Multimodal, broadly neutralizing antibodies against SARS-CoV-2 identified by high-throughput native pairing of BCRs from bulk B cells.

TruAB Discovery is an approach that integrates cellular immunology, high-throughput immunosequencing, bioinformatics, and computational biology in order to discover naturally occurring human antibodies for prophylactic or therapeutic use. We adapted our previously described pairSEQ technology to pair B cell receptor heavy and light chains of SARS-CoV-2 spike protein-binding antibodies derived from enriched antigen-specific memory B cells and bulk antibody-secreting cells. We identified approximately 60,000 productive, in-frame, paired antibody sequences, from which 2,093 antibodies were selected for functional evaluation based on abundance, isotype and patterns of somatic hypermutation. The exceptionally diverse antibodies included RBD-binders with broad neutralizing activity against SARS-CoV-2 variants, and S2-binders with broad specificity against betacoronaviruses and the ability to block membrane fusion. A subset of these RBD- and S2-binding antibodies demonstrated robust protection against challenge in hamster and mouse models. This high-throughput approach can accelerate discovery of diverse, multifunctional antibodies against any target of interest.

Genetic history from the Middle Neolithic to present on the Mediterranean island of Sardinia.

The island of Sardinia has been of particular interest to geneticists for decades. The current model for Sardinia's genetic history describes the island as harboring a founder population that was established largely from the Neolithic peoples of southern Europe and remained isolated from later Bronze Age expansions on the mainland. To evaluate this model, we generate genome-wide ancient DNA data for 70 individuals from 21 Sardinian archaeological sites spanning the Middle Neolithic through the Medieval period. The earliest individuals show a strong affinity to western Mediterranean Neolithic populations, followed by an extended period of genetic continuity on the island through the Nuragic period (second millennium BCE). Beginning with individuals from Phoenician/Punic sites (first millennium BCE), we observe spatially-varying signals of admixture with sources principally from the eastern and northern Mediterranean. Overall, our analysis sheds light on the genetic history of Sardinia, revealing how relationships to mainland populations shifted over time.

Estimating recent migration and population-size surfaces.

In many species a fundamental feature of genetic diversity is that genetic similarity decays with geographic distance; however, this relationship is often complex, and may vary across space and time. Methods to uncover and visualize such relationships have widespread use for analyses in molecular ecology, conservation genetics, evolutionary genetics, and human genetics. While several frameworks exist, a promising approach is to infer maps of how migration rates vary across geographic space. Such maps could, in principle, be estimated across time to reveal the full complexity of population histories. Here, we take a step in this direction: we present a method to infer maps of population sizes and migration rates associated with different time periods from a matrix of genetic similarity between every pair of individuals. Specifically, genetic similarity is measured by counting the number of long segments of haplotype sharing (also known as identity-by-descent tracts). By varying the length of these segments we obtain parameter estimates associated with different time periods. Using simulations, we show that the method can reveal time-varying migration rates and population sizes, including changes that are not detectable when using a similar method that ignores haplotypic structure. We apply the method to a dataset of contemporary European individuals (POPRES), and provide an integrated analysis of recent population structure and growth over the last ∼3,000 years in Europe.

Inference and visualization of DNA damage patterns using a grade of membership model.

MOTIVATION: Quality control plays a major role in the analysis of ancient DNA (aDNA). One key step in this quality control is assessment of DNA damage: aDNA contains unique signatures of DNA damage that distinguish it from modern DNA, and so analyses of damage patterns can help confirm that DNA sequences obtained are from endogenous aDNA rather than from modern contamination. Predominant signatures of DNA damage include a high frequency of cytosine to thymine substitutions (C-to-T) at the ends of fragments, and elevated rates of purines (A & G) before the 5' strand-breaks. Existing QC procedures help assess damage by simply plotting for each sample, the C-to-T mismatch rate along the read and the composition of bases before the 5' strand-breaks. Here we present a more flexible and comprehensive model-based approach to infer and visualize damage patterns in aDNA, implemented in an R package aRchaic. This approach is based on a 'grade of membership' model (also known as 'admixture' or 'topic' model) in which each sample has an estimated grade of membership in each of K damage profiles that are estimated from the data. RESULTS: We illustrate aRchaic on data from several aDNA studies and modern individuals from 1000 Genomes Project Consortium (2012). Here, aRchaic clearly distinguishes modern from ancient samples irrespective of DNA extraction, lab and sequencing protocols. Additionally, through an in-silico contamination experiment, we show that the aRchaic grades of membership reflect relative levels of exogenous modern contamination. Together, the outputs of aRchaic provide a concise visual summary of DNA damage patterns, as well as other processes generating mismatches in the data. AVAILABILITY AND IMPLEMENTATION: aRchaic is available for download from https://www.github.com/kkdey/aRchaic. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genomic history of the Sardinian population.

The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of genetic similarity with mainland ancient DNA samples varies subtly across the island. Together, our results indicate that within-island substructure and sex-biased processes have substantially impacted the genetic history of Sardinia. These results give new insight into the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations.