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A pioneering proposal for a pluralistic extension of evolutionary theory, now updated to reflect the most recent research. This new edition of the widely read Evolution in Four Dimensions has been revised to reflect the spate of new discoveries in biology since the book was first published in 2005, offering corrections, an updated bibliography, and a substantial new chapter. Eva Jablonka and Marion Lamb's pioneering argument proposes that there is more to heredity than genes. They describe four “dimensions” in heredity—four inheritance systems that play a role in evolution: genetic, epigenetic (or non-DNA cellular transmission of traits), behavioral, and symbolic (transmission through language and other forms of symbolic communication). These systems, they argue, can all provide variations on which natural selection can act. Jablonka and Lamb present a richer, more complex view of evolution than that offered by the gene-based Modern Synthesis, arguing that induced and acquired changes also play a role. Their lucid and accessible text is accompanied by artist-physician Anna Zeligowski's lively drawings, which humorously and effectively illustrate the authors' points. Each chapter ends with a dialogue in which the authors refine their arguments against the vigorous skepticism of the fictional “I.M.” (for Ipcha Mistabra—Aramaic for “the opposite conjecture”). The extensive new chapter, presented engagingly as a dialogue with I.M., updates the information on each of the four dimensions—with special attention to the epigenetic, where there has been an explosion of new research. Praise for the first edition “With courage and verve, and in a style accessible to general readers, Jablonka and Lamb lay out some of the exciting new pathways of Darwinian evolution that have been uncovered by contemporary research.” —Evelyn Fox Keller, MIT, author of Making Sense of Life: Explaining Biological Development with Models, Metaphors, and Machines “In their beautifully written and impressively argued new book, Jablonka and Lamb show that the evidence from more than fifty years of molecular, behavioral and linguistic studies forces us to reevaluate our inherited understanding of evolution.” —Oren Harman, The New Republic “It is not only an enjoyable read, replete with ideas and facts of interest but it does the most valuable thing a book can do—it makes you think and reexamine your premises and long-held conclusions.” —Adam Wilkins, BioEssays

Kerstin Kutsche and colleagues report that mutations in GRIN2A and GRIN2B cause variable neurodevelopmental phenotypes including mental retardation and epilepsy. GRIN2A and GRIN2B encode regulatory subunits of N-methyl-D-aspartate (NMDA) receptors, which mediate excitatory neurotransmission in the brain. N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca 2+ -permeable cation channels which are blocked by extracellular Mg 2+ in a voltage-dependent manner 1 . Either GRIN2B or GRIN2A , encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A N615K (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg 2+ block and a decrease in Ca 2+ permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.

John Rioux and colleagues report results of a large genome-wide association meta-analysis and follow-up study of ulcerative colitis. They identify 29 new risk loci for this inflammatory disease and show that many risk loci are shared between ulcerative colitis and Crohn's disease. Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci ( P < 5 × 10 −8 ), increasing the number of ulcerative colitis–associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2 , IL8RA-IL8RB , IL7R , IL12B , DAP , PRDM1 , JAK2 , IRF5 , GNA12 and LSP1 . The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

The widespread use of elite sires by means of artificial insemination in livestock breeding leads to the frequent emergence of recessive genetic defects, which cause significant economic and animal welfare concerns. Here we show that the availability of genome-wide, high-density SNP panels, combined with the typical structure of livestock populations, markedly accelerates the positional identification of genes and mutations that cause inherited defects. We report the fine-scale mapping of five recessive disorders in cattle and the molecular basis for three of these: congenital muscular dystony (CMD) types 1 and 2 in Belgian Blue cattle and ichthyosis fetalis in Italian Chianina cattle. Identification of these causative mutations has an immediate translation into breeding practice, allowing marker assisted selection against the defects through avoidance of at-risk matings.

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis - and trans -expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis -eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans -eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans -eQTL. Trans -eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes. Analyses of expression profiles from whole blood of 31,684 individuals identify cis -expression quantitative trait loci (eQTL) effects for 88% of genes and trans -eQTL effects for 37% of trait-associated variants.

