Despite the universal importance of meiotic recombination for generating genetic diversity, numbers and distribution of recombination events along chromosomes vary among species, genotypes within ...species, and between sexes. Some interspecies differences stem from the diversity of genome size and composition among eukaryotes. Large-genome species, such as humans and most crops, display recombination landscapes that are different from those of small-genome yeasts. Chromatin patterns, including histone modifications and DNA methylation, are also responsible for interspecies differences as well as differences between the sexes. Finally, despite the overall recombination pathway conservation, there are species-specific components that result in distinct recombination patterns. Consequently, characteristics that are defining for the recombination landscape and universally shared by all eukaryotes remain largely to be discovered.
Meiotic recombination is initiated by double-strand break (DSB) formation in chromosomal DNA at a large number of sites in the genome; however, few DSBs, generally one to two per chromosome, result in the formation of crossovers.
Despite evolutionary conservation of recombination mechanisms, there are substantial differences in recombination landscapes among species as well as among genotypes and sexes within species.
Recombination landscapes often differ between male and female meioses with regard to the number of recombination events, their overall distribution along chromosomes, and fine-scale location relative to genes and chromatin features.
Meiotic recombination events occur in open chromatin regions but specific characteristics of chromatin at recombination sites vary among species.
Ability to modify recombination landscapes is of interest to breeding, as many crop species with large and complex genomes exhibit little recombination in large portions of their chromosomes.
Cryptosporidium species differ in host range. Parasite–host coevolution, host adaptation, and geographic segregation have led to the formation of subtype families with unique phenotypic traits within ...the major human-pathogenic species C. parvum and C. hominis. Transmission intensity, genetic diversity, and occurrence of genetic recombination and selective pressure have further shaped their population genetic structures. Panmixia appears to be common within the zoonotic C. parvum, especially its hypertransmissible IIaA15G2R1 subtype. Genetic recombination in C. hominis, in contrast, is more restricted to virulent subtypes, especially IbA10G2. Nonhuman primates and equine animals are commonly infected with genetically divergent C. hominis populations. Systematic studies of these and other host-adapted Cryptosporidium spp. are likely leading to improved understanding of population structures underlying various transmission patterns and intensities of Cryptosporidium.
Cryptosporidium species and subtypes differ in host range and public health significance.
Host-adapted subtype families exist in the human-pathogenic species C. parvum and C. hominis.
Genetic recombination is common within the zoonotic C. parvum, especially its hypertransmissible IIaA15G2R1 subtype.
Genetic recombination in C. hominis is mostly restricted to its virulent subtypes, especially IbA10G2.
Host and geographical segregation, genetic recombination, and selective pressure shape the population structure of C. parvum and C. hominis, leading to the emergence of host-adapted, virulent, and hypertransmissible subtypes with public health significance.
CONTENTS: Summary 752 I. Introduction 752 II. Will migration be enough? 753 III. Can adaptation proceed fast enough? 754 IV. Fitness links demographic and evolutionary processes 755 V. Experimental ...studies: what do they tell us and how can we improve them? 756 VI. Predicting evolutionary change based on genetic variation and natural selection 757 VII. The chronosequence approach 758 VIII. Resurrection of ancestral propagules 759 IX. The mean and variance in fitness, a link between genetics and demography 760 X. Conclusions 762 Acknowledgements 762 References 762 SUMMARY: Evolution proceeds unceasingly in all biological populations. It is clear that climate‐driven evolution has molded plants in deep time and within extant populations. However, it is less certain whether adaptive evolution can proceed sufficiently rapidly to maintain the fitness and demographic stability of populations subjected to exceptionally rapid contemporary climate change. Here, we consider this question, drawing on current evidence on the rate of plant range shifts and the potential for an adaptive evolutionary response. We emphasize advances in understanding based on theoretical studies that model interacting evolutionary processes, and we provide an overview of quantitative genetic approaches that can parameterize these models to provide more meaningful predictions of the dynamic interplay between genetics, demography and evolution. We outline further research that can clarify both the adaptive potential of plant populations as climate continues to change and the role played by ongoing adaptation in their persistence.
