Biology subjects

Band, G.

Publications and source records attributed to Band, G..

17 recordsLinked to original sources

bioRxiv2026

Reconstructing donor genotypes from scRNA-seq for downstream eQTL and HLA-TCR analysis

Single-cell eQTL studies can reveal heterogeneous genetic effects on gene expression that vary with cell type, but their wider application has been constrained by the frequent absence of matched genotype data. Here, we present single-cell Transcriptome Allelic Prediction and Association Studies (scTAPAS), a bioinformatic framework for reconstructing donor genotypes directly from single-cell RNA-sequencing reads and downstream genetic analysis. Applying scTAPAS to 5' single-cell RNA-sequencing data from the COVID-19 Multi-omic Blood Atlas (COMBAT), we show that reference-based imputation of sparse RNA-derived genetic information generates genotype dosages sufficiently accurate for association testing. Despite testing only 18.0% of the variants available from conventional array-based genotyping and imputation, scTAPAS recovers 68.6% of cell type-eGene pairs identified using conventional array-based genotypes, with strong concordance in effect sizes. We further show that scTAPAS-derived variants can support imputation of classical HLA alleles and enable HLA-aware QTL analyses, including associations between HLA variation and TCR repertoire at single-cell resolution. Using matched single-cell TCR-sequencing data, we identify CD4+ T cell-specific associations between HLA class II alleles and T-cell receptor (TCR) Va; gene segment usage, highlighting the potential of analyses that complement TCR sequencing at single-cell resolution with HLA types. These results show that genetic information recovered from single-cell RNA sequencing data can support both regulatory and immunogenetic association analyses, expanding the discovery potential of single-cell cohorts for which conventional genotyping or HLA typing is unavailable.

bioinformatics↗

bioRxiv2026

Emergent smartphone temporal structures reflect cognitive constraints

Fine-grained temporal structures emerge in smartphone behavioral recordings over multi-day periods. Complex systems research suggests that emergent temporal structures reflect underlying resource constraints of the system. Here we test whether cognitive abilities measured through speeded tasks (spanning fractions of a second) are reflected in emergent smartphone temporal structures spanning days, revealing how cognitive resource limitations shape naturalistic behavior. We analyzed smartphone tap interval patterns accumulated over several days and used decision tree regression models to predict performance in simple and choice reaction time tasks from these patterns. Simple reaction time was poorly predicted (R2 = 0.003), indicating that basic sensorimotor constraints play only a marginal role in shaping real-world behavioral timing. In contrast, choice reaction time was moderately predictable (R2 = 0.4), demonstrating that higher-order cognitive constraints prominently influence naturalistic temporal organization. Notably, while task performance operates at sub-second timescales, predictive temporal patterns in smartphone behavior spanned milliseconds to several seconds and was accumulated over days, revealing the broad, multi-scale influence of cognitive resource constraints on everyday behavior. Both predicted and measured choice reaction times showed age-related decline, but the decline was more pronounced in predicted values, suggesting that age-related cognitive changes may be amplified in naturalistic contexts. These findings demonstrate that emergent temporal structures in smartphone use can reveal how cognitive processes measured using speeded tasks manifest, or fail to manifest, in real-world behavior. Complex-systems approaches can bridge laboratory and naturalistic assessments of cognition, revealing which cognitive processes meaningfully constrain real-world behavior.

animal behavior and cognition↗

bioRxiv2025

Sickle cell status skews malaria parasite genotype at infection

Sickle cell hemoglobin (HbS) confers protection against symptomatic malaria caused by Plasmodium falciparum. HbS carriers with symptomatic malaria harbour parasites enriched for sickle-associated alleles (Pfsa+), which appear to partially overcome HbS-mediated protection, but their role in asymptomatic infections is unclear. Here, we conducted a cross-sectional survey of 2,246 healthy school children in a region of high malaria transmission region in Cameroon. Analysing parasite Pfsa and human HbS genotypes for 1,701 asymptomatic P. falciparum infections confirmed that heterozygous HbS (HbAS) and homozygous non-HbS (HbAA) genotypes have similar rates of asymptomatic infection. However, the HbS genotype is strongly associated with parasites carrying Pfsa+ alleles at Pfsa1 and Pfsa3 loci, indicating a selective advantage for these alleles in HbS carriers. Our findings reveal that the protective effect of HbS is complex, where HbS has a protective effect prior to symptoms against Pfsa- parasites and Pfsa+ alleles may contribute to lower rates of symptomatic disease in HbS carriers. HbS protection against malarial disease should consider both resistance and tolerance and ongoing co-evolution with parasites.

