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Gregor Mendel developed the principles of segregation and independent assortment in the mid-1800s based on his detailed analysis of several traits in pea plants. Those principles, now called Mendels laws, in fact, explain the behavior of genes and alleles during meiosis and are now understood to underlie Mendelian inheritance of a wide range of traits and diseases across organisms. When asked to give examples of inheritance that do NOT follow Mendels laws, in other words, examples of non-Mendelian inheritance, students sometimes list incomplete dominance, codominance, multiple alleles, sex-linked traits, and multigene traits and cite as their sources the Khan Academy, Wikipedia, and other online sites. Against this background, the goals of this Perspective are to (1) explain to students, healthcare workers, and other stakeholders why the examples above, in fact, display Mendelian inheritance, as they obey Mendels laws of segregation and independent assortment, even though they do not produce classic Mendelian phenotypic ratios and (2) urge individuals with an intimate knowledge of genetic principles to monitor the accuracy of learning resources and work with us and those resources to correct information that is misleading.

Locally adapted traits can exhibit a wide range of genetic architectures, from pronounced divergence at a few loci to small frequency divergence at many loci. The type of architecture that evolves depends strongly on the migration rate, as weakly selected loci experience swamping and do not make lasting contributions to divergence. Simulations from previous studies showed that even when mutations are strongly selected and should resist migration swamping, the architecture of adaptation can collapse and become transient at high mutation rates. Here, we use an analytical two-population model to study how this transition in genetic architecture depends upon population size, strength of selection, and parameters describing the mutation process. To do this, we develop a mathematical theory based on the diffusion approximation to predict the threshold mutation rate above which the transition occurs. We find that this performs well across a wide range of parameter space, based on comparisons with individual-based simulations. The threshold mutation rate depends most strongly on the average effect size of mutations, weakly on the strength of selection, and marginally on the population size. Across a wide range of the parameter space, we observe that the transition to a transient architecture occurs when the trait-wide mutation rate is 10 − 3 – 10 − 2 ⁠ , suggesting that this phenomenon is potentially relevant to complex traits with a large mutational target. On the other hand, based on the apparent stability of genetic architecture in many classic examples of local adaptation, our theory suggests that per-trait mutation rates are often relatively low. [ABSTRACT FROM AUTHOR]

Heterosis was the catalyst for the domestication of cultivated strawberry (⁠ F r a g a r i a × a n a n a s s a ⁠), an interspecific hybrid species that originated in the 1700s. The hybrid origin was discovered because the phenotypes of spontaneous hybrids transgressed those of their parent species. The transgressions included fruit yield increases and other genetic gains in the twentieth century that sparked the global expansion of strawberry production. The importance of heterosis to the agricultural success of the hybrid species, however, has remained a mystery. Here we show that heterosis has disappeared (become fixed) among improved hybrids within a population (the California population) that has been under long-term selection for increased fruit yield, weight, and firmness. We found that the highest yielding hybrids are among the most highly inbred (59–79%), which seems counterintuitive for a highly heterozygous, outbreeder carrying heavy genetic loads. Although faint remnants of heterosis were discovered, the between-parent allele frequency differences and dispersed favorable dominant alleles necessary for heterosis have decreased nearly genome-wide within the California population. Conversely, heterosis was prevalent and significant among wide hybrids, especially for fruit count, a significant driver of genetic gains for fruit yield. We attributed the disappearance (fixation) of heterosis within the California population to increased homozygosity of favorable dominant alleles and inbreeding associated with selection, random genetic drift, and selective sweeps. Despite historical inbreeding, the highest yielding hybrids reported to-date are estimated to be heterozygous for 20,370–44,280 of 97,000–108,000 genes in the octoploid genome, the equivalent of an entire diploid genome or more. [ABSTRACT FROM AUTHOR]

Germ cell development and gamete production in animals require small RNA pathways. While studies indicate that microRNAs (miRNAs) are necessary for normal sperm production and function, the specific roles for individual miRNAs are largely unknown. Here, we use small RNA sequencing (RNA-seq) of dissected gonads and functional analysis of new loss-of-function alleles to identify functions for miRNAs in the control of fecundity and sperm production in Caenorhabditis elegans males and hermaphrodites. We describe a set of 29 male gonad-enriched miRNAs and identify a set of individual miRNAs (mir-58.1 and mir-235) and a miRNA cluster (mir-4807 -4810.1) that are required for optimal sperm production at 20°C and a set of miRNAs (mir-49 , mir-57 , mir-83 , mir-261 , and mir-357 /358) that are required for sperm production at 25°C. We observed defects in meiotic progression in mutants missing mir-58.1 , mir-83 , mir-235 , and mir-4807 -4810.1 , which may contribute to the observed defects in sperm production. Further, analysis of multiple mutants of these miRNAs suggested genetic interactions between these miRNAs. This study provides insights on the regulatory roles of miRNAs that promote optimal sperm production and fecundity in males and hermaphrodites. [ABSTRACT FROM AUTHOR]

Meiotic recombination is required for faithful chromosome segregation in most sexually reproducing organisms and shapes the distribution of genetic variation in populations. Both the overall rate and the spatial distribution of crossovers vary within and between species. Adjacent crossovers on the same chromosome tend to be spaced more evenly than expected at random, a phenomenon known as crossover interference. Although interference has been observed in many taxa, the factors that influence the strength of interference are not well understood. We used house mice (Mus musculus), a well-established model system for understanding recombination, to study the effects of genetics and age on recombination rate and interference in the male germline. We analyzed crossover positions in 503 progeny from reciprocal F1 hybrids between inbred strains representing the three major subspecies of house mice. Consistent with previous studies, autosomal alleles from M. m. musculus tend to increase recombination rate, while inheriting a M. m. musculus X chromosome decreases recombination rate. Old males transmit an average of 0.6 more crossovers per meiosis (⁠ 5.0 % ⁠) than young males, though the effect varies across genetic backgrounds. We show that the strength of crossover interference depends on genotype, providing a rare demonstration that interference evolves over short timescales. Differences between reciprocal F1s suggest that X-linked factors modulate the strength of interference. Our findings motivate additional comparisons of interference among recently diverged species and further examination of the role of paternal age in determining the number and positioning of crossovers. [ABSTRACT FROM AUTHOR]

Recombination breaks down genetic linkage by reshuffling existing variants onto new genetic backgrounds. These dynamics are traditionally quantified by examining the correlations between alleles, and how they decay as a function of the recombination rate. However, the magnitudes of these correlations are strongly influenced by other evolutionary forces like natural selection and genetic drift, making it difficult to tease out the effects of recombination. Here, we introduce a theoretical framework for analyzing an alternative family of statistics that measure the homoplasy produced by recombination. We derive analytical expressions that predict how these statistics depend on the rates of recombination and recurrent mutation, the strength of negative selection and genetic drift, and the present-day frequencies of the mutant alleles. We find that the degree of homoplasy can strongly depend on this frequency scale, which reflects the underlying timescales over which these mutations occurred. We show how these scaling properties can be used to isolate the effects of recombination and discuss their implications for the rates of horizontal gene transfer in bacteria. [ABSTRACT FROM AUTHOR]