The body-wide human microbiome plays a role in health, but its full diversity remains uncharacterized, particularly outside of the gut and in international populations. We leveraged 9,428 metagenomes ...to reconstruct 154,723 microbial genomes (45% of high quality) spanning body sites, ages, countries, and lifestyles. We recapitulated 4,930 species-level genome bins (SGBs), 77% without genomes in public repositories (unknown SGBs uSGBs). uSGBs are prevalent (in 93% of well-assembled samples), expand underrepresented phyla, and are enriched in non-Westernized populations (40% of the total SGBs). We annotated 2.85 M genes in SGBs, many associated with conditions including infant development (94,000) or Westernization (106,000). SGBs and uSGBs permit deeper microbiome analyses and increase the average mappability of metagenomic reads from 67.76% to 87.51% in the gut (median 94.26%) and 65.14% to 82.34% in the mouth. We thus identify thousands of microbial genomes from yet-to-be-named species, expand the pangenomes of human-associated microbes, and allow better exploitation of metagenomic technologies.
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•Large-scale metagenomic assembly uncovered thousands of new human microbiome species•The new genome resource increases the mappability of gut metagenomes over 87%•Some of the newly discovered species comprise thousands of reconstructed genomes•Non-Westernized populations harbor a large fraction of the newly discovered species
The human microbiome harbors many unidentified species. By large-scale metagenomic assembly of samples from diverse populations, we uncovered >150,000 microbial genomes that are recapitulated in 4,930 species. Many species (77%) were never described before, increase the mappability of metagenomes, and expand our understanding of global body-wide human microbiomes.
Intraspecific variation plays a critical role in extant and future forest responses to climate change. Forest tree species with wide climatic niches rely on the intraspecific variation resulting from ...genetic adaptation and phenotypic plasticity to accommodate spatial and temporal climate variability. A centuries‐old legacy of forest ecological genetics and provenance trials has provided a strong foundation upon which to continue building on this knowledge, which is critical to maintain climate‐adapted forests. Our overall objective is to understand forest trees intraspecific responses to climate across species and biomes, while our specific objectives are to describe ecological genetics models used to build our foundational knowledge, summarize modeling approaches that have expanded the traditional toolset, and extensively review the literature from 1994 to 2021 to highlight the main contributions of this legacy and the new analyzes of provenance trials. We reviewed 103 studies comprising at least three common gardens, which covered 58 forest tree species, 28 of them with range‐wide studies. Although studies using provenance trial data cover mostly commercially important forest tree species from temperate and boreal biomes, this synthesis provides a global overview of forest tree species adaptation to climate. We found that evidence for genetic adaptation to local climate is commonly present in the species studied (79%), being more common in conifers (87.5%) than in broadleaf species (67%). In 57% of the species, clines in fitness‐related traits were associated with temperature variables, in 14% of the species with precipitation, and in 25% of the species with both. Evidence of adaptation lags was found in 50% of the species with range‐wide studies. We conclude that ecological genetics models and analysis of provenance trial data provide excellent insights on intraspecific genetic variation, whereas the role and limits of phenotypic plasticity, which will likely determine the fate of extant forests, is vastly understudied.
We describe ecological genetics models which provided foundational knowledge of forest tree species adaptation to climate, summarize recent modeling approaches, and review the literature from 1994 to 2021 to highlight the main contributions of this legacy and the new analyzes of provenance trials. We reviewed 103 studies comprising at least three common gardens, which covered 58 forest tree species, 28 of them with range‐wide studies. Evidence for genetic adaptation to local climate and of adaptation lags was commonly reported for the species reviewed (79% and 50% of the species, respectively). The role of phenotypic plasticity was vastly understudied.
Abstract
Background
Summary data furnishing a two-sample Mendelian randomization (MR) study are often visualized with the aid of a scatter plot, in which single-nucleotide polymorphism (SNP)–outcome ...associations are plotted against the SNP–exposure associations to provide an immediate picture of the causal-effect estimate for each individual variant. It is also convenient to overlay the standard inverse-variance weighted (IVW) estimate of causal effect as a fitted slope, to see whether an individual SNP provides evidence that supports, or conflicts with, the overall consensus. Unfortunately, the traditional scatter plot is not the most appropriate means to achieve this aim whenever SNP–outcome associations are estimated with varying degrees of precision and this is reflected in the analysis.
Methods
We propose instead to use a small modification of the scatter plot—the Galbraith Radial plot—for the presentation of data and results from an MR study, which enjoys many advantages over the original method. On a practical level, it removes the need to recode the genetic data and enables a more straightforward detection of outliers and influential data points. Its use extends beyond the purely aesthetic, however, to suggest a more general modelling framework to operate within when conducting an MR study, including a new form of MR-Egger regression.
