Detecting positive selection in genomic regions is a recurrent topic in natural population genetic studies. However, there is little consistency among the regions detected in several genome-wide ...scans using different tests and/or populations. Furthermore, few methods address the challenge of classifying selective events according to specific features such as age, intensity or state (completeness).
We have developed a machine-learning classification framework that exploits the combined ability of some selection tests to uncover different polymorphism features expected under the hard sweep model, while controlling for population-specific demography. As a result, we achieve high sensitivity toward hard selective sweeps while adding insights about their completeness (whether a selected variant is fixed or not) and age of onset. Our method also determines the relevance of the individual methods implemented so far to detect positive selection under specific selective scenarios. We calibrated and applied the method to three reference human populations from The 1000 Genome Project to generate a genome-wide classification map of hard selective sweeps. This study improves detection of selective sweep by overcoming the classical selection versus no-selection classification strategy, and offers an explanation to the lack of consistency observed among selection tests when applied to real data. Very few signals were observed in the African population studied, while our method presents higher sensitivity in this population demography.
The genome-wide results for three human populations from The 1000 Genomes Project and an R-package implementing the 'Hierarchical Boosting' framework are available at http://hsb.upf.edu/.
Searching for Darwinian selection in natural populations has been the focus of a multitude of studies over the last decades. Here we present the 1000 Genomes Selection Browser 1.0 ...(http://hsb.upf.edu) as a resource for signatures of recent natural selection in modern humans. We have implemented and applied a large number of neutrality tests as well as summary statistics informative for the action of selection such as Tajima's D, CLR, Fay and Wu's H, Fu and Li's F* and D*, XPEHH, ΔiHH, iHS, F(ST), ΔDAF and XPCLR among others to low coverage sequencing data from the 1000 genomes project (Phase 1; release April 2012). We have implemented a publicly available genome-wide browser to communicate the results from three different populations of West African, Northern European and East Asian ancestry (YRI, CEU, CHB). Information is provided in UCSC-style format to facilitate the integration with the rich UCSC browser tracks and an access page is provided with instructions and for convenient visualization. We believe that this expandable resource will facilitate the interpretation of signals of selection on different temporal, geographical and genomic scales.
Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and ...clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus.
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•IgM+ PCs generating SIgM are relatively abundant in human but not mouse gut•IgM+ PCs clonally relate to a large gut repertoire of memory IgM+ B cells•Gut memory IgM+ B cells express a tissue-specific signature and can switch to IgA•Human but not mouse SIgM binds a highly diverse microbiota dually coated by SIgA
Magri et al. found that the human gut includes a large memory IgM+ B cell repertoire clonally related to plasma cells mounting SIgM responses against mucus-embedded commensals co-targeted by SIgA. Dually coated bacteria are detected in humans but not mice and show increased diversity and richness compared to SIgA-only-coated or uncoated bacteria.
Abstract
Background
Inherited kidney diseases are one of the leading causes of chronic kidney disease (CKD) that manifests before the age of 30 years. Precise clinical diagnosis of early-onset CKD is ...complicated due to the high phenotypic overlap, but genetic testing is a powerful diagnostic tool. We aimed to develop a genetic testing strategy to maximize the diagnostic yield for patients presenting with early-onset CKD and to determine the prevalence of the main causative genes.
Methods
We performed genetic testing of 460 patients with early-onset CKD of suspected monogenic cause using next-generation sequencing of a custom-designed kidney disease gene panel in addition to targeted screening for c.428dupC MUC1.
Results
We achieved a global diagnostic yield of 65% (300/460), which varied depending on the clinical diagnostic group: 77% in cystic kidney diseases, 76% in tubulopathies, 67% in autosomal dominant tubulointerstitial kidney disease, 61% in glomerulopathies and 38% in congenital anomalies of the kidney and urinary tract. Among the 300 genetically diagnosed patients, the clinical diagnosis was confirmed in 77%, a specific diagnosis within a clinical diagnostic group was identified in 15%, and 7% of cases were reclassified. Of the 64 causative genes identified in our cohort, 7 (COL4A3, COL4A4, COL4A5, HNF1B, PKD1, PKD2 and PKHD1) accounted for 66% (198/300) of the genetically diagnosed patients.
Conclusions
Two-thirds of patients with early-onset CKD in this cohort had a genetic cause. Just seven genes were responsible for the majority of diagnoses. Establishing a genetic diagnosis is crucial to define the precise aetiology of CKD, which allows accurate genetic counselling and improved patient management.
Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, ...COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS).
Retrospective cohort study.
82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected.
A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P=0.8), causative genes (P=0.6), or type of variant (P=0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was−1.46 (−1.66 to−1.26) mL/min/1.73m2 per year for the overall group, with no significant differences between ADAS genes (P=0.2).
The relatively small size of this series from a single country, potentially limiting generalizability.
Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.