One problem that has hampered the use of red fluorescent proteins in the fast-developing nematode Caenorhabditis elegans has been the substantial time delay in maturation of several generations of red fluorophores. The recently described mScarlet-I3 protein has properties that may overcome this limitation. We compare here the brightness and onset of expression of CRISPR/Cas9 genome-engineered mScarlet, mScarlet3, mScarlet-I3, and GFP reporter knock-ins. Comparing the onset and brightness of expression of reporter alleles of C. elegans golg-4 , encoding a broadly expressed Golgi resident protein, we found that the onset of detection of mScarlet-I3 in the embryo is several hours earlier than older versions of mScarlet and comparable to GFP. These findings were further supported by comparing mScarlet-I3 and GFP reporter alleles for pks-1 , a gene expressed in the CAN neuron and cells of the alimentary system, as well as reporter alleles for the pan-neuronal, nuclear marker unc-75. Hence, the relative properties of mScarlet-I3 and GFP do not depend on cellular or subcellular context. In all cases, mScarlet-I3 reporters also show improved signal-to-noise ratio compared to GFP. [ABSTRACT FROM AUTHOR]

Observations of genetically repeated evolution (repeatability) in complex organisms are incongruent with the Fisher–Orr model, which implies that repeated use of the same gene should be rare when mutations are pleiotropic (i.e. affect multiple traits). When spatially divergent selection occurs in the presence of migration, mutations of large effect are more strongly favored, and hence, repeatability is more likely, but it is unclear whether this observation is limited by pleiotropy. Here, we explore this question using individual-based simulations of a two-patch model incorporating multiple quantitative traits governed by mutations with pleiotropic effects. We explore the relationship between fitness trade-offs and repeatability by varying the alignment between mutation effect and spatial variation in trait optima. While repeatability decreases with increasing trait dimensionality, trade-offs in mutation effects on traits do not strongly limit the contribution of a locus of large effect to repeated adaptation, particularly under increased migration. These results suggest that repeatability will be more pronounced for local rather than global adaptation. Whereas pleiotropy limits repeatability in a single-population model, when there is local adaptation with gene flow, repeatability can occur if some loci are able to produce alleles of large effect, even when there are pleiotropic trade-offs. [ABSTRACT FROM AUTHOR]

The elongation of Caenorhabditis elegans embryos allows examination of mechanical interactions between adjacent tissues. Muscle contractions during late elongation induce the remodeling of epidermal circumferential actin filaments through mechanotransduction. Force inputs from the muscles deform circumferential epidermal actin filament, which causes them to be severed, eventually reformed, and shortened. This squeezing force drives embryonic elongation. We investigated the possible role of the nonmuscle myosins NMY-1 and NMY-2 in this process using nmy-1 and nmy-2 thermosensitive alleles. Our findings show these myosins act redundantly in late elongation, since double nmy-2(ts); nmy-1(ts) mutants immediately stop elongation when raised to 25°C. Their inactivation does not reduce muscle activity, as measured from epidermis deformation, suggesting that they are directly involved in the multistep process of epidermal remodeling. Furthermore, NMY-1 and NMY-2 inactivation is reversible when embryos are kept at the nonpermissive temperature for a few hours. However, after longer exposure to 25°C double mutant embryos fail to resume elongation, presumably because NMY-1 was seen to form protein aggregates. We propose that the two C. elegans nonmuscle myosin II act during actin remodeling either to bring severed ends or hold them. [ABSTRACT FROM AUTHOR]

Detecting introgression between closely related populations or species is a fundamental objective in evolutionary biology. Existing methods for detecting migration and inferring migration rates from population genetic data often assume a neutral model of evolution. Growing evidence of the pervasive impact of selection on large portions of the genome across diverse taxa suggests that this assumption is unrealistic in most empirical systems. Further, ignoring selection has previously been shown to negatively impact demographic inferences (e.g. of population size histories). However, the impacts of biologically realistic selection on inferences of migration remain poorly explored. Here, we simulate data under models of background selection, selective sweeps, balancing selection, and adaptive introgression. We show that ignoring selection sometimes leads to false inferences of migration in popularly used methods that rely on the site frequency spectrum. Specifically, balancing selection and some models of background selection result in the rejection of isolation-only models in favor of isolation-with-migration models and lead to elevated estimates of migration rates. BPP, a method that analyzes sequence data directly, showed false positives for all conditions at recent divergence times, but balancing selection also led to false positives at medium-divergence times. Our results suggest that such methods may be unreliable in some empirical systems, such that new methods that are robust to selection need to be developed. [ABSTRACT FROM AUTHOR]

Characterizing spatial patterns in allele frequencies is fundamental to evolutionary biology because these patterns contain evidence of underlying processes. However, the spatial scales at which gene flow, changing selection, and drift act are often unknown. Many of these processes can operate inconsistently across space, causing nonstationary patterns. We present a wavelet approach to characterize spatial pattern in allele frequency that helps solve these problems. We show how our approach can characterize spatial patterns in relatedness at multiple spatial scales, i.e. a multilocus wavelet genetic dissimilarity. We also develop wavelet tests of spatial differentiation in allele frequency and quantitative trait loci (QTL). With simulation, we illustrate these methods under different scenarios. We also apply our approach to natural populations of Arabidopsis thaliana to characterize population structure and identify locally adapted loci across scales. We find, for example, that Arabidopsis flowering time QTL show significantly elevated genetic differentiation at 300–1,300 km scales. Wavelet transforms of allele frequencies offer a flexible way to reveal geographic patterns and underlying evolutionary processes. [ABSTRACT FROM AUTHOR]

Sex-biased demography, including sex-biased survival or migration, can alter allele frequency changes across the genome. In particular, we can expect different patterns of genetic variation on autosomes and sex chromosomes due to sex-specific differences in life histories, as well as differences in effective population size, transmission modes, and the strength and mode of selection. Here, we demonstrate the role that sex differences in life history played in shaping short-term evolutionary dynamics across the genome. We used a 25-year pedigree and genomic dataset from a long-studied population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of sex-biased demography and inheritance in shaping genome-wide allele frequency trajectories. We used gene dropping simulations to estimate individual genetic contributions to future generations and to model drift and immigration on the known pedigree. We quantified differential expected genetic contributions of males and females over time, showing the impact of sex-biased dispersal in a monogamous system. Due to female-biased dispersal, more autosomal variation is introduced by female immigrants. However, due to male-biased transmission, more Z variation is introduced by male immigrants. Finally, we partitioned the proportion of variance in allele frequency change through time due to male and female contributions. Overall, most allele frequency change is due to variance in survival and births. Males and females make similar contributions to autosomal allele frequency change, but males make higher contributions to allele frequency change on the Z chromosome. Our work shows the importance of understanding sex-specific demographic processes in characterizing genome-wide allele frequency change in wild populations. [ABSTRACT FROM AUTHOR]

Inversions have been proposed to facilitate local adaptation, by linking together locally coadapted alleles at different loci. Prior work addressing this question theoretically has considered the spread of inversions in "continent-island" scenarios in which there is a unidirectional flow of maladapted migrants into the island population. In this setting, inversions capturing locally adaptive haplotypes are most likely to invade when selection is weak, because stronger local selection (i) more effectively purges maladaptive alleles and (ii) generates linkage disequilibrium between adaptive alleles, thus lessening the advantage of inversions. We show this finding only holds under limited conditions by studying the establishment of inversions in a more general two-deme model, which explicitly considers the dynamics of allele frequencies in both populations linked by bidirectional migration. In this model, the level of symmetry between demes can be varied from complete asymmetry (continent-island) to complete symmetry. For symmetric selection and migration, strong selection increases the allele frequency divergence between demes thereby increasing the frequency of maladaptive alleles in migrants, favoring inversions—the opposite of the pattern seen in the asymmetric continent-island scenario. We also account for the likelihood that a new inversion captures an adaptive haplotype in the first instance. When considering the combined process of capture and invasion in "continent island" and symmetric scenarios, relatively strong selection increases inversion establishment probability. Migration must also be low enough that the inversion is likely to capture an adaptive allele combination, but not so low as to eliminate the inversion's advantage. Overall, our analysis suggests that inversions are likely to harbor larger effect alleles that experience relatively strong selection. [ABSTRACT FROM AUTHOR]

