Universidad de Antioquia

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics. The 1000 Genomes Project has sought to comprehensively catalogue human genetic variation across populations, providing a valuable public genomic resource. The data obtained so far have found applications ranging from association studies and fine mapping studies to the filtering of likely neutral variants in rare-disease cohorts. The authors now report on the final phase of the project, phase 3, which covers previously uncharacterized areas of human genetic diversity in terms of the populations sampled and categories of characterized variation. The sample now includes more than 2,500 individuals from 26 global populations, with low coverage whole-genome and deep exome sequencing, as well as dense microarray genotyping. They find that while most common variants are shared across populations, rarer variants are often restricted to closely related populations. The authors also demonstrate the use of the phase 3 dataset as a reference panel for imputation to improve the resolution in genetic association studies.

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations. This report from the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations; hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites, can be found in each individual. This report by the 1000 Genomes Project describes the genomes of 1,092 individuals from 14 human populations, providing a resource for common and low-frequency variant analysis in individuals from diverse populations. Integrative analyses reveal profiles of rare and common variants in different populations. The frequencies of rare variants vary across biological pathways, and hundreds of rare, non-coding variants at conserved sites — such as changes disrupting transcription-factor motifs — can be established for each individual.

Rhinosinusitis is a significant and increasing health problem which results in a large financial burden on society. This evidence based position paper describes what is known about rhinosinusitis and nasal polyps, offers evidence based recommendations on diagnosis and treatment, and considers how we can make progress with research in this area. Rhinitis and sinusitis usually coexist and are concurrent in most individuals; thus, the correct terminology is now rhinosinusitis. Rhinosinusitis (including nasal polyps) is defined as inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), +/- facial pain/pressure, +/- reduction or loss of smell; and either endoscopic signs of polyps and/or mucopurulent discharge primarily from middle meatus and/or; oedema/mucosal obstruction primarily in middle meatus, and/or CT changes showing mucosal changes within the ostiomeatal complex and/or sinuses. The paper gives different definitions for epidemiology, first line and second line treatment and for research. Furthermore the paper describes the anatomy and (patho)physiology, epidemiology and predisposing factors, inflammatory mechanisms, evidence based diagnosis, medical and surgical treatment in acute and chronic rhinosinusitis and nasal polyposis in adults and children. Evidence based schemes for diagnosis and treatment are given for the first and second line clinicians. Moreover attention is given to complications and socio-economic cost of chronic rhinosinusitis and nasal polyps. Last but not least the relation to the lower airways is discussed.

As part of a World Health Organization-led effort to update the empirical evidence base for the leishmaniases, national experts provided leishmaniasis case data for the last 5 years and information regarding treatment and control in their respective countries and a comprehensive literature review was conducted covering publications on leishmaniasis in 98 countries and three territories (see 'Leishmaniasis Country Profiles Text S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, S14, S15, S16, S17, S18, S19, S20, S21, S22, S23, S24, S25, S26, S27, S28, S29, S30, S31, S32, S33, S34, S35, S36, S37, S38, S39, S40, S41, S42, S43, S44, S45, S46, S47, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S65, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, S100, S101'). Additional information was collated during meetings conducted at WHO regional level between 2007 and 2011. Two questionnaires regarding epidemiology and drug access were completed by experts and national program managers. Visceral and cutaneous leishmaniasis incidence ranges were estimated by country and epidemiological region based on reported incidence, underreporting rates if available, and the judgment of national and international experts. Based on these estimates, approximately 0.2 to 0.4 cases and 0.7 to 1.2 million VL and CL cases, respectively, occur each year. More than 90% of global VL cases occur in six countries: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil. Cutaneous leishmaniasis is more widely distributed, with about one-third of cases occurring in each of three epidemiological regions, the Americas, the Mediterranean basin, and western Asia from the Middle East to Central Asia. The ten countries with the highest estimated case counts, Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica and Peru, together account for 70 to 75% of global estimated CL incidence. Mortality data were extremely sparse and generally represent hospital-based deaths only. Using an overall case-fatality rate of 10%, we reach a tentative estimate of 20,000 to 40,000 leishmaniasis deaths per year. Although the information is very poor in a number of countries, this is the first in-depth exercise to better estimate the real impact of leishmaniasis. These data should help to define control strategies and reinforce leishmaniasis advocacy.