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The genetic background of the European Mesolithic and the extent of population replacement during the Neolithic 1–10 is poorly understood, both due to the scarcity of human remains from that period ...11–18 and the inherent methodological difficulties of ancient DNA research. However, advances in sequencing technologies are both increasing data yields and providing supporting evidence for data authenticity, such as nucleotide misincorporation patterns 19–22. We use these methods to characterize both the mitochondrial DNA genome and generate shotgun genomic data from two exceptionally well-preserved 7,000-year-old Mesolithic individuals from La Braña-Arintero site in León (Northwestern Spain) 23. The mitochondria of both individuals are assigned to U5b2c1, a haplotype common among the small number of other previously studied Mesolithic individuals from Northern and Central Europe. This suggests a remarkable genetic uniformity and little phylogeographic structure over a large geographic area of the pre-Neolithic populations. Using Approximate Bayesian Computation, a model of genetic continuity from Mesolithic to Neolithic populations is poorly supported. Furthermore, analyses of 1.34% and 0.53% of their nuclear genomes, containing about 50,000 and 20,000 ancestry informative SNPs, respectively, show that these two Mesolithic individuals are not related to current populations from either the Iberian Peninsula or Southern Europe.
► The first complete Mesolithic mtDNA genome retrieved ► There is a remarkable genetic uniformity in Europe during the Mesolithic period ► Modern Iberians are not direct descendants of the 7,000-year-old hunter-gatherers ► Genetic discontinuity between Mesolithic/Neolithic populations supported by simulations
Integrating demography and adaptive evolution is pivotal to understanding the evolutionary history and conservation of great apes. However, little is known about the adaptive evolution of our closest ...relatives, in particular if and to what extent adaptions to environmental differences have occurred. Here, we used whole-genome sequencing data from critically endangered orangutans from North Sumatra (Pongo abelii) and Borneo (P. pygmaeus) to investigate adaptive responses of each species to environmental differences during the Pleistocene.
Taking into account the markedly disparate demographic histories of each species after their split ~ 1 Ma ago, we show that persistent environmental differences on each island had a strong impact on the adaptive evolution of the genus Pongo. Across a range of tests for positive selection, we find a consistent pattern of between-island and species differences. In the more productive Sumatran environment, the most notable signals of positive selection involve genes linked to brain and neuronal development, learning, and glucose metabolism. On Borneo, however, positive selection comprised genes involved in lipid metabolism, as well as cardiac and muscle activities.
We find strikingly different sets of genes appearing to have evolved under strong positive selection in each species. In Sumatran orangutans, selection patterns were congruent with well-documented cognitive and behavioral differences between the species, such as a larger and more complex cultural repertoire and higher degrees of sociality. However, in Bornean orangutans, selective responses to fluctuating environmental conditions appear to have produced physiological adaptations to generally lower and temporally more unpredictable food supplies.
Six extant species of non-human great apes are currently recognized: Sumatran and Bornean orangutans, eastern and western gorillas, and chimpanzees and bonobos 1. However, large gaps remain in our ...knowledge of fine-scale variation in hominoid morphology, behavior, and genetics, and aspects of great ape taxonomy remain in flux. This is particularly true for orangutans (genus: Pongo), the only Asian great apes and phylogenetically our most distant relatives among extant hominids 1. Designation of Bornean and Sumatran orangutans, P. pygmaeus (Linnaeus 1760) and P. abelii (Lesson 1827), as distinct species occurred in 2001 1, 2. Here, we show that an isolated population from Batang Toru, at the southernmost range limit of extant Sumatran orangutans south of Lake Toba, is distinct from other northern Sumatran and Bornean populations. By comparing cranio-mandibular and dental characters of an orangutan killed in a human-animal conflict to those of 33 adult male orangutans of a similar developmental stage, we found consistent differences between the Batang Toru individual and other extant Ponginae. Our analyses of 37 orangutan genomes provided a second line of evidence. Model-based approaches revealed that the deepest split in the evolutionary history of extant orangutans occurred ∼3.38 mya between the Batang Toru population and those to the north of Lake Toba, whereas both currently recognized species separated much later, about 674 kya. Our combined analyses support a new classification of orangutans into three extant species. The new species, Pongo tapanuliensis, encompasses the Batang Toru population, of which fewer than 800 individuals survive.
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•We describe a new species of great apes, the Tapanuli orangutan Pongo tapanuliensis•Genomic analyses corroborate morphological distinctiveness of P. tapanuliensis•P. tapanuliensis comprises the oldest evolutionary lineage in the genus Pongo•With fewer than 800 individuals, P. tapanuliensis is among the most endangered great apes
Nater et al. describe a new great ape species, the Tapanuli orangutan Pongo tapanuliensis. An isolated population from Batang Toru is highly distinct from the northern Sumatran and Bornean species, based on morphological variation, corroborated by population genomic analyses. Fewer than 800 individuals of P. tapanuliensis survive in the wild.
Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a ...pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin-sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-κB. Disruption of TACI-mTOR interaction by rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional mTOR deficiency interrupts TACI signaling via NF-κB and cooperation with TLRs, thereby hampering IgG production to T-cell-independent antigens but not B-cell survival. Thus, mTOR drives innate-like antibody responses by linking proximal TACI signaling events with distal immunometabolic transcription programs.
To shed light on the peopling of South Asia and the origins of the morphological adaptations found there, we analyzed whole-genome sequences from 10 Andamanese individuals and compared them with ...sequences for 60 individuals from mainland Indian populations with different ethnic histories and with publicly available data from other populations. We show that all Asian and Pacific populations share a single origin and expansion out of Africa, contradicting an earlier proposal of two independent waves of migration. We also show that populations from South and Southeast Asia harbor a small proportion of ancestry from an unknown extinct hominin, and this ancestry is absent from Europeans and East Asians. The footprints of adaptive selection in the genomes of the Andamanese show that the characteristic distinctive phenotypes of this population (including very short stature) do not reflect an ancient African origin but instead result from strong natural selection on genes related to human body size.
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