August GENETICS Highlights
This Month’s Centennial Articles
Horvitz and Sulston on Caenorhabditis elegans cell lineage mutants, pp. 1485-1487
Kenneth J. Kemphues
Kenneth Kemphues introduces Horvitz and Sulston’s 1980 GENETICS Classic, which demonstrated that systematic mutational analysis could dissect the regulation of the precise cell lineage of Caenorhabditis elegans. The paper heralded a new wave of developmental analysis that would eventually reveal much about the previously unknown relationship between genes and development.
Marcus Rhoades on preferential segregation in maize, pp. 1489-1490
James A. Birchler
GENETICS Associate Editor James A. Birchler introduces Marchus Rhoades’ 1942 Classic on the discovery of preferential segregation, a striking violation of Mendelian inheritance later known as meiotic drive.
Navigating the phenotype frontier: the Monarch Initiative, pp. 1491-1495
Julie A. McMurry, Sebastian Kohler, Nicole L. Washington, James P Balhoff, Charles Borromeo, Matthew Brush, Seth Carbon, Tom Conlin, Nathan Dunn, Mark Engelstad, Erin Foster, Jean-Philippe Gourdine, Julius O. B. Jacobsen, Daniel Keith, Bryan Laraway, Jeremy Nguyen Xuan, Kent Shefchek, Nicole A. Vasilevsky, Zhou Yuan, Suzanna E. Lewis, Harry Hochheiser, Tudor Groza, Damian Smedley, Peter N. Robinson, Christopher J. Mungall, and Melissa A. Haendel
Although numerous model organism resources exist, it is challenging to obtain a global mechanistic picture, since each resource focuses on a different species, disease, or data type. This Centennial commentary highlights challenges in integrating phenotypic data and introduces the Monarch Initiative, which aims to develop a computational infrastructure to bring together disparate data across sources, organisms, and scales.
The Hiroshima/Nagasaki survivor studies: discrepancies between results and general perception, pp. 1505-1512
Bertrand R. Jordan
Many people believe that survivors of the bombing of Hiroshima and Nagasaki in August 1945 suffered a very high cancer burden, dramatically shortened life span, and that their children also had higher mutation rates and frequent abnormalities. In fact, extensive and ongoing follow-up of 120,000 survivors and 77,000 of their children reveal more modest effects. This Perspectives article summarizes the results of these studies, which have been crucial for setting safe radiation exposure limits, and discusses possible reasons for the very striking discrepancy between the facts and general beliefs about this situation.
Hubby and Lewontin on protein variation in natural populations: when molecular genetics came to the rescue of population genetics, pp. 1497-1503
Brian Charlesworth, Deborah Charlesworth, Jerry A. Coyne, and Charles H. Langley
The 1966 GENETICS papers by John Hubby and Richard Lewontin were landmarks in the study of genome-wide levels of variability, revealing a surprisingly high level of protein sequence variability in natural populations. To mark the fiftieth anniversary of the papers and the hundredth anniversary of the journal, Charlesworth et al. discuss the methods used in these pioneering studies, and show how they led to subsequent developments in empirical and theoretical research on natural variation.
Principles of microRNA regulation revealed through modeling microRNA expression quantitative trait loci, pp. 1629-1640
Stefan Budach, Matthias Heinig, and Annalisa Marsico
Transcriptional regulation of microRNAs is poorly understood, due to difficulties determining the start sites of transient primary transcripts. This challenge can be addressed using expression quantitative trait loci (eQTLs), whose effects represent a natural perturbation of cis-regulatory elements. Budach et al. describe a model to predict microRNA-eQTL SNPs in human lymphoblastoid cell lines based on their overlap with regulatory regions. Interestingly, the majority of overlapping microRNA- eQTLs and mRNA-eQTLs affect microRNA and host expression independently. MicroRNA-only eQTLs are enriched for intronic promoters, validating the existence of alternative microRNA promoters that can decouple microRNA and host transcription.
Crosstalk between mitochondrial fusion and the hippo pathway in controlling cell proliferation during Drosophila development, pp. 1777-1788
Qiannan Deng, Ting Guo, Xiu Zhou, Yongmei Xi, Xiaohang Yang, and Wanzhong Ge
Mitochondrial function and the highly conserved Hippo signaling pathway have been linked in growth control, but the molecular mechanisms are unclear. Deng et al. identify mitochondrial inner membrane protein ChChd3 as a regulator of tissue growth in Drosophila. The authors also show crosstalk between mitochondrial fusion and the Hippo pathway that is essential in controlling cell proliferation and tissue homeostasis in Drosophila.
