Duplicate genes act as a source of genetic material from which new functions arise. They exist in large numbers in every sequenced eukaryotic genome and may be responsible for many differences in phenotypes between species. However, recent work searching for the targets of positive selection in humans has largely ignored duplicated genes due to complications in orthology assignment. Here we find that a high proportion of young gene duplicates in the human, macaque, mouse, and rat genomes have experienced adaptive natural selection. Approximately 10% of all lineage-specific duplicates show evidence for positive selection on their protein sequences, larger than any reported amount of selection among single-copy genes in these lineages using similar methods. We also find that newly duplicated genes that have been transposed to new chromosomal locations are significantly more likely to have undergone positive selection than the ancestral copy. Human-specific duplicates evolving under adaptive natural selection include a surprising number of genes involved in neuronal and cognitive functions. Our results imply that genome scans for selection that ignore duplicated loci are missing a large fraction of all adaptive substitutions. The results are also in agreement with the classical model of evolution by gene duplication, supporting a common role for neofunctionalization in the long-term maintenance of gene duplicates.[Supplemental material is available online at www.genome.org.]Recently duplicated loci suffer one of two long-term fates: maintenance or loss (Ohno 1970;Walsh 1995). While pseudogenization is the more likely fate of recently duplicated genes, many models have been proposed that could lead to the long-term maintenance of multiple paralogs (Spofford 1969;Ohno 1970;Dykhuizen and Hartl 1980;Hughes 1994;Force et al. 1999;Stoltzfus 1999). The maintenance of duplicates can be a by-product of neutral evolution (Dykhuizen and Hartl 1980;Force et al. 1999;Stoltzfus 1999), or there can be adaptive substitutions either during (Spofford 1969;Ohno 1970) or after (Ohno 1970Hughes 1994) the fixation of the duplicated locus. Previous studies have found signatures of adaptive evolution among individual duplicated genes, suggesting that selection for new functions (''neofunctionalization'') is the mechanism acting to retain new paralogs (Zhang et al. 1998;Merritt and Quattro 2001;Betran and Long 2003;Moore and Purugganan 2003;Rodriguez-Trelles et al. 2003;Thornton and Long 2005). While these studies support the neofunctionalization model, the genome-wide proportion of all duplicates fixed and maintained by natural selection is still not known (Hahn 2009).Gene duplication supplies the raw material necessary to evolve novel functions and is therefore a source of adaptive change. Previous studies in mammals have searched for positively selected genes in the hope of identifying the nucleotide substitutions that underlie phenotypic divergence between species, but these genome-wide scans have intentionally ignored duplicated loci ...

The Paramecium aurelia complex is a group of 15 species that share at least three past whole-genome duplications (WGDs). The macronuclear genome sequences of P. biaurelia and P. sexaurelia are presented and compared to the published sequence of P. tetraurelia. Levels of duplicate-gene retention from the recent WGD differ by >10% across species, with P. sexaurelia losing significantly more genes than P. biaurelia or P. tetraurelia. In addition, historically high rates of gene conversion have homogenized WGD paralogs, probably extending the paralogs' lifetimes. The probability of duplicate retention is positively correlated with GC content and expression level; ribosomal proteins, transcription factors, and intracellular signaling proteins are overrepresented among maintained duplicates. Finally, multiple sources of evidence indicate that P. sexaurelia diverged from the two other lineages immediately following, or perhaps concurrent with, the recent WGD, with approximately half of gene losses between P. tetraurelia and P. sexaurelia representing divergent gene resolutions (i.e., silencing of alternative paralogs), as expected for random duplicate loss between these species. Additionally, though P. biaurelia and P. tetraurelia diverged from each other much later, there are still more than 100 cases of divergent resolution between these two species. Taken together, these results indicate that divergent resolution of duplicate genes between lineages acts to reinforce reproductive isolation between species in the Paramecium aurelia complex.