The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between homologs. In baker's yeast approximately 80% of meiotic crossovers result from Mlh1 – Mlh3 and Exo1 acting to resolve double-Holliday junction intermediates in a biased manner. Little is known about how Mlh1 – Mlh3 is recruited to recombination intermediates to perform its role in crossover resolution. We performed a gene dosage screen in baker's yeast to identify novel genetic interactors with Mlh1 – Mlh3. Specifically, we looked for genes whose lowered dosage reduced meiotic crossing over using sensitized mlh3 alleles that disrupt the stability of the Mlh1 – Mlh3 complex and confer defects in mismatch repair but do not disrupt meiotic crossing over. To our surprise we identified genetic interactions between MLH3 and DMC1 , the recombinase responsible for recombination between homologous chromosomes during meiosis. We then showed that Mlh3 physically interacts with Dmc1 in vitro and in vivo. Partial complementation of Mlh3 crossover functions was observed when MLH3 was expressed under the control of the CLB1 promoter (NDT80 regulon), suggesting that Mlh3 function can be provided late in meiotic prophase at some functional cost. A model for how Dmc1 could facilitate Mlh1 – Mlh3 's role in crossover resolution is presented. [ABSTRACT FROM AUTHOR]

Gene duplication is an important substrate for the evolution of new gene functions, but the impacts of gene duplicates on their own activities and on the developmental networks in which they act are poorly understood. Here, we use a natural experiment of lin-12 /Notch gene duplication within the nematode genus Caenorhabditis , combined with characterization of loss- and gain-of-function mutations, to uncover functional distinctions between the duplicate genes in 1 species (Caenorhabditis briggsae) and their single-copy ortholog in Caenorhabditis elegans. First, using improved genomic sequence and gene model characterization, we confirm that the C. briggsae genome includes 2 complete lin-12 genes, whereas most other genes encoding proteins that participate in the LIN-12 signaling pathway retain a one-to-one orthology with C. elegans. We use CRISPR-mediated genome editing to introduce alleles predicted to cause gain-of-function (gf) or loss-of-function (lf) into each C. briggsae gene and find that the gf mutations uncover functional distinctions not apparent from the lf alleles. Specifically, Cbr-lin-12.1 (gf) , but not Cbr-lin-12.2 (gf) , causes developmental defects similar to those observed in Cel-lin-12 (gf). In contrast to Cel-lin-12 (gf) , however, the Cbr-lin-12.1 (gf) alleles do not cause dominant phenotypes as compared to the wild type, and the mutant phenotype is observed only when 2 gf alleles are present. Our results demonstrate that gene duplicates can exhibit differential capacities to compensate for each other and to interfere with normal development, and uncover coincident gene duplication and evolution of developmental sensitivity to LIN-12 /Notch activity. [ABSTRACT FROM AUTHOR]

The major loci for the large primary ribosomal RNA (rRNA) genes (35S rRNAs) exist as hundreds to thousands of tandem repeats in all organisms and dozens to hundreds in Drosophila. The highly repetitive nature of the ribosomal DNA (rDNA) makes it intrinsically unstable, and many conditions arise from the reduction in or magnification of copy number, but the conditions under which it does so remain unknown. By targeted DNA damage to the rDNA of the Y chromosome, we created and investigated a series of rDNA alleles. We found that complete loss of rDNA leads to lethality after the completion of embryogenesis, blocking larval molting and metamorphosis. We find that the resident retrotransposons— R1 and R2 —are regulated by active rDNA such that reduction in copy number derepresses these elements. Their expression is highest during the early first instar, when loss of rDNA is lethal. Regulation of R1 and R2 may be related to their structural arrangement within the rDNA , as we find they are clustered in the flanks of the nucleolus organizing region (NOR ; the cytological appearance of the rDNA). We assessed the complex nucleolar dominance relationship between X - and Y -linked rDNA using a histone H3.3–GFP reporter construct and incorporation at the NOR and found that dominance is controlled by rDNA copy number as at high multiplicity the Y -linked array is dominant, but at low multiplicity the X -linked array becomes derepressed. Finally, we found that multiple conditions that disrupt nucleolar dominance lead to increased rDNA magnification, suggesting that the phenomena of dominance and magnification are related, and a single mechanism may underlie and unify these two longstanding observations in Drosophila. [ABSTRACT FROM AUTHOR]

An attractive perfume is a complex mixture of compounds, some of which may be unpleasant on their own. This is also true for the volatile combinations from yeast fermentation products in vineyards and orchards when assessed by Drosophila. Here, we used crosses between a yeast strain with an attractive fermentation profile and another strain with a repulsive one and tested fly responses using a T-maze. QTL analysis reveals allelic variation in four yeast genes, namely PTC6 , SAT4 , YFL040W , and ARI1 , that modulated expression levels of volatile compounds [assessed by gas chromatography–mass spectrometry (GC–MS)] and in different combinations, generated various levels of attractiveness. The parent strain that is more attractive to Drosophila has repulsive alleles at two of the loci, while the least attractive parent has attractive alleles. Behavioral assays using artificial mixtures mimicking the composition of odors from fermentation validated the results of GC–MS and QTL mapping, thereby directly connecting genetic variation in yeast to attractiveness in flies. This study can be used as a basis for dissecting the combination of olfactory receptors that mediate the attractiveness/repulsion of flies to yeast volatiles and may also serve as a model for testing the attractiveness of pest species such as Drosophila suzukii to their host fruit. [ABSTRACT FROM AUTHOR]

Studies of allele-specific expression in interspecific hybrids have provided important insights into gene-regulatory divergence and hybrid incompatibilities. Many such investigations in Drosophila have used transcriptome data from complex mixtures of many tissues or from gonads, however, regulatory divergence may vary widely among species, sexes, and tissues. Thus, we lack sufficiently broad sampling to be confident about the general biological principles of regulatory divergence. Here, we seek to fill some of these gaps in the literature by characterizing regulatory evolution and hybrid misexpression in a somatic male sex organ, the accessory gland, in F1 hybrids between Drosophila melanogaster and D. simulans. The accessory gland produces seminal fluid proteins, which play an important role in male and female fertility and may be subject to adaptive divergence due to male–male or male–female interactions. We find that trans differences are relatively more abundant than cis , in contrast to most of the interspecific hybrid literature, though large effect-size trans differences are rare. Seminal fluid protein genes have significantly elevated levels of expression divergence and tend to be regulated through both cis and trans divergence. We find limited misexpression (over- or underexpression relative to both parents) in this organ compared to most other Drosophila studies. As in previous studies, male-biased genes are overrepresented among misexpressed genes and are much more likely to be underexpressed. ATAC-Seq data show that chromatin accessibility is correlated with expression differences among species and hybrid allele-specific expression. This work identifies unique regulatory evolution and hybrid misexpression properties of the accessory gland and suggests the importance of tissue-specific allele-specific expression studies. [ABSTRACT FROM AUTHOR]

The rate at which beneficial alleles fix in a population depends on the probability of and time to fixation of such alleles. Both of these quantities can be significantly impacted by population subdivision and limited gene flow. Here, we investigate how limited dispersal influences the rate of fixation of beneficial de novo mutations, as well as fixation time from standing genetic variation. We investigate this for a population structured according to the island model of dispersal allowing us to use the diffusion approximation, which we complement with simulations. We find that fixation may take on average fewer generations under limited dispersal than under panmixia when selection is moderate. This is especially the case if adaptation occurs from de novo recessive mutations, and dispersal is not too limited (such that approximately F ST < 0.2 ⁠). The reason is that mildly limited dispersal leads to only a moderate increase in effective population size (which slows down fixation), but is sufficient to cause a relative excess of homozygosity due to inbreeding, thereby exposing rare recessive alleles to selection (which accelerates fixation). We also explore the effect of metapopulation dynamics through local extinction followed by recolonization, finding that such dynamics always accelerate fixation from standing genetic variation, while de novo mutations show faster fixation interspersed with longer waiting times. Finally, we discuss the implications of our results for the detection of sweeps, suggesting that limited dispersal mitigates the expected differences between the genetic signatures of sweeps involving recessive and dominant alleles. [ABSTRACT FROM AUTHOR]

