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

ISSUE HIGHLIGHTS

This Month’s Centennial Articles

Charlesworth et al. on background selection and neutral diversity, pp. 829-832

Stephen I. Wright

Associate Editor Stephen I. Wright introduces the 1993 GENETICS Classic by Charlesworth. This landmark article revealed an important effect structuring neutral genetic variation, a phenomenon they named “background selection.” This work forced the reinterpretation of influential empirical results and stimulated a major research program on how to distinguish background selection from other influences on neutral diversity.

Alfred Sturtevant walks into a Bar: gene dosage, gene position, and unequal crossing over in Drosophila, pp. 833-835

Mariana F. Wolfner and Danny E. Miller

Associate Editor Mariana F. Wolfner introduces Alfred Sturtevant’s 1925 Classic that revealed how unequal crossing over could generate the puzzling Bar mutant pheno-types in Drosophila. Sturtevant’s work showed that Bar alleles were comprised of units that could be added together or separated by recombination, a remarkable insight that would take nearly 90 years to confirm at the molecular level.

Selfish DNA and epigenetic repression revisited, pp. 837-839

Susan M. Gasser

In this Centennial Commentary, Susan M. Gasser discusses unanswered questions about the repeat sequences that riddle eukaryotic genomes.

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Commonalities in development of pure breeds and population isolates revealed in the genome of the Sardinian Fonni’s Dog, pp. 737–755

Dayna L. Dreger, Brian W. Davis, Raffaella Cocco, Sara Sechi, Alessandro Di Cerbo, Heidi G. Parker, Michele Polli, Stefano P Marelli, Paola Crepaldi, and Elaine A Ostrander

The Italian island of Sardinia is well-known in studies of human population isolates. It is also home to the Fonni’s Dog, a breed that has not been subjected to intensive artificial selection, but rather has developed alongside the human population, influenced by geographic isolation and unregulated selection. Dreger et al. characterized the Fonni’s Dog relative to 27 other dog breeds from the Mediterranean region and describe how the breed presents an intriguing model exhibiting the unique demographic composition of the people of Sardinia.

Identification of the target of the retrograde response that mediates replicative lifespan extension in Saccharomyces cerevisiae, pp. 659–673

James C. Jiang, Stefan W. Stumpferl, Anurag Tiwari, Qian Qin, Jose F. Rodriguez-Quihones, and S. Michal Jazwinski

Defective mitochondria signal the nucleus to activate a transcriptional program called the retrograde response in Saccharomyces cerevisiae. This compensates for the accumulation of dysfunctional mitochondria, allowing the cells to live longer under metabolic stress. Jiang et al. show this response requires the transcriptional co-activator SAGA or SLIK/SALSA, and the participation of Sir2 histone deacetylase. Out of the 410 retrograde response target genes, PHO84, encoding a plasma membrane phosphate transporter, was both necessary and sufficient for lifespan extension. This result establishes a link between three cellular compartments in determining yeast longevity.

Restructuring of holocentric centromeres during meiosis in the plant Rhynchospora pubera, pp. 555–568

Andre Marques, Veit Schubert, Andreas Houben, and Andrea Pedrosa-Harand

Holocentric chromosomes, characterized by multiple centromere units along each chromatid, have particular centromere adaptations to ensure regular disjunction during meiosis. Marques et al. show that holocentromeres are organized differently in mitosis and meiosis of Rhynchospora pubera. During meiosis I, several clusters of centromere units accumulate along the poleward surface of bivalents. During meiosis II, cluster-holocentromeres are mostly present in the mid-region of each chromatid. A linear holocentromere organization is restored after meiosis during pollen mitosis.

Comparing the statistical fate of paralogous and orthologous sequences, pp. 475–482

Florian Massip, Michael Sheinman, Sophie Schbath, and Peter F. Arndt

Comparison of exonic sequences from a wide range of vertebrate species reveals a puzzling distribution in the lengths of exact sequence matches. Massip et al. develop a simple mathematical model that explains this observation and show that it stems from the high rate of segmental duplication in exonic sequences and is not a consequence of their coding potential. This model provides a better understanding of the statistical properties and evolution of genomic sequences.

Mitochondrial-nuclear interactions mediate sex-specific transcriptional profiles in Drosophila, pp. 613–630

Jim A. Mossman, Jennifer G. Tross, Nan Li, Zhijin Wu, and David M. Rand

Emerging mitochondrial replacement therapies aim to eliminate deleterious mitochondrial DNA (mtDNA) mutations in offspring. This process involves introducing nuclear DNA into an enucleated donor oocyte containing ‘healthy’ mitochondria. Although a promising avenue for effective therapy, the outcomes of this process will partly depend on how well the mtDNA haplotype and nuclear DNA communicate. Using a mitonuclear genotype panel of Drosophila melanogaster, Mossman et al. show that gene expression is sensitive to mitonuclear co-variation (epistasis) in both sexes. Nuclear DNA variation had similar effects in females and males. However, mtDNA variation had a larger effect in females.

Gene and network analysis of common variants reveals novel associations in multiple complex diseases, pp. 783–798

Priyanka Nakka, Benjamin J. Raphael, and Sohini Ramachandran

A major difficulty in identifying genetic variants underlying complex diseases is that affected individuals may possess multiple and different variants in the same gene or pathway. To address this issue, Nakka et al. introduce PEGASUS, a method for combining information from multiple loci within a gene into a single “gene score” that quantifies its statistical association with a trait of interest. PEGASUS produces gene scores with as much as 10 orders of magnitude higher numerical precision than competing methods. The authors use PEGASUS to discover networks of interacting genes associated with Waist-Hip Ratio, Ulcerative Colitis and Attention-Deficit/Hyperactivity Disorder.

Accurate chromosome segregation at first meiotic division requires AGO4, a protein involved in RNA-dependent DNA methylation in Arabidopsis thaliana, pp. 543–553

Cecilia Oliver, Juan Luis Santos, and Monica Pradillo

Oliver et al. report the importance of a protein required for RNA- dependent DNA methylation (RdDM), AGO4, during meiosis. Mutants defective for this protein display alterations in chromatin conformation around centromeric regions, lagging chromosomes at anaphase I, and defects in spindle organization. These results highlight the importance of AGO4 in ensuring accurate chromosome segregation at first meiotic division in Arabidopsis thaliana.

Statistical methods for testing genetic pleiotropy, pp. 483–497

Daniel J. Schaid, Xingwei Tong, Beth Larrabee, Richard B. Kennedy, Gregory A. Poland, and Jason P Sinnwell

Pleiotropy occurs when a single gene influences more than one trait Current multivariate methods to evaluate pleiotropy test the null hypothesis that none of the traits are associated with a genetic variant. But that means the null will be rejected when only a single trait is associated. To address this limitation, Schaid et al. developed rigorous statistical methods for identifying which traits are associated with genetic variants, and how many are associated, while accounting for correlations among the traits.

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