal input by transcription factors.

Multiple barriers to the evolution of alternative gene orders in a positive-strand RNA virus

pp. 1503–1521

Anouk Willemsen, Mark P. Zwart, Nicolas Tromas, Eszter Majer, José-Antonio Daròs and Santiago F. Elena

In contrast to complex organisms, virus gene order is generally conserved. To better understand conservation of gene order, Willemsen et al. used a plant RNA virus as an in vivo model to explore evolutionary trajectories that result in viable reordered viruses. They identified five barriers to the evolution of alternative gene orders, revealing important constraints on virus evolution. The results of this study could serve as a road map for investigating the factors that constrain or promote the diversity of gene order in a range of organisms.