Results
We illustrate the methods using data from a two-sample MR study to probe the causal effect of systolic blood pressure on coronary heart disease risk, allowing for the possible effects of pleiotropy. The Radial plot is shown to aid the detection of a single outlying variant that is responsible for large differences between IVW and MR-Egger regression estimates. Several additional plots are also proposed for informative data visualization.
Conclusions
The Radial plot should be considered in place of the scatter plot for visualizing, analysing and interpreting data from a two-sample summary data MR study. Software is provided to help facilitate its use.
Next-generation sequencing (NGS) data are used for both clinical care and clinical research. DNA sequence variants identified using NGS are often returned to patients/participants as part of clinical ...or research protocols. The current standard of care is to validate NGS variants using Sanger sequencing, which is costly and time-consuming.
We performed a large-scale, systematic evaluation of Sanger-based validation of NGS variants using data from the ClinSeq® project. We first used NGS data from 19 genes in 5 participants, comparing them to high-throughput Sanger sequencing results on the same samples, and found no discrepancies among 234 NGS variants. We then compared NGS variants in 5 genes from 684 participants against data from Sanger sequencing.
Of over 5800 NGS-derived variants, 19 were not validated by Sanger data. Using newly designed sequencing primers, Sanger sequencing confirmed 17 of the NGS variants, and the remaining 2 variants had low quality scores from exome sequencing. Overall, we measured a validation rate of 99.965% for NGS variants using Sanger sequencing, which was higher than many existing medical tests that do not necessitate orthogonal validation.
A single round of Sanger sequencing is more likely to incorrectly refute a true-positive variant from NGS than to correctly identify a false-positive variant from NGS. Validation of NGS-derived variants using Sanger sequencing has limited utility, and best practice standards should not include routine orthogonal Sanger validation of NGS variants.
Ensembl (http://www.ensembl.org) is a genomic interpretation system providing the most up-to-date annotations, querying tools and access methods for chordates and key model organisms. This year we ...released updated annotation (gene models, comparative genomics, regulatory regions and variation) on the new human assembly, GRCh38, although we continue to support researchers using the GRCh37.p13 assembly through a dedicated site (http://grch37.ensembl.org). Our Regulatory Build has been revamped to identify regulatory regions of interest and to efficiently highlight their activity across disparate epigenetic data sets. A number of new interfaces allow users to perform large-scale comparisons of their data against our annotations. The REST server (http://rest.ensembl.org), which allows programs written in any language to query our databases, has moved to a full service alongside our upgraded website tools. Our online Variant Effect Predictor tool has been updated to process more variants and calculate summary statistics. Lastly, the WiggleTools package enables users to summarize large collections of data sets and view them as single tracks in Ensembl. The Ensembl code base itself is more accessible: it is now hosted on our GitHub organization page (https://github.com/Ensembl) under an Apache 2.0 open source license.
Acquired drug resistance in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer is a persistent challenge in cancer therapy. Previous studies of trisubstituted imidazole ...inhibitors led to the serendipitous discovery of inhibitors that target the drug resistant EGFR(L858R/T790M/C797S) mutant with nanomolar potencies in a reversible binding mechanism. To dissect the molecular basis for their activity, we determined the binding modes of several trisubstituted imidazole inhibitors in complex with the EGFR kinase domain with X-ray crystallography. These structures reveal that the imidazole core acts as an H-bond acceptor for the catalytic lysine (K745) in the “αC-helix out” inactive state. Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, noncovalent inhibition of the C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small-cell lung cancer.
Over the past decade, long-read, single-molecule DNA sequencing technologies have emerged as powerful players in genomics. With the ability to generate reads tens to thousands of kilobases in length ...with an accuracy approaching that of short-read sequencing technologies, these platforms have proven their ability to resolve some of the most challenging regions of the human genome, detect previously inaccessible structural variants and generate some of the first telomere-to-telomere assemblies of whole chromosomes. Long-read sequencing technologies will soon permit the routine assembly of diploid genomes, which will revolutionize genomics by revealing the full spectrum of human genetic variation, resolving some of the missing heritability and leading to the discovery of novel mechanisms of disease.
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