Improvements in technology have reduced the cost of DNA sequencing to the point that the limiting factor for many experiments is the time and reagent cost of sample preparation. We present an ...approach in which 192 sequencing libraries can be produced in a single day of technician time at a cost of about $15 per sample. These libraries are effective not only for low-pass whole-genome sequencing, but also for simultaneously enriching them in pools of approximately 100 individually barcoded samples for a subset of the genome without substantial loss in efficiency of target capture. We illustrate the power and effectiveness of this approach on about 2000 samples from a prostate cancer study.
Objective
Coronavirus disease 2019 (COVID‐19) continues to spread, and younger patients are also being critically affected. This study analyzed obesity as an independent risk factor for mortality in ...hospitalized patients younger than 50.
Methods
This study retrospectively analyzed data of patients with COVID‐19 who were hospitalized to a large academic hospital system in New York City between March 1, 2020, and May 17, 2020. Data included demographics, comorbidities, BMI, and smoking status. Obesity groups included the following: BMI of 30 to < 40 kg/m2 and BMI ≥ 40 kg/m2. Multivariable logistic regression models identified variables independently associated with mortality in patients younger and older than 50.
Results
Overall, 3,406 patients were included; 572 (17.0%) patients were younger than 50. In the younger age group, 60 (10.5%) patients died. In the older age group, 1,076 (38.0%) patients died. For the younger population, BMI ≥ 40 was independently associated with mortality (adjusted odds ratio 5.1; 95% CI: 2.3‐11.1). For the older population, BMI ≥ 40 was also independently associated with mortality to a lesser extent (adjusted odds ratio 1.6; 95% CI: 1.2‐2.3).
Conclusions
This study demonstrates that hospitalized patients younger than 50 with severe obesity are more likely to die of COVID‐19. This is particularly relevant in the Western world, where obesity rates are high.
Some present-day humans derive up to ∼5% 1 of their ancestry from archaic Denisovans, an even larger proportion than the ∼2% from Neanderthals 2. We developed methods that can disambiguate the ...locations of segments of Denisovan and Neanderthal ancestry in present-day humans and applied them to 257 high-coverage genomes from 120 diverse populations, among which were 20 individual Oceanians with high Denisovan ancestry 3. In Oceanians, the average size of Denisovan fragments is larger than Neanderthal fragments, implying a more recent average date of Denisovan admixture in the history of these populations (p = 0.00004). We document more Denisovan ancestry in South Asia than is expected based on existing models of history, reflecting a previously undocumented mixture related to archaic humans (p = 0.0013). Denisovan ancestry, just like Neanderthal ancestry, has been deleterious on a modern human genetic background, as reflected by its depletion near genes. Finally, the reduction of both archaic ancestries is especially pronounced on chromosome X and near genes more highly expressed in testes than other tissues (p = 1.2 × 10−7 to 3.2 × 10−7 for Denisovan and 2.2 × 10−3 to 2.9 × 10−3 for Neanderthal ancestry even after controlling for differences in level of selective constraint across gene classes). This suggests that reduced male fertility may be a general feature of mixtures of human populations diverged by >500,000 years.
•Denisovan admixture into modern humans occurred after Neanderthal admixture•There is more Denisovan ancestry in South Asians than expected from current models•Denisovan ancestry has been subject to positive and negative selection after admixture•Male infertility most likely occurred after modern human interbreeding with Denisovans
Sankararaman et al. present a map of Denisovan and Neanderthal ancestry in 120 diverse populations and show that Denisovan admixture post-dated Neanderthal admixture. South Asians have more Denisovan ancestry than expected. There was selection both for and against archaic ancestry. Hybridization with Denisovans was probably associated with reduced male fertility.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic with millions infected and more than 1 million fatalities. Questions regarding the robustness, functionality, ...and longevity of the antibody response to the virus remain unanswered. Here, on the basis of a dataset of 30,082 individuals screened at Mount Sinai Health System in New York City, we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust immunoglobulin G antibody responses against the viral spike protein. We also show that titers are relatively stable for at least a period of about 5 months and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggest that more than 90% of seroconverters make detectable neutralizing antibody responses. These titers remain relatively stable for several months after infection.
Abstract
qpAdm is a statistical tool for studying the ancestry of populations with histories that involve admixture between two or more source populations. Using qpAdm, it is possible to identify ...plausible models of admixture that fit the population history of a group of interest and to calculate the relative proportion of ancestry that can be ascribed to each source population in the model. Although qpAdm is widely used in studies of population history of human (and nonhuman) groups, relatively little has been done to assess its performance. We performed a simulation study to assess the behavior of qpAdm under various scenarios in order to identify areas of potential weakness and establish recommended best practices for use. We find that qpAdm is a robust tool that yields accurate results in many cases, including when data coverage is low, there are high rates of missing data or ancient DNA damage, or when diploid calls cannot be made. However, we caution against co-analyzing ancient and present-day data, the inclusion of an extremely large number of reference populations in a single model, and analyzing population histories involving extended periods of gene flow. We provide a user guide suggesting best practices for the use of qpAdm.