The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. eabd4570 , p. eabd4585 ; see also p. 404

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

Importance: There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). Objective: To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and Participants: Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). Exposures: Plasma P-tau217. Main Outcomes and Measures: Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). Results: Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22). Conclusions and Relevance: Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.

Abstract In August 2022, these guidelines were reviewed by an expert work group convened by ASH. Review included limited searches for new evidence and discussion of the search results. Following this review, the ASH Committee on Quality agreed to continue monitoring the supporting evidence rather than revise or retire these guidelines at this time. Limited searches and expert review will be repeated annually going forward until these guidelines are revised or retired. Background: Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), occurs in ∼1 to 2 individuals per 1000 each year, corresponding to ∼300 000 to 600 000 events in the United States annually. Objective: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support patients, clinicians, and others in decisions about treatment of VTE. Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and adult patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 28 recommendations for the initial management of VTE, primary treatment, secondary prevention, and treatment of recurrent VTE events. Conclusions: Strong recommendations include the use of thrombolytic therapy for patients with PE and hemodynamic compromise, use of an international normalized ratio (INR) range of 2.0 to 3.0 over a lower INR range for patients with VTE who use a vitamin K antagonist (VKA) for secondary prevention, and use of indefinite anticoagulation for patients with recurrent unprovoked VTE. Conditional recommendations include the preference for home treatment over hospital-based treatment for uncomplicated DVT and PE at low risk for complications and a preference for direct oral anticoagulants over VKA for primary treatment of VTE.

EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. no immunosuppressants IV D no nasal saline irrigation Ib, no data in single use D yes for symptomatic relief topical antibiotics no data D no anti-IL-5 no data D unclear phytotherapy no data D no decongestant topical / oral no data in single use D no mucolytics no data D no oral antihistamine in allergic patients no data D no antimycotics -topical Ia (-) ** A(-) no antimycotics -systemic Ib (-)# A(-) $ no anti leukotrienes Ib (-) A(-) no anti-IgE Ib (-) A(-) no * Some of these studies also included patients with CRS with nasal polyps. % short term antibiotics shows one positive and one negative study. Therefore recommendation C. oral antibiotic short term <4 weeks Ib(-) # A(-)* no intravenous antibiotics III(-) ## C(-) ** no # Ib (-): Ib study with a negative outcome.

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.

We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

Protecting plants from the inside out Some soils show a remarkable ability to suppress disease caused by plant pathogens, an ability that is attributed to plant-associated microbiota. Carrión et al. investigated the role of endophytes, the intimate microbial community found within roots, in fungal disease suppression (see the Perspective by Tringe). The wilt fungus Rhizoctonia solani infects sugar beets, whereupon transcriptional analysis shows that several bacterial endophyte species activate biosynthetic gene clusters to cause disease suppression. These organisms produce antifungal effectors, including enzymes that can digest fungal cell walls, and secondary metabolites, including phenazines, polyketides, and siderophores, which may contribute to the antifungal phenotype. Science , this issue p. 606 ; see also p. 568

Large-scale biogeographical shifts in vegetation are predicted in response to the altered precipitation and temperature regimes associated with global climate change. Vegetation shifts have profound ecological impacts and are an important climate-ecosystem feedback through their alteration of carbon, water, and energy exchanges of the land surface. Of particular concern is the potential for warmer temperatures to compound the effects of increasingly severe droughts by triggering widespread vegetation shifts via woody plant mortality. The sensitivity of tree mortality to temperature is dependent on which of 2 non-mutually-exclusive mechanisms predominates--temperature-sensitive carbon starvation in response to a period of protracted water stress or temperature-insensitive sudden hydraulic failure under extreme water stress (cavitation). Here we show that experimentally induced warmer temperatures (approximately 4 degrees C) shortened the time to drought-induced mortality in Pinus edulis (piñon shortened pine) trees by nearly a third, with temperature-dependent differences in cumulative respiration costs implicating carbon starvation as the primary mechanism of mortality. Extrapolating this temperature effect to the historic frequency of water deficit in the southwestern United States predicts a 5-fold increase in the frequency of regional-scale tree die-off events for this species due to temperature alone. Projected increases in drought frequency due to changes in precipitation and increases in stress from biotic agents (e.g., bark beetles) would further exacerbate mortality. Our results demonstrate the mechanism by which warmer temperatures have exacerbated recent regional die-off events and background mortality rates. Because of pervasive projected increases in temperature, our results portend widespread increases in the extent and frequency of vegetation die-off.