Across diverse insect taxa, the behavior and physiology of females dramatically changes after mating—processes largely triggered by the transfer of seminal proteins from their mates. In the vinegar fly Drosophila melanogaster , the seminal protein sex peptide (SP) decreases the likelihood of female flies remating and causes additional behavioral and physiological changes that promote fertility including increasing egg production. Although SP is only found in the Drosophila genus, its receptor, sex peptide receptor (SPR), is the widely conserved myoinhibitory peptide (MIP) receptor. To test the functional role of SPR in mediating postmating responses in a non- Drosophila dipteran, we generated 2 independent Spr -knockout alleles in the yellow fever mosquito, Aedes aegypti. Although SPR is needed for postmating responses in Drosophila and the cotton bollworm Helicoverpa armigera , Spr mutant Ae. aegypti show completely normal postmating decreases in remating propensity and increases in egg laying. In addition, injection of synthetic SP or accessory gland homogenate from D. melanogaster into virgin female mosquitoes did not elicit these postmating responses. Our results demonstrate that Spr is not required for these canonical postmating responses in Ae. aegypti , indicating that other, as yet unknown, signaling pathways are likely responsible for these behavioral switches in this disease vector. [ABSTRACT FROM AUTHOR]

Vertebrate limbs start to develop as paired protrusions from the lateral plate mesoderm at specific locations of the body with forelimb buds developing anteriorly and hindlimb buds posteriorly. During the initiation process, limb progenitor cells maintain active proliferation to form protrusions and start to express Fgf10 , which triggers molecular processes for outgrowth and patterning. Although both processes occur in both types of limbs, forelimbs (Tbx5), and hindlimbs (Isl1) utilize distinct transcriptional systems to trigger their development. Here, we report that Sall1 and Sall4 , zinc finger transcription factor genes, regulate hindlimb initiation in mouse embryos. Compared to the 100% frequency loss of hindlimb buds in TCre; Isl1 conditional knockouts, Hoxb6Cre; Isl1 conditional knockout causes a hypomorphic phenotype with only approximately 5% of mutants lacking the hindlimb. Our previous study of SALL4 ChIP-seq showed SALL4 enrichment in an Isl1 enhancer, suggesting that SALL4 acts upstream of Isl1. Removing 1 allele of Sall4 from the hypomorphic Hoxb6Cre; Isl1 mutant background caused loss of hindlimbs, but removing both alleles caused an even higher frequency of loss of hindlimbs, suggesting a genetic interaction between Sall4 and Isl1. Furthermore, TCre -mediated conditional double knockouts of Sall1 and Sall4 displayed a loss of expression of hindlimb progenitor markers (Isl1, Pitx1, Tbx4) and failed to develop hindlimbs, demonstrating functional redundancy between Sall1 and Sall4. Our data provides genetic evidence that Sall1 and Sall4 act as master regulators of hindlimb initiation. [ABSTRACT FROM AUTHOR]

Mouse Genome Informatics (MGI) is a federation of expertly curated information resources designed to support experimental and computational investigations into genetic and genomic aspects of human biology and disease using the laboratory mouse as a model system. The Mouse Genome Database (MGD) and the Gene Expression Database (GXD) are core MGI databases that share data and system architecture. MGI serves as the central community resource of integrated information about mouse genome features, variation, expression, gene function, phenotype, and human disease models acquired from peer-reviewed publications, author submissions, and major bioinformatics resources. To facilitate integration and standardization of data, biocuration scientists annotate using terms from controlled metadata vocabularies and biological ontologies (e.g. Mammalian Phenotype Ontology, Mouse Developmental Anatomy, Disease Ontology, Gene Ontology, etc.), and by applying international community standards for gene, allele, and mouse strain nomenclature. MGI serves basic scientists, translational researchers, and data scientists by providing access to FAIR-compliant data in both human-readable and compute-ready formats. The MGI resource is accessible at https://informatics.jax.org. Here, we present an overview of the core data types represented in MGI and highlight recent enhancements to the resource with a focus on new data and functionality for MGD and GXD. [ABSTRACT FROM AUTHOR]

We consider a simple diploid population-genetic model with potentially high variability of offspring numbers among individuals. Specifically, against a backdrop of Wright–Fisher reproduction and no selection, there is an additional probability that a big family occurs, meaning that a pair of individuals has a number of offspring on the order of the population size. We study how the pedigree of the population generated under this model affects the ancestral genetic process of a sample of size two at a single autosomal locus without recombination. Our population model is of the type for which multiple-merger coalescent processes have been described. We prove that the conditional distribution of the pairwise coalescence time given the random pedigree converges to a limit law as the population size tends to infinity. This limit law may or may not be the usual exponential distribution of the Kingman coalescent, depending on the frequency of big families. But because it includes the number and times of big families, it differs from the usual multiple-merger coalescent models. The usual multiple-merger coalescent models are seen as describing the ancestral process marginal to, or averaging over, the pedigree. In the limiting ancestral process conditional on the pedigree, the intervals between big families can be modeled using the Kingman coalescent but each big family causes a discrete jump in the probability of coalescence. Analogous results should hold for larger samples and other population models. We illustrate these results with simulations and additional analysis, highlighting their implications for inference and understanding of multilocus data. [ABSTRACT FROM AUTHOR]

The genetic architecture of trait variance has long been of interest in genetics and evolution. One of the earliest attempts to understand this architecture was presented in Lerner's Genetic Homeostasis (1954). Lerner proposed that heterozygotes should be better able to tolerate environmental perturbations because of functional differences between the alleles at a given locus , with each allele optimal for slightly different environments. This greater robustness to environmental variance, he argued, would result in smaller trait variance for heterozygotes. The evidence for Lerner's hypothesis has been inconclusive. To address this question using modern genomic methods, we mapped loci associated with differences in trait variance (vQTL) on 1,101 individuals from the F34 of an advanced intercross between LG/J and SM/J mice. We also mapped epistatic interactions for these vQTL in order to understand the influence of epistasis for the architecture of trait variance. We did not find evidence supporting Lerner's hypothesis, that heterozygotes tend to have smaller trait variances than homozygotes. We further show that the effects of most mapped loci on trait variance are produced by epistasis affecting trait means and that those epistatic effects account for about a half of the differences in genotypic-specific trait variances. Finally, we propose a model where the different interactions between the additive and dominance effects of the vQTL and their epistatic partners can explain Lerner's original observations but can also be extended to include other conditions where heterozygotes are not the least variable genotype. [ABSTRACT FROM AUTHOR]