Paramecium has long been a model eukaryote. The sequence of the Paramecium tetraurelia genome reveals a history of three successive whole-genome duplications (WGDs), and the sequences of P. biaurelia and P. sexaurelia suggest that these WGDs are shared by all members of the aurelia species complex. Here, we present the genome sequence of P. caudatum, a species closely related to the P. aurelia species group. P. caudatum shares only the most ancient of the three WGDs with the aurelia complex. We found that P. caudatum maintains twice as many paralogs from this early event as the P. aurelia species, suggesting that post-WGD gene retention is influenced by subsequent WGDs and supporting the importance of selection for dosage in gene retention. The availability of P. caudatum as an outgroup allows an expanded analysis of the aurelia intermediate and recent WGD events. Both the Guanine+Cytosine (GC) content and the expression level of preduplication genes are significant predictors of duplicate retention. We find widespread asymmetrical evolution among aurelia paralogs, which is likely caused by gradual pseudogenization rather than by neofunctionalization. Finally, cases of divergent resolution of intermediate WGD duplicates between aurelia species implicate this process acts as an ongoing reinforcement mechanism of reproductive isolation long after a WGD event.T HE genus Paramecium has been used as a model unicellular eukaryotic system for over a century, beginning with research by Jennings (1908) and leading to some of the earliest derivations of mathematical population-genetics properties (Jennings 1916(Jennings , 1917. The subsequent discovery of mating types in members of the Paramecium aurelia complex (Sonneborn 1937) permitted the first systematic crossbreeding of different genotypes in any unicellular eukaryote. Later work provided fundamental insights into major issues in biology, including mutagenesis (Igarashi 1966), molecular and developmental genetics (Sonneborn 1947), symbiosis (Beale et al. 1969), mitochondrial genetics (Adoutte and Beisson 1972), aging (Siegel 1967), nuclear differentiation (Berger 1937), and gene regulation (Allen and Gibson 1972). More recently, Paramecium has been used to study maternal inheritance (Nowacki et al. 2005), programmed genome rearrangements and transposon domestication (Arnaiz et al. 2012), epigenetic inheritance (Singh et al. 2014), and whole-genome duplication (Aury et al. 2006; Lynn McGrath, Jean-Francois Gout, Parul Johri, Thomas Graeme Doak, and Michael Lynch, unpublished results). Although not as well-studied as the P. aurelia complex of species, P. caudatum also has a long history of research (Calkins 1902;Sonneborn 1933). Recent studies on P. caudatum involve investigations into quorum sensing (Fellous et al. 2012), thermal adaptation (Krenek et al. 2012), learning (Armus et al. 2006), endosymbiosis and parasite-mediated selection (Duncan et al. 2010(Duncan et al. , 2011, and ecotoxicology (Rao et al. 2007;Kawamoto et al. 2010;Hailong et al. 2011). P...

BackgroundBipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA) and beta (RORB), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in RORA and RORB.MethodsWe genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching.ResultsWe report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs.ConclusionOur findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.

Studies of microbial eukaryotes have been pivotal in the discovery of biological phenomena, including RNA editing, self-splicing RNA, and telomere addition. Here we extend this list by demonstrating that genome architecture, namely the extensive processing of somatic (macronuclear) genomes in some ciliate lineages, is associated with elevated rates of protein evolution. Using newly developed likelihood-based procedures for studying molecular evolution, we investigate 6 genes to compare 1) ciliate protein evolution to that of 3 other clades of eukaryotes (plants, animals, and fungi) and 2) protein evolution in ciliates with extensively processed macronuclear genomes to that of other ciliate lineages. In 5 of the 6 genes, ciliates are estimated to have a higher ratio of nonsynonymous/synonymous substitution rates, consistent with an increase in the rate of protein diversification in ciliates relative to other eukaryotes. Even more striking, there is a significant effect of genome architecture within ciliates as the most divergent proteins are consistently found in those lineages with the most highly processed macronuclear genomes. We propose a model whereby genome architecture-specifically chromosomal processing, amitosis within macronuclei, and epigenetics-allows ciliates to explore protein space in a novel manner. Further, we predict that examination of diverse eukaryotes will reveal additional evidence of the impact of genome architecture on molecular evolution.

Gene conversion between duplicated genes has been implicated in homogenization of gene families and reassortment of variation among paralogs. If conversion is common, this process could lead to errors in gene tree inference and subsequent overestimation of rates of gene duplication. After performing simulations to assess our power to detect gene conversion events, we determined rates of conversion among young, lineage-specific gene duplicates in four mammal species: human, rhesus macaque, mouse, and rat. Gene conversion rates (number of conversion events/number of gene pairs) among young duplicates range from 8.3% in macaque to 18.96% in rat, including a 5% false-positive rate. For all lineages, only 1-3% of the total amount of sequence examined was converted. There is no increase in GC content in conversion tracts compared to flanking regions of the same genes nor in conversion tracts compared to the same region in nonconverted gene-family members, suggesting that ectopic gene conversion does not significantly alter nucleotide composition in these duplicates. While the majority of gene duplicate pairs reside on different chromosomes in mammalian genomes, the majority of gene conversion events occur between duplicates on the same chromosome, even after controlling for divergence between duplicates. Among intrachromosomal duplicates, however, there is no correlation between the probability of conversion and physical distance between duplicates after controlling for divergence. Finally, we use a novel method to show that at most 5-10% of all gene trees involving young duplicates are likely to be incorrect due to gene conversion. We conclude that gene conversion has had only a small effect on mammalian genomes and gene duplicate evolution in general.

The norepinephrine transporter (NET) gene is an attractive candidate gene for attention-deficit hyperactivity disorder (ADHD). Noradrenergic systems are critical to higher brain functions such as attention and executive function, which are defective in ADHD. The clinical efficacy of medications that target NET also supports its role in the etiology of ADHD. Here, we have applied a dense mapping strategy to capture all genetic variations within the NET gene in a large number of ADHD families (474 trios). As a result, we found association of the same alleles from two single-nucleotide polymorphisms (rs3785143 and rs11568324) previously identified in another large-scale ADHD genetic study (International Multisite ADHD Geneproject). Furthermore, the effect sizes were consistent across both studies. This is the first time that identical alleles of NET from different studies were implicated, and thus our report provides further evidence that the NET gene is involved in the etiology of ADHD.

We report on COVID-19 risk among HCWs exposed to a patient diagnosed with COVID-19 on day 13 of hospitalization. There were 44 HCWs exposed to the patient before contact and droplet precautions were implemented: of these, 2 of 44 (5%) developed COVID-19 potentially attributable to the exposure.