Background Goldfish is an important model for various areas of research, including neural development and behavior and a species of significant importance in aquaculture, especially as an ornamental species. It has a male heterogametic (XX/XY) sex determination system that relies on both genetic and environmental factors, with high temperatures being able to produce female-to-male sex reversal. Little, however, is currently known on the molecular basis of genetic sex determination in this important cyprinid model. Here we used sequencing approaches to better characterize sex determination and sex-chromosomes in an experimental strain of goldfish. Results Our results confirmed that sex determination in goldfish is a mix of environmental and genetic factors and that its sex determination system is male heterogametic (XX/XY). Using reduced representation (RAD-seq) and whole genome (pool-seq) approaches, we characterized sex-linked polymorphisms and developed male specific genetic markers. These male specific markers were used to distinguish sex-reversed XX neomales from XY males and to demonstrate that XX female-to-male sex reversal could even occur at a relatively low rearing temperature (18 °C), for which sex reversal has been previously shown to be close to zero. We also characterized a relatively large non-recombining region (~ 11.7 Mb) on goldfish linkage group 22 (LG22) that contained a high-density of male-biased genetic polymorphisms. This large LG22 region harbors 373 genes, including a single candidate as a potential master sex gene, i.e., the anti-Mullerian hormone gene ( amh ). However, no sex-linked polymorphisms were detected in the coding DNA sequence of the goldfish amh gene. Conclusions These results show that our goldfish strain has a relatively large sex locus on LG22, which is likely the Y chromosome of this experimental population. The presence of a few XX males even at low temperature also suggests that other environmental factors in addition to temperature could trigger female-to-male sex reversal. Finally, we also developed sex-linked genetic markers, which will be important tools for future research on sex determination in our experimental goldfish population. However, additional work would be needed to explore whether this sex locus is conserved in other populations of goldfish.

Genome-wide association studies are used to identify common genetic variants that affect the structure of selected subcortical regions of the human brain; their identification provides insight into the causes of variability in brain development and may help to determine mechanisms of neuropsychiatric dysfunction. Genetic variants that alter brain development This genome-wide association study of 30,717 individuals identifies common genetic variants that affect the structure of selected subcortical regions of the brain known to be involved in functions associated with movement, learning, memory and motivation. The results provide insight into the causes of variability in human brain development and may help elucidate mechanisms of neuropsychiatric dysfunction. Of particular interest are six novel genetic loci influencing the volumes of the putamen, caudate nucleus and global head size. The highly complex structure of the human brain is strongly shaped by genetic influences 1 . Subcortical brain regions form circuits with cortical areas to coordinate movement 2 , learning, memory 3 and motivation 4 , and altered circuits can lead to abnormal behaviour and disease 2 . To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume 5 and intracranial volume 6 . These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10 −33 ; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

In this work, we query the Chlamydomonas reinhardtii copper regulon at a whole-genome level. Our RNA-Seq data simulation and analysis pipeline validated a 2-fold cutoff and 10 RPKM (reads per kilobase of mappable length per million mapped reads) (~1 mRNA per cell) to reveal 63 CRR1 targets plus another 86 copper-responsive genes. Proteomic and immunoblot analyses captured 25% of the corresponding proteins, whose abundance was also dependent on copper nutrition, validating transcriptional regulation as a major control mechanism for copper signaling in Chlamydomonas. The impact of copper deficiency on the expression of several O₂-dependent enzymes included steps in lipid modification pathways. Quantitative lipid profiles indicated increased polyunsaturation of fatty acids on thylakoid membrane digalactosyldiglycerides, indicating a global impact of copper deficiency on the photosynthetic apparatus. Discovery of a putative plastid copper chaperone and a membrane protease in the thylakoid suggest a mechanism for blocking copper utilization in the chloroplast. We also found an example of copper sparing in the N assimilation pathway: the replacement of copper amine oxidase by a flavin-dependent backup enzyme. Forty percent of the targets are previously uncharacterized proteins, indicating considerable potential for new discovery in the biology of copper.