PRDM9-mediated reproductive isolation was first described in the progeny of Mus musculus musculus (MUS) PWD/Ph and Mus musculus domesticus (DOM) C57BL/6J inbred strains. These male F1 hybrids fail to complete chromosome synapsis and arrest meiosis at prophase I, due to incompatibilities between the Prdm9 gene and hybrid sterility locus Hstx2. We identified 14 alleles of Prdm9 in exon 12, encoding the DNA-binding domain of the PRDM9 protein in outcrossed wild mouse populations from Europe, Asia, and the Middle East, 8 of which are novel. The same allele was found in all mice bearing introgressed t -haplotypes encompassing Prdm9. We asked whether 7 novel Prdm9 alleles in MUS populations and the t -haplotype allele in 1 MUS and 3 DOM populations induce Prdm9 -mediated reproductive isolation. The results show that only combinations of the dom2 allele of DOM origin and the MUS msc1 allele ensure complete infertility of intersubspecific hybrids in outcrossed wild populations and inbred mouse strains examined so far. The results further indicate that MUS mice may share the erasure of PRDM9msc1 binding motifs in populations with different Prdm9 alleles, which implies that erased PRDM9 binding motifs may be uncoupled from their corresponding Prdm9 alleles at the population level. Our data corroborate the model of Prdm9-mediated hybrid sterility beyond inbred strains of mice and suggest that sterility alleles of Prdm9 may be rare. [ABSTRACT FROM AUTHOR]

Numerous genetic loci and several functionally characterized genes have been linked to determination of lint percentage (lint%), one of the most important cotton yield components, but we still know little about the major genetic components underlying lint%. Here, we first linked the genetic loci containing MYB25-like_At and HD1_At to the fiberless seed trait of 'SL1-7-1' and found that MYB25-like_At and HD1_At were very lowly expressed in 'SL1-7-1' ovules during fiber initiation. We then dissected the genetic components involved in determination of lint% using segregating populations derived from crosses of fuzzless mutants and intermediate segregants with different lint%, which not only confirmed the HD1_At locus but identified the HD1_Dt locus as being the major genetic components contributing to fiber initiation and lint%. The segregating populations also allowed us to evaluate the relative contributions of MYB25-like_At , MYB25-like_Dt , HD1_At , and HD1_Dt to lint%. Haplotype analysis of an Upland cotton (Gossypium hirsutum) population with 723 accessions (including 81 fuzzless seed accessions) showed that lint% of the accessions with the LP allele (higher lint%) at MYB25-like_At , MYB25-like_Dt , or HD1_At was significantly higher than that with the lp allele (lower lint%). The lint% of the Upland cotton accessions with 3 or 4 LP alleles at MYB25-like and HD1 was significantly higher than that with 2 LP alleles. The results prompted us to propose a strategy for breeding high-yielding cotton varieties, i.e. pyramiding the LP alleles of MYB25-like and HD1 with new lint% LP alleles without negative impact on seed size and fiber quality. [ABSTRACT FROM AUTHOR]

Genes regulating recombination in specific chromosomal intervals of Neurospora crassa were described in the 1960s, but the mechanism is still unknown. For each of the rec-1 , rec-2 , and rec-3 genes, a single copy of the putative dominant allele, for example, rec-2SL found in St Lawrence OR74 A wild type, reduces recombination in chromosomal regions specific to that gene. However, when we sequenced the recessive allele, rec-2LG (derived from the Lindegren 1A wild type), we found that a 10 kb region in rec-2SL strains was replaced by a 2.7 kb unrelated sequence, making the "alleles" idiomorphs. When we introduced sad-1 , a mutant lacking the RNA-dependent RNA polymerase that silences unpaired coding regions during meiosis into crosses heterozygous rec-2SL/rec-2LG , it increased recombination, indicating that meiotic silencing of a gene promoting recombination is responsible for dominant suppression of recombination. Consistent with this, mutation of rec-2LG by Repeat-Induced Point mutation generated an allele with multiple stop codons in the predicted rec-2 gene, which does not promote recombination and is recessive to rec-2LG. Sad-1 also relieves suppression of recombination in relevant target regions, in crosses heterozygous for rec-1 alleles and in crosses heterozygous for rec-3 alleles. We conclude that for all 3 known rec genes, 1 allele appears dominant only because meiotic silencing prevents the product of the active, "recessive," allele from stimulating recombination during meiosis. In addition, the proposed amino acid sequence of REC-2 suggests that regulation of recombination in Neurospora differs from any currently known mechanism. [ABSTRACT FROM AUTHOR]

CRISPR/Cas9 technologies are important tools for the development of gene-drive systems to modify mosquito vector populations to control the transmission of pathogens that cause diseases such as malaria. However, one of the challenges for current Cas9-based drive systems is their ability to produce drive-resistant alleles resulting from insertions and deletions (indels) caused principally by nonhomologous end-joining following chromosome cleavage. Rapid increases in the frequency of such alleles may impair gene-drive dynamics. We explored the generation of indels in the germline and somatic cells in female gene-drive lineages using a series of selective crosses between a gene-drive line, AgNosCd-1, and wild-type mosquitoes. We find that potential drive-resistant mutant alleles are generated largely during embryonic development, most likely caused by deposition of the Cas9 endonuclease and guide RNAs in oocytes and resulting embryos by homozygous and hemizygous gene-drive mothers.

The ancestral recombination graph is a structure that describes the joint genealogies of sampled DNA sequences along the genome. Recent computational methods have made impressive progress toward scalably estimating whole-genome genealogies. In addition to inferring the ancestral recombination graph, some of these methods can also provide ancestral recombination graphs sampled from a defined posterior distribution. Obtaining good samples of ancestral recombination graphs is crucial for quantifying statistical uncertainty and for estimating population genetic parameters such as effective population size, mutation rate, and allele age. Here, we use standard neutral coalescent simulations to benchmark the estimates of pairwise coalescence times from 3 popular ancestral recombination graph inference programs: ARGweaver, Relate, and tsinfer+tsdate. We compare (1) the true coalescence times to the inferred times at each locus; (2) the distribution of coalescence times across all loci to the expected exponential distribution; (3) whether the sampled coalescence times have the properties expected of a valid posterior distribution. We find that inferred coalescence times at each locus are most accurate in ARGweaver, and often more accurate in Relate than in tsinfer+tsdate. However, all 3 methods tend to overestimate small coalescence times and underestimate large ones. Lastly, the posterior distribution of ARGweaver is closer to the expected posterior distribution than Relate's, but this higher accuracy comes at a substantial trade-off in scalability. The best choice of method will depend on the number and length of input sequences and on the goal of downstream analyses, and we provide guidelines for the best practices.

The Alliance of Genome Resources (the Alliance) is a combined effort of 7 knowledgebase projects: Saccharomyces Genome Database, WormBase, FlyBase, Mouse Genome Database, the Zebrafish Information Network, Rat Genome Database, and the Gene Ontology Resource. The Alliance seeks to provide several benefits: better service to the various communities served by these projects; a harmonized view of data for all biomedical researchers, bioinformaticians, clinicians, and students; and a more sustainable infrastructure. The Alliance has harmonized cross-organism data to provide useful comparative views of gene function, gene expression, and human disease relevance. The basis of the comparative views is shared calls of orthology relationships and the use of common ontologies. The key types of data are alleles and variants, gene function based on gene ontology annotations, phenotypes, association to human disease, gene expression, protein-protein and genetic interactions, and participation in pathways. The information is presented on uniform gene pages that allow facile summarization of information about each gene in each of the 7 organisms covered (budding yeast, roundworm Caenorhabditis elegans, fruit fly, house mouse, zebrafish, brown rat, and human). The harmonized knowledge is freely available on the alliancegenome.org portal, as downloadable files, and by APIs. We expect other existing and emerging knowledge bases to join in the effort to provide the union of useful data and features that each knowledge base currently provides.