genetics↗

bioRxiv2025

Geographical variation drives adaptive equilibrium of the P. falciparum sickle-associated mutations

The recent discovery of genetic mutations in Plasmodium falciparum--the most lethal malaria parasite--that enable it to overcome the protective effects of sickle cell trait, raises fundamental questions about the underlying biological and evolutionary interactions. Here we develop a geostatistical model to compare sickle haemoglobin genotype frequencies to the Plasmodium falciparum sickle-associated alleles across global populations, and find a robust association at multiple geographical scales, implying that sickle drives positive selection for these parasite mutations. A model of parasite evolution and an analysis of local haplotype patterns suggest that key features of these mutations - that they are polymorphic in all African populations and are mutually correlated despite lying in different genome regions - are caused by geographical variation in selection pressure, and that the alleles may have been maintained by balancing selection over timescales comparable to the age of the sickle mutation itself. The predicted impact of this host-parasite interaction on disease outcomes varies widely across populations, and functional data are needed to discover the biological mechanisms involved.

genetics↗

bioRxiv2024

Large-scale genotyping and meta-analysis of PIEZO1 short tandem repeat alleles suggest a modest association with malaria susceptibility

PIEZO1 forms a mechanosensitive ion channel involved in regulating calcium levels in red blood cells. E756del, a deletion allele within a short tandem repeat (STR) in PIEZO1, is common in many African populations and has been proposed to be associated with protection from malarial disease, but epidemiological evidence has been inconsistent. Here, we use Illumina sequencing of amplicons covering the PIEZO1 STR to genotype 5,558 severe malaria cases and 8,174 population controls from The Gambia, Kenya, and Malawi. We estimate a modest effect for E756del and meta-analysis with two published studies, for a total of 8,224 cases and 10,103 controls, reveals a consistent protective effect (OR=0.93, 95% CI 0.88-0.99). By comprehensively genotyping the STR, we identify additional, less common alleles, with two (Q745del and E756ins) showing consistent, but also modest, risk effects across studies. Although allele frequency differentiation between African and non-African populations could be consistent with a selective effect, we show that it is not exceptional compared with STR variants genome wide. Thus, our results support a protective effect of E756del against risk of malaria but with a much smaller effect size than initially reported.

genetics↗

bioRxiv2023

A fourth locus in the Plasmodium falciparum genome associated with sickle haemoglobin

BackgroundHeterozygosity for sickle haemoglobin (HbS) confers protection against severe malaria caused by the parasite Plasmodium falciparum. Recent work has suggested that this protective effect can depend on the parasite genotype: P. falciparum sickle-associated (Pfsa) variants were found disproportionately in individuals with severe malaria carrying HbS alleles in The Gambia and Kenya. Interactions between the P. falciparum genome and HbS have not previously been investigated in mild malaria cases or in Ghana. MethodsWe performed a genome-wide association analysis of P. falciparum against human {beta}-globin genotypes in a sample of 1,368 people with mild malaria in northern Ghana. ResultsWe replicated the previously identified associations with HbS at two parasite loci (Pfsa1 and Pfsa3). Pfsa2 was absent from this population. A candidate newly identified locus within the serine/ threonine kinase FIKK4.2, which we putatively term Pfsa4, was also associated with HbS; this finding replicated in a published sample from Mali. The Pfsa1-4 mutations vary widely in frequencies across Africa, are absent or very low frequency in Asia, and are highly correlated with each-other across multiple populations. We found no strong associations with haemoglobin C. ConclusionsThis study replicates previously reported sickle-associated loci in the P. falciparum genome and has produced new evidence of a potential association with sickle haemoglobin at a fourth parasite locus. Further research is needed to validate the tentative fourth locus. These findings add new complexity to the emerging picture of association between human and co-evolving malaria parasite genomes, suggesting new avenues for functional exploration.

