ISSUE HIGHLIGHTS

The sister chromatid cohesion pathway suppresses multiple chromosome gain and chromosome amplification, pp. 373–384

Shay Covo, Christopher M. Puccia, Juan Lucas Argueso, Dmitry A. Gordenin, and Michael A. Resnick

Aneuploidy—the gain or loss of chromosomes—is an important factor in diseases and evolution. While chromosome loss has been well studied, few assays are available to study chromosome gain. This article presents a novel assay to study chromosome gain in yeasts and its use to measure properties that cannot be properly addressed with chromosome loss assays, such as the effects of ploidy on aneuploidy. Defects in sister chromatid cohesion were found to lead to severe genome instability that enables cells to survive toxic exposure.

Genetic variation for life history sensitivity to seasonal warming in Arabidopsis thaliana, pp. 569–577

Yan Li, Riyan Cheng, Kurt A. Spokas, Abraham A. Palmer, and Justin O. Borevitz

Climate change is accelerating, altering growing seasons, and affecting the developmental timings or phenology of plant species. This study investigates the complex genetic basis of Arabidopsis flowering time under seasonal warming. In genotypes that switch from over-wintering to rapid fall flowering in warmer winter seasons’ thermal sensitive alleles were identified in genes of the heat shock and hormone response pathways. A genetic model accurately predicted flowering time of new genotypes in future conditions, illustrating an important method for breeding that may facilitate adaptation in other species.

Genetic complexity in a Drosophila model of diabetes-associated misfolded human proinsulin, pp. 539–555

Soo-Young Park, Michael Z. Ludwig, Natalia A. Tamarina, Bin Z. He, Sarah H. Carl, Desiree A. Dickerson, Levi Barse, Bharath Arun, Calvin L. Williams, Cecelia M. Miles, Louis H. Philipson, Donald F. Steiner, Graeme I. Bell, and Martin Kreitman

and

Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin, pp. 557–567

Bin Z. He, Michael Z. Ludwig, Desiree A. Dickerson, Levi Barse, Bharath Arun, Bjarni J. Vilhjálmsson Soo-Young Park, Natalia A. Tamarina, Scott B. Selleck, Patricia J. Wittkopp, Graeme I. Bell, and Martin Kreitman

These two articles illustrate how model organisms can inform the genetic basis of complex traits. The authors describe a fly model of neonatal diabetes, a human disease caused by expression of misfolded proinsulin. They expressed a human mutant proinsulin in several tissues of the fly, where it caused a severe reduction of adult structures and reorganized gene expression. Exploiting natural variation in the fly that modifies these phenotypes, they mapped an associated QTL to an intron of the sulfateless gene. They identified two additional genes involved in heparin sulfate biosynthesis that also influence the phenotype, revealing a novel post translational pathway potentially associated with unfolded protein response.

Genome destabilizing mutator alleles drive specific mutational trajectories in Saccharomyces cerevisiae, pp. 403–412

Peter C. Stirling, Yaoqing Shen, Richard Corbett, Steven J. M. Jones, and Philip Hieter

The kinds of mutations that accumulate in tumors are influenced by genetic changes that occur in precancerous cells and by extrinsic genotoxic stresses. This article reports identification of 38 mutator genes in yeast, and the examination of genome-wide mutational patterns in some of these mutator strains. Allele-specific biases in the types and positions of the mutations that accumulate were found. These results should be generalizable and helpful for interpreting mutational signatures found in individual tumor genes.

Speed of invasion of an expanding population by a horizontally-transmitted trait, pp. 497–507

Juan Venegas-Ortiz, Rosalind J. Allen, and Martin R. Evans

Populations invading new territories often bring with them new genetic variants, diseases, or (for humans) new technologies. These traits can have profound effects - from the extinction of native species to the spread of farming. But how fast do they spread? These authors used coupled Fisher-KPP equations to predict the speed at which traits spread through an expanding population. They find that, remarkably, it can be much faster than in an established population.

Evidence for paternal age-related alterations in meiotic chromosome dynamics in the mouse, pp. 385–396

Lisa A. Vrooman, So I. Nagaoka, Terry J. Hassold, and Patricia A. Hunt

Most aneuploid pregnancies in humans are maternally derived, with advancing age of the woman the most significant risk factor, but the effect of age on male meiosis remains poorly understood. These investigators assessed paternal age effects on meiosis in the mouse and discovered that recombination patterns are influenced by age. An age-related increase in meiotic errors was evident, but the data suggest that effective elimination of these cells prevents them from completing meiosis.

Additive, epistatic, and environmental effects through the lens of expression variability QTL in a twin cohort, pp. 413–425

Gang Wang, Ence Yang, Candice L. Brinkmeyer-Langford, and James J. Cai

Gene expression can vary among unrelated individuals as well as between monozygotic twins. This variability is attributed to both genetic and nongenetic factors. To assess the contributions of these factors on expression variability, these authors investigated a set of evQTLs, expression QTLs associated with variance in gene expression, in a large twin cohort. Their findings shed light on some of the sources of phenotypic variability in complex traits.

This Month’s Perspectives

The synthesis paradigm in genetics, pp. 367–371

William R. Rice

Most progress in genetics is generally attributed to two major approaches: experimental studies with model organisms and/or mathematically explicit theory. This Perspective article author surveys some of the major advances in genetics and concludes that this dichotomy is incomplete because pivotal discoveries are also made by synthesizing diverse threads of extant information rather than from new experimental information or mathematical theory. The author also concludes that the current exponential growth of numerous “-omics” data sets will soon expand the importance of the synthesis paradigm.

This Month in the American Journal of Human Genetics

Revisiting the thrifty gene hypothesis using 65 loci associated with susceptibility to type 2 diabetes, Am. J. Hum. Genet. 94(2)

Qasim Ayub, Loukas Moutsianas, Yuan Chen, Kalliope Panoutsopoulou, Vincenza Colonna, Luca Pagani, Inga Prokopenko, Graham R. S. Ritchie, Chris Tyler-Smith, Mark I. McCarthy, Eleftheria Zeggini, Yali Xue

In 1962, Jim Neel authored an instantly classic and controversial paper that put forth the idea of ‘thrifty genes’: a ‘thrifty’ genotype would have been advantageous at some time in human history, e.g. during times of food scarcity, but, in modern times when ‘feast’ is more the rule than the exception, it would instead render individuals susceptible to modern diseases such as diabetes. Although this hypothesis has been revisited many times, Ayub and colleagues are now able to harness the vast amounts of data available from recent GWASs, in conjunction with information about haplotype structure and population genetics. Although they find evidence for some amount of positive selection at a few GWAS loci, their overall analysis suggests that today’s high prevalence of type 2 diabetes cannot be explained by the thrifty gene hypothesis