The balanced segregation of homologous chromosomes during meiosis is essential for fertility and is mediated by crossovers (COs). A strong reduction of CO number leads to the unpairing of homologous chromosomes after the withdrawal of the synaptonemal complex. This results in the random segregation of univalents during meiosis I and ultimately to the production of unbalanced and sterile gametes. However, if CO shortage is combined with another meiotic alteration that restitutes the first meiotic division, then uniform and balanced unreduced male gametes, essentially composed of nonrecombinant homologs, are produced. This mitosis-like division is of interest to breeders because it transmits most of the parental heterozygosity to the gametes. In potato, CO shortage, a recessive trait previously referred to as desynapsis, was tentatively mapped to chromosome 8. In this article, we have fine-mapped the position of the CO shortage locus and identified StMSH4 , an essential component of the class I CO pathway, as the most likely candidate gene. A 7 base-pair insertion in the second exon of StMSH4 was found to be associated with CO shortage in our mapping population. We also identified a second allele with a 3,820 base-pair insertion and confirmed that both alleles cannot complement each other. Such nonfunctional alleles appear to be common in potato cultivars. More than half of the varieties we tested are carriers of mutational load at the StMSH4 locus. With this new information, breeders can choose to remove alleles associated with CO shortage from their germplasm to improve fertility or to use them to produce highly uniform unreduced male gametes in alternative breeding schemes. [ABSTRACT FROM AUTHOR]

Loss of heterozygosity (LOH) can occur when a heterozygous mutant cell loses the remaining wild-type allele to become a homozygous mutant. LOH can have physiological consequences if, for example, the affected gene encodes a tumor suppressor. We used fluorescent reporters to study the mechanisms of LOH induction by X-rays, a type of ionizing radiation (IR), in Drosophila melanogaster larval wing discs. IR is used to treat more than half of patients with cancer, so understanding its effects is of biomedical relevance. Quantitative analysis of IR-induced LOH at different positions between the telomere and the centromere on the X chromosome showed a strong sex dependence and the need for a recombination-proficient homologous chromosome, whereas, paradoxically, position along the chromosome made little difference in LOH incidence. We propose that published data documenting high recombination frequency within centromeric heterochromatin on the X chromosome can explain these data. Using a focused screen, we identified E2F1 as a key promotor of LOH and further testing suggests a mechanism involving its role in cell-cycle regulation. We leveraged the loss of a transcriptional repressor through LOH to express transgenes specifically in cells that have already acquired LOH. This approach identified JNK signaling and apoptosis as key determinants of LOH maintenance. These studies reveal previously unknown mechanisms for the generation and elimination of cells with chromosome aberrations after exposure to IR. [ABSTRACT FROM AUTHOR]

The discovery that experimental delivery of dsRNA can induce gene silencing at target genes revolutionized genetics research, by both uncovering essential biological processes and creating new tools for developmental geneticists. However, the efficacy of exogenous RNA interference (RNAi) varies dramatically within the Caenorhabditis elegans natural population, raising questions about our understanding of RNAi in the lab relative to its activity and significance in nature. Here, we investigate why some wild strains fail to mount a robust RNAi response to germline targets. We observe diversity in mechanism: in some strains, the response is stochastic, either on or off among individuals, while in others, the response is consistent but delayed. Increased activity of the Argonaute PPW-1 , which is required for germline RNAi in the laboratory strain N2 , rescues the response in some strains but dampens it further in others. Among wild strains, genes known to mediate RNAi exhibited very high expression variation relative to other genes in the genome as well as allelic divergence and strain-specific instances of pseudogenization at the sequence level. Our results demonstrate functional diversification in the small RNA pathways in C. elegans and suggest that RNAi processes are evolving rapidly and dynamically in nature. [ABSTRACT FROM AUTHOR]

Sec1/Munc18 (SM) proteins are important regulators of SNARE complex assembly during exocytosis throughout all major animal tissue types. However, expression of a founding member of the SM family, UNC-18, is mostly restricted to the nervous system of the nematode Caenorhabditis elegans, where it is important for synaptic transmission. Moreover, unc-18 null mutants do not display the lethality phenotype associated with (a) loss of all Drosophila and mouse orthologs of unc-18 and (b) with complete elimination of synaptic transmission in C. elegans. We investigated whether a previously uncharacterized unc-18 paralog, which we named uncp-18, may be able to explain the restricted expression and limited phenotypes of unc-18 null mutants. A reporter allele shows ubiquitous expression of uncp- 18. Analysis of uncp-18 null mutants, unc-18 and uncp-18 double null mutants, as well as overexpression of uncp-18 in an unc-18 null mutant background, shows that these 2 genes can functionally compensate for one another and are redundantly required for embryonic viability. Our results indicate that the synaptic transmission defects of unc-18 null mutants cannot necessarily be interpreted as constituting a null phenotype for SM protein function at the synapse. [ABSTRACT FROM AUTHOR]

The highly active family of Mutator (Mu) DNA transposons has been widely used for forward and reverse genetics in maize. There are examples of Mu-suppressible alleles that result in conditional phenotypic effects based on the activity of Mu. Phenotypes from these Mu-suppressible mutations are observed in Mu-active genetic backgrounds, but absent when Mu activity is lost. For some Mu-suppressible alleles, phenotypic suppression likely results from an outward-reading promoter within Mu that is only active when the autonomous Mu element is silenced or lost. We isolated 35 Mu alleles from the UniformMu population that represent insertions in 24 different genes. Most of these mutant alleles are due to insertions within gene coding sequences, but several 5′ UTR and intron insertions were included. RNA-seq and de novo transcript assembly were utilized to document the transcripts produced from 33 of these Mu insertion alleles. For 20 of the 33 alleles, there was evidence of transcripts initiating within the Mu sequence reading through the gene. This outward-reading promoter activity was detected in multiple types of Mu elements and does not depend on the orientation of Mu. Expression analyses of Mu-initiated transcripts revealed the Mu promoter often provides gene expression levels and patterns that are similar to the wild-type gene. These results suggest the Mu promoter may represent a minimal promoter that can respond to gene cis-regulatory elements. Findings from this study have implications for maize researchers using the UniformMu population, and more broadly highlight a strategy for transposons to co-exist with their host. [ABSTRACT FROM AUTHOR]

Candida albicans, a normal member of the human microbiome and an opportunistic fungal pathogen, undergoes several morphological transitions. One of these transitions is white–opaque switching, where C. albicans alternates between 2 stable cell types with distinct cellular and colony morphologies, metabolic preferences, mating abilities, and interactions with the innate immune system. White-toopaque switching is regulated by mating type; it is repressed by the a1/α2 heterodimer in a/α cells, but this repression is lifted in a/a and α/α mating type cells (each of which are missing half of the repressor). The widely used C. albicans reference strain, SC5314, is unusual in that white–opaque switching is completely blocked when the cells are a/α; in contrast, most other C. albicans a/α strains can undergo white–opaque switching at an observable level. In this paper, we uncover the reason for this difference. We show that, in addition to repression by the a1/α2 heterodimer, SC5314 contains a second block to white–opaque switching: 4 transcription regulators of filamentous growth are upregulated in this strain and collectively suppress white–opaque switching. This second block is missing in the majority of clinical strains, and, although they still contain the a1/α2 heterodimer repressor, they exhibit a/α white–opaque switching at an observable level. When both blocks are absent, white–opaque switching occurs at very high levels. This work shows that white–opaque switching remains intact across a broad group of clinical strains, but the precise way it is regulated and therefore the frequency at which it occurs varies from strain to strain. [ABSTRACT FROM AUTHOR]