Mutations occur at vastly different rates across the genome, and populations, leading to differences in the spectrum of segregating polymorphisms. Here, we investigate variation in the rare variant ...spectrum in a sample of human genomes representing all major world populations. We find at least two distinct signatures of variation. One, consistent with a previously reported signature is characterized by an increased rate of TCC>TTC mutations in people from Western Eurasia and South Asia, likely related to differences in the rate, or efficiency of repair, of damage due to deamination of methylated guanine. We describe the geographic extent of this signature and show that it is detectable in the genomes of ancient, but not archaic humans. The second signature is private to certain Native American populations, and is concentrated at CpG sites. We show that this signature is not driven by differences in the CpG mutation rate, but is a result of the fact that highly mutable CpG sites are more likely to undergo multiple independent mutations across human populations, and the spectrum of such mutations is highly sensitive to recent demography. Both of these effects dramatically affect the spectrum of rare variants across human populations, and should be taken into account when using mutational clocks to make inference about demography.
The challenge of sequencing ancient DNA has led to the development of specialized laboratory protocols that have focused on reducing contamination and maximizing the number of molecules that are ...extracted from ancient remains. Despite the fact that success in ancient DNA studies is typically obtained by screening many samples to identify a promising subset, ancient DNA protocols have not, in general, focused on reducing the time required to screen samples. We present an adaptation of a popular ancient library preparation method that makes screening more efficient. First, the DNA extract is treated using a protocol that causes characteristic ancient DNA damage to be restricted to the terminal nucleotides, while nearly eliminating it in the interior of the DNA molecules, allowing a single library to be used both to test for ancient DNA authenticity and to carry out population genetic analysis. Second, the DNA molecules are ligated to a unique pair of barcodes, which eliminates undetected cross-contamination from this step onwards. Third, the barcoded library molecules include incomplete adapters of short length that can increase the specificity of hybridization-based genomic target enrichment. The adapters are completed just before sequencing, so the same DNA library can be used in multiple experiments, and the sequences distinguished. We demonstrate this protocol on 60 ancient human samples.
Selective sweeps can increase genetic differentiation among populations and cause allele frequency spectra to depart from the expectation under neutrality. We present a likelihood method for ...detecting selective sweeps that involves jointly modeling the multilocus allele frequency differentiation between two populations. We use Brownian motion to model genetic drift under neutrality, and a deterministic model to approximate the effect of a selective sweep on single nucleotide polymorphisms (SNPs) in the vicinity. We test the method with extensive simulated data, and demonstrate that in some scenarios the method provides higher power than previously reported approaches to detect selective sweeps, and can provide surprisingly good localization of the position of a selected allele. A strength of our technique is that it uses allele frequency differentiation between populations, which is much more robust to ascertainment bias in SNP discovery than methods based on the allele frequency spectrum. We apply this method to compare continentally diverse populations, as well as Northern and Southern Europeans. Our analysis identifies a list of loci as candidate targets of selection, including well-known selected loci and new regions that have not been highlighted by previous scans for selection.
One enduring question in evolutionary biology is the extent of archaic admixture in the genomes of present-day populations. In this paper, we present a test for ancient admixture that exploits the ...asymmetry in the frequencies of the two nonconcordant gene trees in a three-population tree. This test was first applied to detect interbreeding between Neandertals and modern humans. We derive the analytic expectation of a test statistic, called the D statistic, which is sensitive to asymmetry under alternative demographic scenarios. We show that the D statistic is insensitive to some demographic assumptions such as ancestral population sizes and requires only the assumption that the ancestral populations were randomly mating. An important aspect of D statistics is that they can be used to detect archaic admixture even when no archaic sample is available. We explore the effect of sequencing error on the false-positive rate of the test for admixture, and we show how to estimate the proportion of archaic ancestry in the genomes of present-day populations. We also investigate a model of subdivision in ancestral populations that can result in D statistics that indicate recent admixture.
Genomic studies have shown that Neanderthals interbred with modern humans, and that non-Africans today are the products of this mixture. The antiquity of Neanderthal gene flow into modern humans ...means that genomic regions that derive from Neanderthals in any one human today are usually less than a hundred kilobases in size. However, Neanderthal haplotypes are also distinctive enough that several studies have been able to detect Neanderthal ancestry at specific loci. We systematically infer Neanderthal haplotypes in the genomes of 1,004 present-day humans. Regions that harbour a high frequency of Neanderthal alleles are enriched for genes affecting keratin filaments, suggesting that Neanderthal alleles may have helped modern humans to adapt to non-African environments. We identify multiple Neanderthal-derived alleles that confer risk for disease, suggesting that Neanderthal alleles continue to shape human biology. An unexpected finding is that regions with reduced Neanderthal ancestry are enriched in genes, implying selection to remove genetic material derived from Neanderthals. Genes that are more highly expressed in testes than in any other tissue are especially reduced in Neanderthal ancestry, and there is an approximately fivefold reduction of Neanderthal ancestry on the X chromosome, which is known from studies of diverse species to be especially dense in male hybrid sterility genes. These results suggest that part of the explanation for genomic regions of reduced Neanderthal ancestry is Neanderthal alleles that caused decreased fertility in males when moved to a modern human genetic background.
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