Haplotype-based inference of the distribution of fitness effects

Recent genome sequencing studies with large sample sizes in humans have discovered a vast quantity of low-frequency variants, providing an important source of information to analyze how selection is acting on human genetic variation. In order to estimate the strength of natural selection acting on low-frequency variants, we have developed a likelihood-based method that uses the lengths of pairwise identity-by-state between haplotypes carrying low-frequency variants. We show that in some non-equilibrium populations (such as those that have had recent population expansions) it is possible to distinguish between positive or negative selection acting on a set of variants. With our new framework, one can infer a fixed selection intensity acting on a set of variants at a particular frequency, or a distribution of selection coefficients for standing variants and new mutations. We show an application of our method to the UK10K phased haplotype dataset of individuals.

The combined impact of persistent infections and human genetic variation on C-reactive protein levels

Multiple human pathogens establish chronic, sometimes life-long infections. Even if they are often latent, these infections can trigger some degree of local or systemic immune response, resulting in chronic low-grade inflammation. There remains an incomplete understanding of the potential contribution of both persistent infections and human genetic variation on chronic low-grade inflammation. We searched for potential associations between seropositivity for 13 persistent pathogens and the plasma levels of the inflammatory biomarker C-reactive protein (CRP), using data collected in the context of the UK Biobank and the CoLaus|PsyCoLaus Study, two large population-based cohorts. We performed backward stepwise regression starting with the following potential predictors: serostatus for each pathogen, polygenic risk score for CRP, as well as demographic and clinical factors known to be associated with CRP. We found evidence for an association between Chlamydia trachomatis (P-value = 5.04e-3) and Helicobacter pylori (P-value = 8.63e-4) seropositivity and higher plasma levels of CRP. We also found an association between pathogen burden and CRP levels (P-value = 4.12e-4). These results improve our understanding of the relationship between persistent infections and chronic inflammation, an important determinant of long-term morbidity in humans.

Molecular and cellular mechanisms that regulate human erythropoiesis

To enable effective oxygen transport, approximately 200 billion red blood cells (RBCs) need to be produced every day in the bone marrow through the fine-tuned process of erythropoiesis. Erythropoiesis is regulated at multiple levels to ensure that defective RBC maturation or overproduction can be avoided. Here, we provide an overview of different layers of this control, ranging from cytokine signaling mechanisms that enable extrinsic regulation of RBC production to intrinsic transcriptional pathways necessary for effective erythropoiesis. Recent studies have also elucidated the importance of post-transcriptional regulation and highlighted additional gatekeeping mechanisms necessary for effective erythropoiesis. We additionally discuss the insights gained by studying human genetic variation impacting erythropoiesis and highlight the discovery of BCL11A as a regulator of hemoglobin switching through genetic studies. Finally, we provide an outlook of how our ability to measure multiple facets of this process at single-cell resolution, while accounting for the impact of human variation, will continue to refine our knowledge of erythropoiesis and how this process is perturbed in disease. As we learn more about this intricate and important process, additional opportunities to modulate erythropoiesis for therapeutic purposes will undoubtedly emerge.

Mid-pass whole genome sequencing enables biomedical genetic studies of diverse populations

Background Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at “mid-pass” 1-7x coverage. Results Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). Conclusion Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.

The apportionment of citations: A scientometric analysis of Lewontin, 1972

"The Apportionment of Human Diversity" (1972) is the most highly cited research article published by geneticist Richard Lewontin in his career. This study's primary result--that most genetic diversity in humans can be accounted for by within-population differences, not between-population differences--along with Lewontin's outspoken, politically-charged interpretations thereof, has become foundational to the scientific and cultural discourse pertaining to human genetic variation. The article has an unusual bibliometric trajectory in that it is much more salient in the bibliographic record today compared to the first 20 years after its publication. Here, we show how the paper's fame was shaped by four factors: 1) citations in influential publications across several disciplines; 2) Lewontin's own popular books and media appearances; 3) the renaissance of population genetics research of the early 1990s; and 4) the serendipitous collision of scientific progress, influential books/papers, and heated controversies in the year 1994. We conclude with an analysis of Twitter data to characterize the communities and conversations that continue to keep this study at the epicenter of discussions about race and genetics, prompting new challenges for scientists who have inherited Lewontin's legacy.

A unified model of human hemoglobin switching through single-cell genome editing

Key mechanisms of fetal hemoglobin (HbF) regulation and switching have been elucidated through studies of human genetic variation, including mutations in the HBG1/2 promoters, deletions in the β-globin locus, and variation impacting BCL11A. While this has led to substantial insights, there has not been a unified understanding of how these distinct genetically-nominated elements, as well as other key transcription factors such as ZBTB7A, collectively interact to regulate HbF. A key limitation has been the inability to model specific genetic changes in primary isogenic human hematopoietic cells to uncover how each of these act individually and in aggregate. Here, we describe a single-cell genome editing functional assay that enables specific mutations to be recapitulated individually and in combination, providing insights into how multiple mutation-harboring functional elements collectively contribute to HbF expression. In conjunction with quantitative modeling and chromatin capture analyses, we illustrate how these genetic findings enable a comprehensive understanding of how distinct regulatory mechanisms can synergistically modulate HbF expression.

A complete reference genome improves analysis of human genetic variation

Compared to its predecessors, the Telomere-to-Telomere CHM13 genome adds nearly 200 Mbp of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome to clinical and functional study. Here we demonstrate how the new reference universally improves read mapping and variant calling for 3,202 and 17 globally diverse samples sequenced with short and long reads, respectively. We identify hundreds of thousands of novel variants per sample - a new frontier for evolutionary and biomedical discovery. Simultaneously, the new reference eliminates tens of thousands of spurious variants per sample, including up to a 12-fold reduction of false positives in 269 medically relevant genes. The vast improvement in variant discovery coupled with population and functional genomic resources position T2T-CHM13 to replace GRCh38 as the prevailing reference for human genetics.