Genomic prediction for quantitative traits is improved by mapping variants to gene ontology categories in Drosophila melanogaster, pp. 1871-1883
Stefan M. Edwards, Izel F. Sørensen, Pernille Sarup, Trudy F. C. Mackay, and Peter Sørensen
Predicting quantitative phenotypes from high resolution genomic polymorphism data is important for personalized medicine, plant and animal breeding and adaptive evolution. Edwards et al. hypothesized that mapping polymorphisms to genes and their gene ontology categories could increase the accuracy of genomic prediction models. They evaluate a Genomic Feature Best Linear Unbiased Prediction (GFBLUP) model using prior information on Gene Ontology categories and show it can increase the predictive ability of the genomic value for three quantitative traits in the unrelated, sequenced inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP).
Refining the use of linkage disequilibrium as a robust signature of selective sweeps, pp. 1807-1825
Guy S. Jacobs, Tim J. Sluckin, and Toomas Kivisild
One signal used to infer positive selection at specific genome regions is a characteristic local distortion in linkage disequilibrium between loci. However, recombination rate can be highly variable along the genome, creating a rough linkage disequilibrium landscape that may confound this approach. The authors explore this effect, and suggest methods that use information on recombination rate variation to retrieve the true signal of selection.
The chromatin remodeling component Aridla is a suppressor of spontaneous mammary tumors in mice, pp. 1601-1611
Nithya Kartha, Lishuang Shen, Carolyn Maskin, Marsha Wallace, and John C. Schimenti
ARID1A is commonly mutated in many cancers. Using a mouse model of sporadic breast cancer, Kartha et al. show that most tumors lack one copy of Arid1a, and have decreased Arid1a mRNA. Re-expression/ overexpression of ARID1A in tumor cells slowed their growth and prevented re-formation of tumors upon transplantation, but only in p53-proficient cells. Overall, the results provide evidence for a tumor suppressive and/or maintenance role for ARID1a in breast cancer and suggest a potential strategy for therapeutic intervention.
Plasticity in the meiotic epigenetic landscape of sex chromosomes in Caenorhabditis Species, pp. 1641-1658
Braden J. Larson, Mike V. Van, Taylor Nakayama, and JoAnne Engebrecht
Successful meiosis relies on homology between chromosomes. But the sex chromosomes of the heterogametic sex are non homologous. To facilitate transmission despite lack of homology, such chromosomes are epigenetically modified by Meiotic Sex Chromosome Inactivation (MSCI). The role and conservation of MSCI has been controversial. Larson et al. examined MSCI in closely related Caenorhabditis species and found that, although conserved, the repressive chromatin marks which mediate MSCI and their underlying gene networks have diverged. The study provides evidence for epigenetic plasticity in regulation of transcription, checkpoint signaling, and DNA replication timing.
Contrasting levels of molecular evolution on the mouse X chromosome, pp. 1841-1857
Erica L. Larson, Dan Vanderpool, Sara Keeble, Meng Zhou, Brice A. J. Sarver, Andrew D. Smith, Matthew D. Dean, and Jeffrey M. Good
Evolutionary theory predicts that the X chromosome should evolve rapidly under some conditions, particularly for genes involved in male reproduction. Larson et al. tested these predictions in mouse spermatogenesis. They found faster protein evolution late in spermatogenesis and faster-X protein evolution at all stages, while expression divergence was slower late on the X chromosome. They also found slower-X DNA methylation divergence in sperm. The authors propose that slower-late regulatory evolution is a consequence of strong constraints during sperm development.
Restriction of retrotransposon mobilization in Schizosaccharomyces pombe by transcriptional silencing and higher-order chromatin organization, pp. 1669-1678
Heather E. Murton, Patrick J. R. Grady, Tsun Ho Chan, Hugh P. Cam, and Simon K. Whitehall
Uncontrolled propagation of retrotransposons is potentially harmful to host genome integrity. Murton et al. reveal a novel host mechanism for controlling transposon mobilization through nuclear organization. The authors used a sensitive reporter assay to characterize the factors that suppress mobilization of an endogenous Tf2 LTR retrotransposon in the fission yeast Schizosaccharomyces pombe. Their analysis suggests S. pombe deploys the clustering of Tf2 elements in concert with transcriptional silencing to suppress retrotransposition.