Structural variants (SVs) and short tandem repeats (STRs) are significant sources of genetic variation. However, the impacts of these variants on gene regulation have not been investigated in cattle. Here, we genotyped and characterized 19,408 SVs and 374,821 STRs in 183 bovine genomes and investigated their impact on molecular phenotypes derived from testis transcriptomes. We found that 71% STRs were multiallelic. The vast majority (95%) of STRs and SVs were in intergenic and intronic regions. Only 37% SVs and 40% STRs were in high linkage disequilibrium (LD) (R² > 0.8) with surrounding SNPs/insertions and deletions (Indels), indicating that SNP-based association testing and genomic prediction are blind to a nonnegligible portion of genetic variation. We showed that both SVs and STRs were more than 2-fold enriched among expression and splicing QTL (e/sQTL) relative to SNPs/Indels and were often associated with differential expression and splicing of multiple genes. Deletions and duplications had larger impacts on splicing and expression than any other type of SV. Exonic duplications predominantly increased gene expression either through alternative splicing or other mechanisms, whereas expression- and splicing-associated STRs primarily resided in intronic regions and exhibited bimodal effects on the molecular phenotypes investigated. Most e/sQTL resided within 100 kb of the affected genes or splicing junctions. We pinpoint candidate causal STRs and SVs associated with the expression of SLC13A4 and TTC7B and alternative splicing of a lncRNA and CAPP1. We provide a catalog of STRs and SVs for taurine cattle and show that these variants contribute substantially to gene expression and splicing variation. [ABSTRACT FROM AUTHOR]

Upon DNA replication stress, cells utilize the postreplication repair pathway to repair single-stranded DNA and maintain genome integrity. Postreplication repair is divided into 2 branches: error-prone translesion synthesis, signaled by proliferating cell nuclear antigen (PCNA) monoubiquitination, and error-free template switching, signaled by PCNA polyubiquitination. In Saccharomyces cerevisiae, Rad5 is involved in both branches of repair during DNA replication stress. When the PCNA polyubiquitination function of Rad5 s disrupted, Rad5 recruits translesion synthesis polymerases to stalled replication forks, resulting in mutagenic repair. Details of how mutagenic repair is carried out, as well as the relationship between Rad5-mediated mutagenic repair and the canonical PCNA-mediated mutagenic repair, remain to be understood. We find that Rad5-mediated mutagenic repair requires the translesion synthesis polymerase ζ but does not require other yeast translesion polymerase activities. Furthermore, we show that Rad5-mediated mutagenic repair is independent of PCNA binding by Rev1 and so is separable from canonical mutagenic repair. In the absence of error-free template switching, both modes of mutagenic repair contribute additively to replication stress response in a replication timing-independent manner. Cellular contexts where error-free template switching is compromised are not simply laboratory phenomena, as we find that a natural variant in RAD5 is defective in PCNA polyubiquitination and therefore defective in error-free repair, resulting in Rad5- and PCNAmediated mutagenic repair. Our results highlight the importance of Rad5 in regulating spontaneous mutagenesis and genetic diversity in S. cerevisiae through different modes of postreplication repair. [ABSTRACT FROM AUTHOR]

Standardized nomenclature for genes, gene products, and isoforms is crucial to prevent ambiguity and enable clear communication of scientific data, facilitating efficient biocuration and data sharing. Standardized genotype nomenclature, which describes alleles present in a specific strain that differ from those in the wild-type reference strain, is equally essential to maximize research impact and ensure that results linking genotypes to phenotypes are Findable, Accessible, Interoperable, and Reusable (FAIR). In this publication, we extend the fission yeast clade gene nomenclature guidelines to support the curation efforts at PomBase (www.pombase.org), the Schizosaccharomyces pombe Model Organism Database. This update introduces nomenclature guidelines for noncoding RNA genes, following those set forth by the Human Genome Organisation Gene Nomenclature Committee. Additionally, we provide a significant update to the allele and genotype nomenclature guidelines originally published in 1987, to standardize the diverse range of genetic modifications enabled by the fission yeast genetic toolbox. These updated guidelines reflect a community consensus between numerous fission yeast researchers. Adoption of these rules will improve consistency in gene and genotype nomenclature, and facilitate machine-readability and automated entity recognition of fission yeast genes and alleles in publications or datasets. In conclusion, our updated guidelines provide a valuable resource for the fission yeast research community, promoting consistency, clarity, and FAIRness in genetic data sharing and interpretation. [ABSTRACT FROM AUTHOR]

In plants, mammals and insects, some genes are methylated in the CG dinucleotide context, a phenomenon called gene body methylation (gbM). It has been controversial whether this phenomenon has any functional role. Here, we took advantage of the availability of 876 leaf methylomes in Arabidopsis thaliana to characterize the population frequency of methylation at the gene level and to estimate the site-frequency spectrum of allelic states. Using a population genetics model specifically designed for epigenetic data, we found that genes with ancestral gbM are under significant selection to remain methylated. Conversely, ancestrally unmethylated genes were under selection to remain unmethylated. Repeating the analyses at the level of individual cytosines confirmed these results. Estimated selection coefficients were small, on the order of 4 Nes = 1.4, which is similar to the magnitude of selection acting on codon usage. We also estimated that A. thaliana is losing gbM threefold more rapidly than gaining it, which could be due to a recent reduction in the efficacy of selection after a switch to selfing. Finally, we investigated the potential function of gbM through its link with gene expression. Across genes with polymorphic methylation states, the expression of gene body methylated alleles was consistently and significantly higher than unmethylated alleles. Although it is difficult to disentangle genetic from epigenetic effects, our work suggests that gbM has a small but measurable effect on fitness, perhaps due to its association to a phenotype-like gene expression.

Admixture has the potential to facilitate adaptation by providing alleles that are immediately adaptive in a new environment or by simply increasing the long-term reservoir of genetic diversity for future adaptation. A growing number of cases of adaptive introgression are being identified in species across the tree of life, however the timing of selection, and therefore the importance of the different evolutionary roles of admixture, is typically unknown. Here, we investigate the spatio-temporal history of selection favoring Neanderthal-introgressed alleles in modern human populations. Using both ancient and present-day samples of modern humans, we integrate the known demographic history of populations, namely population divergence and migration, with tests for selection. We model how a sweep placed along different branches of an admixture graph acts to modify the variance and covariance in neutral allele frequencies among populations at linked loci. Using a method based on this model of allele frequencies, we study previously identified cases of adaptive Neanderthal introgression. From these, we identify cases in which Neanderthal-introgressed alleles were quickly beneficial and other cases in which they persisted at low frequency for some time. For some of the alleles that persisted at low frequency, we show that selection likely independently favored them later on in geographically separated populations. Our work highlights how admixture with ancient hominins has contributed to modern human adaptation and contextualizes observed levels of Neanderthal ancestry in present-day and ancient samples.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

Rapid phenotypic adaptation is widespread in nature, but the underlying genetic dynamics remain controversial. Whereas population genetics envisages sequential beneficial substitutions, quantitative genetics assumes a collective response through subtle shifts in allele frequencies. This dichotomy of a monogenic and a highly polygenic view of adaptation raises the question of a middle ground, as well as the factors controlling the transition. Here, we consider an additive quantitative trait with equal locus effects under Gaussian stabilizing selection that adapts to a new trait optimum after an environmental change. We present an analytical framework based on Yule branching processes to describe how phenotypic adaptation is achieved by collective changes in allele frequencies at the underlying loci. In particular, we derive an approximation for the joint allele-frequency distribution conditioned on the trait mean as a comprehensive descriptor of the adaptive architecture. Depending on the model parameters, this architecture reproduces the well-known patterns of sequential, monogenic sweeps, or of subtle, polygenic frequency shifts. Between these endpoints, we observe oligogenic architecture types that exhibit characteristic patterns of partial sweeps. We find that a single compound parameter, the population-scaled background mutation rate Θbg, is the most important predictor of the type of adaptation, while selection strength, the number of loci in the genetic basis, and linkage only play a minor role. [ABSTRACT FROM AUTHOR]

