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Pardis Sabeti

Publications and source records attributed to Pardis Sabeti.

6 recordsLinked to original sources
PubMed2026

A scalable, low-cost, sample hashing workflow for multiomic single-cell analysis using the Seq-Well S3 platform.

In-depth analyses of clinical samples have the potential to provide unparalleled insights into the cellular mechanisms that underlie both health and disease, as well as therapeutic and prophylactic responses. However, these specimens are often paucicellular, necessitating the use of workflows that maximize the amount of information that can be learned. Here we provide a detailed protocol for generating and analyzing single-cell multiomic data from low-input samples with the Seq-Well S3 platform. We further describe a matched pipeline for sample hashing that reduces costs and sources of technical variation in the resulting data while also enhancing throughput. In brief, our streamlined and efficient methodology involves: (1) optionally staining single-cell suspensions with antibody-oligonucleotide conjugates for cell surface protein quantification and/or sample multiplexing; (2) generating Seq-Well S3 sequencing libraries; (3) optionally producing bulk-RNA sequencing libraries via SMART-seq2 to support genetic demultiplexing; and (4) computationally analyzing the resulting data. Each step herein has been designed to leverage readily available reagents and standard laboratory equipment, substantially lowering barriers to entry for researchers. The overall Protocol can yield high-quality multiomic insights from samples in under a week.

Single-Cell Analysis↗
PubMed2006

Signatures of strong population differentiation shape extended haplotypes across the human CD28, CTLA4, and ICOS costimulatory genes.

The three members of the costimulatory receptor family, CD28, CTLA-4, and ICOS, have complementary effects on T cell activation, and their balance controls the overall outcome of immune and autoimmune responses. They are encoded in a short genomic interval, and overall activity may result from interplay between allelic variants at each locus. With multiethnic DNA panels that represent a wide spectrum of human populations, we demonstrate long-range linkage disequilibrium among the three genes. A large fraction of the variation found in the locus can be explained by the presence of extended haplotypes encompassing variants at CD28, CTLA4, and the ICOS promoter. There are unusual differences in the distribution of some variants and haplotypes between geographic regions. The differences may reflect demographic events and/or the adaptation to diverse environmental and microbial challenges encountered in the course of human migrations and will be important to consider when interpreting association to immune/autoimmune responsiveness.

Antigens, CD↗
PubMed2006

Spread of an inactive form of caspase-12 in humans is due to recent positive selection.

The human caspase-12 gene is polymorphic for the presence or absence of a stop codon, which results in the occurrence of both active (ancestral) and inactive (derived) forms of the gene in the population. It has been shown elsewhere that carriers of the inactive gene are more resistant to severe sepsis. We have now investigated whether the inactive form has spread because of neutral drift or positive selection. We determined its distribution in a worldwide sample of 52 populations and resequenced the gene in 77 individuals from the HapMap Yoruba, Han Chinese, and European populations. There is strong evidence of positive selection from low diversity, skewed allele-frequency spectra, and the predominance of a single haplotype. We suggest that the inactive form of the gene arose in Africa approximately 100-500 thousand years ago (KYA) and was initially neutral or almost neutral but that positive selection beginning approximately 60-100 KYA drove it to near fixation. We further propose that its selective advantage was sepsis resistance in populations that experienced more infectious diseases as population sizes and densities increased.

Base Sequence↗
PubMed2005

Searching for signals of evolutionary selection in 168 genes related to immune function.

Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing immune function. We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency (MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH). Six of the 168 genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent data from the International HapMap Project. These analyses identify two loci involved in immune function that are candidates for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection in genome-wide polymorphism data.

Algorithms↗
PubMed2003

Variants of the CD40 ligand gene are not associated with increased susceptibility to tuberculosis in West Africa.

Evidence for linkage between tuberculosis and human chromosomal region Xq26 has previously been described. The costimulatory molecule CD40 ligand, encoded by TNFSF5 and located at Xq26.3, is a promising positional candidate. Interactions between CD40 ligand and CD40 are involved in the development of humoral- and cell-mediated immunity, as well as the activation of macrophages, which are the primary host and effector cells for Mycobacterium tuberculosis. We hypothesised that common variation within TNFSF5 might affect susceptibility to tuberculosis disease and, thus, might be responsible for the observed linkage to Xq26. Sequencing 32 chromosomes from a Gambian population identified nine common polymorphisms within the coding, 3' and 5' regulatory sequences of the gene. Six single nucleotide polymorphisms (SNPs) and a 3' microsatellite were genotyped in 121 tuberculosis patients and their available parents. No association with tuberculosis was detected for these variants using a transmission disequilibrium test, although one SNP at -726 showed some evidence of association in males. This finding, however, did not replicate in a separate case control study of over 1,200 West African individuals. We conclude that common genetic variation in TNFSF5 is not likely to affect tuberculosis susceptibility in West Africa and the linkage observed in this region is not due to variation in TNFSF5.

Africa, Western↗