, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of this pathogen and 7,863 identified protein-coding genes, and we show that the majority of clinical isolates possess high levels of allelic diversity, genetic admixture, heterozygosity, and extensive aneuploidy. By utilizing paired genome-wide high-throughput DNA sequencing (DNA-seq) with RNA-seq, we found that gene dosage, at the level of individual genes or chromosomal "somy" (a general term covering disomy, trisomy, tetrasomy, etc.), accounted for greater than 85% of total gene expression variation in genes with a 2-fold or greater change in expression. High gene copy number variation (CNV) among membrane-bound transporters, a class of proteins previously implicated in drug resistance, was found for the most highly differentially expressed genes. Our results suggest that gene dosage is an adaptive trait that confers phenotypic plasticity among natural populations by rapid down- or upregulation of transporter proteins to limit the effects of environmental stresses, such as drug selection. is a genus of unicellular eukaryotic parasites that is responsible for a spectrum of human diseases that range from cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) to life-threatening visceral leishmaniasis (VL). Developmental and strain-specific gene expression is largely thought to be due to mRNA message stability or posttranscriptional regulatory networks for this species, whose genome is organized into polycistronic gene clusters in the absence of promoter-mediated regulation of transcription initiation of nuclear genes. Genetic hybridization has been demonstrated to yield dramatic structural genomic variation, but whether such changes in gene dosage impact gene expression has not been formally investigated. Here we show that the predominant mechanism determining transcript abundance differences (>85%) in is that of gene dosage at the level of individual genes or chromosomal somy.

Hybrid genotypes have been repeatedly described among natural isolates of Leishmania , and the recovery of experimental hybrids from sand flies co-infected with different strains or species of Leishmania has formally demonstrated that members of the genus possess the machinery for genetic exchange. As neither gamete stages nor cell fusion events have been directly observed during parasite development in the vector, we have relied on a classical genetic analysis to determine if Leishmania has a true sexual cycle. Here, we used whole genome sequencing to follow the chromosomal inheritance patterns of experimental hybrids generated within and between different strains of L . major and L . infantum . We also generated and sequenced the first experimental hybrids in L . tropica . We found that in each case the parental somy and allele contributions matched the inheritance patterns expected under meiosis 97–99% of the time. The hybrids were equivalent to F1 progeny, heterozygous throughout most of the genome for the markers that were homozygous and different between the parents. Rare, non-Mendelian patterns of chromosomal inheritance were observed, including a gain or loss of somy, and loss of heterozygosity, that likely arose during meiosis or during mitotic divisions of the progeny clones in the fly or culture. While the interspecies hybrids appeared to be sterile, the intraspecies hybrids were able to produce backcross and outcross progeny. Analysis of 5 backcross and outcross progeny clones generated from an L . major F1 hybrid, as well as 17 progeny clones generated from backcrosses involving a natural hybrid of L . tropica , revealed genome wide patterns of recombination, demonstrating that classical crossing over occurs at meiosis, and allowed us to construct the first physical and genetic maps in Leishmania . Altogether, the findings provide strong evidence for meiosis-like sexual recombination in Leishmania , presenting clear opportunities for forward genetic analysis and positional cloning of important genes.

Multiple sequence alignment (MSA) is a fundamental and ubiquitous technique in bioinformatics used to infer related residues among biological sequences. Thus alignment accuracy is crucial to a vast range of analyses, often in ways difficult to assess in those analyses. To compare the performance of different aligners and help detect systematic errors in alignments, a number of benchmarking strategies have been pursued. Here we present an overview of the main strategies-based on simulation, consistency, protein structure, and phylogeny-and discuss their different advantages and associated risks. We outline a set of desirable characteristics for effective benchmarking, and evaluate each strategy in light of them. We conclude that there is currently no universally applicable means of benchmarking MSA, and that developers and users of alignment tools should base their choice of benchmark depending on the context of application-with a keen awareness of the assumptions underlying each benchmarking strategy.

Objective: Characterization of COVID-19 in the Latinx community is necessary for guiding public health initiatives, health system policy, clinical management practices, and improving outcomes. Our aim was to describe the socioeconomic background and clinical profile of patients with COVID-19 at a large public hospital in Los Angeles to improve health disparities leading to poor outcomes during the pandemic. Design, Setting andParticipants: A single center retrospective cross-sectional study of all patients with a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who presented to Los Angeles County (LAC)+University of Southern California (USC) Medical Center between March 15, 2020 and April 30, 2020. Methods: We describe patient characteristics, socioeconomic factors, laboratory findings, and outcomes of the first 278 patients to present to LAC+USC Medical Center with COVID-19.Results: Patients self-identified as Hispanic (82.4%) or non-Hispanic (17.6%). Hispanic patients presented later from symptom onset (6 days vs 3 days, P = 0.027) and had higher post-intubation mortality (40.9% vs. 33.3%, P = 1), intensive care unit (ICU) mortality (31.1% vs. 22.2%, P = 0.87), and overall mortality (11.1% vs 10.2%, P = 1). However, the difference in admission rates, mechanical ventilation rates, and overall mortality rates were not statistically significant. A majority of patients, 275/278 (98.9%), reported residency ZIP codes in areas of higher population density, higher percentage of Latinx, born outside the United States, lower median income, and lower high school graduation rate when compared to the rest of Los Angeles County. Regression analysis within the Hispanic cohort found that age, history of hypertension, history of diabetes, lactate dehydrogenase (LDH), and C-reactive protein (CRP) were predictors of mechanical ventilation and mortality. Conclusion:We show the Latinx community has been disproportionally affected by the pandemic in Los Angeles and we identified multiple socioeconomic and clinical characteristics that predispose this population to COVID-19 infection. This study highlights the need for change in local and national strategies to protect vulnerable communities during public health outbreaks.

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