We construct a reliable estimation method for evolutionary parameters within the Wright-Fisher model, which describes changes in allele frequencies due to selection and genetic drift, from time-series data. Such data exist for biological populations, for example via artificial evolution experiments, and for the cultural evolution of behavior, such as linguistic corpora that document historical usage of different words with similar meanings. Our method of analysis builds on a Beta-with-Spikes approximation to the distribution of allele frequencies predicted by the Wright-Fisher model. We introduce a self-contained scheme for estimating parameters in the approximation, and demonstrate its robustness with synthetic data, especially in the strong-selection and near-extinction regimes where previous approaches fail. We further apply the method to allele frequency data for baker's yeast (Saccharomyces cerevisiae), finding a significant signal of selection in cases where independent evidence supports such a conclusion. We further demonstrate the possibility of detecting time points at which evolutionary parameters change in the context of a historical spelling reform in the Spanish language. [ABSTRACT FROM AUTHOR]

Genetic selection has been applied for many generations in animal, plant, and experimental populations. Selection changes the allelic architecture of traits to create genetic gain. It remains unknown whether the changes in allelic architecture are different for the recently introduced technique of genomic selection compared to traditional selection methods and whether they depend on the genetic architectures of traits. Here, we investigate the allele frequency changes of old and new causal loci under 50 generations of phenotypic, pedigree, and genomic selection, for a trait controlled by either additive, additive and dominance, or additive, dominance, and epistatic effects. Genomic selection resulted in slightly larger and faster changes in allele frequencies of causal loci than pedigree selection. For each locus, allele frequency change per generation was not only influenced by its statistical additive effect but also to a large extent by the linkage phase with other loci and its allele frequency. Selection fixed a large number of loci, and 5 times more unfavorable alleles became fixed with genomic and pedigree selection than with phenotypic selection. For pedigree selection, this was mainly a result of increased genetic drift, while genetic hitchhiking had a larger effect on genomic selection. When epistasis was present, the average allele frequency change was smaller (~15% lower), and a lower number of loci became fixed for all selection methods. We conclude that for long-term genetic improvement using genomic selection, it is important to consider hitchhiking and to limit the loss of favorable alleles. [ABSTRACT FROM AUTHOR]

The mutation rate plays an important role in adaptive evolution. It can be modified by mutator and anti-mutator alleles. Recent empirical evidence hints that the mutation rate may vary among genetically identical individuals: evidence from bacteria suggests that the mutation rate can be affected by expression noise of a DNA repair protein and potentially also by translation errors in various proteins. Importantly, this non-genetic variation may be heritable via a transgenerational epigenetic mode of inheritance, giving rise to a mutator phenotype that is independent from mutator alleles. Here, we investigate mathematically how the rate of adaptive evolution is affected by the rate of mutation rate phenotype switching. We model an asexual population with two mutation rate phenotypes, non-mutator and mutator. An offspring may switch from its parental phenotype to the other phenotype. We find that switching rates that correspond to sofar empirically described non-genetic systems of inheritance of the mutation rate lead to higher rates of adaptation on both artificial and natural fitness landscapes. These switching rates can maintain within the same individuals both a mutator phenotype and intermediary mutations, a combination that facilitates adaptation. Moreover, non-genetic inheritance increases the proportion of mutators in the population, which in turn increases the probability of hitchhiking of the mutator phenotype with adaptive mutations. This in turns facilitates the acquisition of additional adaptive mutations. Our results rationalize recently observed noise in the expression of proteins that affect the mutation rate and suggest that non-genetic inheritance of this phenotype may facilitate evolutionary adaptive processes. [ABSTRACT FROM AUTHOR]

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common spliceregulatory variants may play a role in reducing the damaging effects of rare exonic variants. [ABSTRACT FROM AUTHOR]

In the later part of the 1980s, the time was ripe for identifying genes controlling flower development. In that pregenomic era, the easiest way to do this was to induce random mutations in seeds by chemical mutagens (or irradiation) and to screen thousands of plants for those with phenotypes specifically defective in floral morphogenesis. Here, we discuss the results of premolecular screens for flower development mutants in Arabidopsis thaliana, carried out at Caltech and Monash University, emphasizing the usefulness of saturation mutagenesis, multiple alleles to identify full loss-of-function, conclusions based on multiple mutant analyses, and from screens for enhancer and suppressor modifiers of original mutant phenotypes. One outcome was a series of mutants that led to the ABC floral organ identity model (AP1, AP2, AP3, PI, and AG). In addition, genes controlling flower meristem identity (AP1, CAL, and LFY), floral meristem size (CLV1 and CLV3), development of individual floral organ types (CRC, SPT, and PTL), and inflorescence meristem properties (TFL1, PIN1, and PID) were defined. These occurrences formed targets for cloning that eventually helped lead to an understanding of transcriptional control of the identity of floral organs and flower meristems, signaling within meristems, and the role of auxin in initiating floral organogenesis. These findings in Arabidopsis are now being applied to investigate how orthologous and paralogous genes act in other flowering plants, allowing us to wander in the fertile fields of evo-devo. [ABSTRACT FROM AUTHOR]

The Escherichia coli system of Cairns and Foster employs a lac frameshift mutation that reverts rarely (10-9/cell/division) during unrestricted growth. However, when 108 cells are plated on lactose medium, the nongrowing lawn produces ∼50 Lac+ revertant colonies that accumulate linearly with time over 5 days. Revertants carry very few associated mutations. This behavior has been attributed to an evolved mechanism ("adaptive mutation" or "stress-induced mutagenesis") that responds to starvation by preferentially creating mutations that improve growth. We describe an alternative model, "selective inbreeding," in which natural selection acts during intercellular transfer of the plasmid that carries the mutant lac allele and the dinB gene for an error-prone polymerase. Revertant genome sequences show that the plasmid is more intensely mutagenized than the chromosome. Revertants vary widely in their number of plasmid and chromosomal mutations. Plasmid mutations are distributed evenly, but chromosomal mutations are focused near the replication origin. Rare, heavily mutagenized, revertants have acquired a plasmid tra mutation that eliminates conjugation ability. These findings support the new model, in which revertants are initiated by rare pre-existing cells (105) with many copies of the F'lac plasmid. These cells divide under selection, producing daughters that mate. Recombination between donor and recipient plasmids initiates rolling-circle plasmid over-replication, causing a mutagenic elevation of DinB level. A lac+ reversion event starts chromosome replication and mutagenesis by accumulated DinB. After reversion, plasmid transfer moves the revertant lac+ allele into an unmutagenized cell, and away from associated mutations. Thus, natural selection explains why mutagenesis appears stress-induced and directed.

Bidirectional flow of information shapes the outcome of the host–pathogen interactions and depends on the genetics of each organism. Recent work has begun to use co-transcriptomic studies to shed light on this bidirectional flow, but it is unclear how plastic the co-transcriptome is in response to genetic variation in both the host and pathogen. To study co-transcriptome plasticity, we conducted transcriptomics using natural genetic variation in the pathogen, Botrytis cinerea, and large-effect genetic variation abolishing defense signaling pathways within the host, Arabidopsis thaliana. We show that genetic variation in the pathogen has a greater influence on the co-transcriptome than mutations that abolish defense signaling pathways in the host. Genome-wide association mapping using the pathogens’ genetic variation and both organisms’ transcriptomes allowed an assessment of how the pathogen modulates plasticity in response to the host. This showed that the differences in both organism’s responses were linked to trans-expression quantitative trait loci (eQTL) hotspots within the pathogen’s genome. These hotspots control gene sets in either the host or pathogen and show differential allele sensitivity to the host’s genetic variation rather than qualitative host specificity. Interestingly, nearly all the trans-eQTL hotspots were unique to the host or pathogen transcriptomes. In this system of differential plasticity, the pathogen mediates the shift in the co-transcriptome more than the host. [ABSTRACT FROM AUTHOR]