Mutations of alleles at microsatellite loci tend to result in alleles with repeat scores similar to those of the alleles from which they were derived. Therefore the difference in repeat score between alleles carries information about the amount of time that has passed since they shared a common ancestral allele. This information is ignored by genetic distances based on the infinite alleles model. Here we develop a genetic distance based on the stepwise mutation model that includes allelic repeat score. We adapt earlier treatments of the stepwise mutation model to show analytically that the expectation of this distance is a linear function of time. We then use computer simulations to evaluate the overall reliability of this distance and to compare it with allele sharing and Nei's distance. We find that no distance is uniformly superior for all purposes, but that for phylogenetic reconstruction of taxa that are sufficiently diverged, our new distance is preferable.

Network functions virtualization (NFV) is a new network architecture framework where network function that traditionally used dedicated hardware (middleboxes or network appliances) are now implemented in software that runs on top of general purpose hardware such as high volume server. NFV emerges as an initiative from the industry (network operators, carriers, and manufacturers) in order to increase the deployment flexibility and integration of new network services with increased agility within operator's networks and to obtain significant reductions in operating expenditures and capital expenditures. NFV promotes virtualizing network functions such as transcoders, firewalls, and load balancers, among others, which were carried out by specialized hardware devices and migrating them to software-based appliances. One of the main challenges for the deployment of NFV is the resource allocation of demanded network services in NFV-based network infrastructures. This challenge has been called the NFV resource allocation (NFV-RA) problem. This paper presents a comprehensive state of the art of NFV-RA by introducing a novel classification of the main approaches that pose solutions to solve it. This paper also presents the research challenges that are still subject of future investigation in the NFV-RA realm.

Multilocus genotyping of microbial pathogens has revealed a range of population structures, with some bacteria showing extensive recombination and others showing almost complete clonality. The population structure of the protozoan parasite Plasmodium falciparum has been harder to evaluate, since most studies have used a limited number of antigen-encoding loci that are known to be under strong selection. We describe length variation at 12 microsatellite loci in 465 infections collected from 9 locations worldwide. These data reveal dramatic differences in parasite population structure in different locations. Strong linkage disequilibrium (LD) was observed in six of nine populations. Significant LD occurred in all locations with prevalence <1% and in only two of five of the populations from regions with higher transmission intensities. Where present, LD results largely from the presence of identical multilocus genotypes within populations, suggesting high levels of self-fertilization in populations with low levels of transmission. We also observed dramatic variation in diversity and geographical differentiation in different regions. Mean heterozygosities in South American countries (0.3-0.4) were less than half those observed in African locations (0. 76-0.8), with intermediate heterozygosities in the Southeast Asia/Pacific samples (0.51-0.65). Furthermore, variation was distributed among locations in South America (F:(ST) = 0.364) and within locations in Africa (F:(ST) = 0.007). The intraspecific patterns of diversity and genetic differentiation observed in P. falciparum are strikingly similar to those seen in interspecific comparisons of plants and animals with differing levels of outcrossing, suggesting that similar processes may be involved. The differences observed may also reflect the recent colonization of non-African populations from an African source, and the relative influences of epidemiology and population history are difficult to disentangle. These data reveal a range of population structures within a single pathogen species and suggest intimate links between patterns of epidemiology and genetic structure in this organism.

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

We introduce a new genetic distance for microsatellite loci, incorporating features of the stepwise mutation model, and test its performance on microsatellite polymorphisms in humans, chimpanzees, and gorillas. We find that it performs well in determining the relations among the primates, but less well than other distance measures (not based on the stepwise mutation model) in determining the relations among closely related human populations. However, the deepest split in the human phylogeny seems to be accurately reconstructed by the new distance and separates African and non-African populations. The new distance is independent of population size and therefore allows direct estimation of divergence times if the mutation rate is known. Based on 30 microsatellite polymorphisms and a recently reported average mutation rate of 5.6 x 10(-4) at 15 dinucleotide microsatellites, we estimate that the deepest split in the human phylogeny occurred about 156,000 years ago. Unlike most previous estimates, ours requires no external calibration of the rate of molecular evolution. We can use such calibrations, however, to test our estimate.