microbiology↗

bioRxiv2022

Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria

Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA, BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that "double dose" non-O genotypes (AA, BB, AB) are associated with increased risk of severe malaria and larger rosettes than "single dose" heterozygotes (AO, BO). In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (P=0.02, Wald test). In vitro experiments with blood group A-preferring P. falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO, whereas AO genotype rosettes were indistinguishable from OO. Overall, the data show that ABO genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity.

genetics↗

bioRxiv2021

Temporal clusters of age-related behavioral alterations captured in smartphone touchscreen interactions

Cognitive and behavioral abilities alter across the adult life span. Smartphones engage various cognitive functions and the corresponding touchscreen interactions may help resolve if and how the behavior is systematically structured by aging. Here, in a sample spanning the adult lifespan (16 to 86 years, N = 598, accumulating 355 million interactions) we analyzed a range of interaction intervals - from a few milliseconds to a minute. We used probability distributions to cluster the interactions according to their next inter-touch interval dynamics to discover systematic age-related changes at the distinct temporal clusters. There were age-related behavioral losses at the clusters occupying short intervals (~ 100 ms, R2 ~ 0.8) but gains at the long intervals (~ 4 s, R2 ~ 0.4). These correlates were independent of the years of experience on the phone or the choice of fingers used on the screen. We found further evidence for a compartmentalized influence of aging, as individuals simultaneously demonstrated both accelerated and decelerated aging at distant temporal clusters. In contrast to these strong correlations, cognitive tests probing sensorimotor, working memory, and executive processes revealed rather weak age-related decline. Contrary to the common notion of a simple behavioral decline with age based on conventional cognitive tests, we show that real-world behavior does not simply decline and the nature of aging systematically varies according to the underlying temporal dynamics. Of all the imaginable factors determining smartphone interactions in the real world, age-sensitive cognitive and behavioral processes can dominatingly dictate smartphone temporal dynamics.

animal behavior and cognition↗

bioRxiv2021

The protective effect of sickle cell haemoglobin against severe malaria depends on parasite genotype

Host genetic factors can confer resistance against malaria, raising the question of whether this has led to evolutionary adaptation of parasite populations. In this study we investigated the correlation between host and parasite genetic variation in 4,171 Gambian and Kenya children ascertained with severe malaria due to Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and variation in three regions of the parasite genome, including nonsynonymous variants in the acyl-CoA synthetase family member PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The HbS-associated parasite alleles are in strong linkage disequilibrium and have frequencies which covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome, and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.

genetics↗

bioRxiv2021

Using de novo assembly to identify structural variation of complex immune system gene regions

Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity, to which several factors contribute including inheritable structural polymorphism of the underlying genes. Characterizing this variation is challenging due to the complexity of these loci, which contain extensive regions of paralogy, segmental duplication and high copy-number repeats, but recent progress in long-read sequencing and optical mapping techniques suggests this problem may now be tractable. Here we assess this by using long-read sequencing platforms from PacBio and Oxford Nanopore, supplemented with short-read sequencing and Bionano optical mapping, to sequence DNA extracted from CD14+ monocytes and peripheral blood mononuclear cells from a single European individual identified as HV31. We use this data to build a de novo assembly of eight genomic regions encoding four key components of the immune system, namely the human leukocyte antigen, immunoglobulins, T cell receptors, and killer-cell immunoglobulin-like receptors. Validation of our assembly using k-mer based and alignment approaches suggests that it has high accuracy, with estimated base-level error rates below 1 in 10 kb, although we identify a small number of remaining structural errors. We use the assembly to identify heterozygous and homozygous structural variation in comparison to GRCh38. Despite analyzing only a single individual, we find multiple large structural variants affecting core genes at all three immunoglobulin regions and at two of the three T cell receptor regions. Several of these variants are not accurately callable using current algorithms, implying that further methodological improvements are needed. Our results demonstrate that assessing haplotype variation in these regions is possible given sufficiently accurate long-read and associated data; application of these methods to larger samples would provide a broader catalogue of germline structural variation at these loci, an important step toward making these regions accessible to large-scale genetic association studies.

bioinformatics↗

bioRxiv2019

The genetic landscape of Ethiopia: diversity, intermixing and the association with culture

The rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with -- and shape -- genetic structure in human populations. Using primarily novel genetic variation data covering 1,214 Ethiopians representing 68 different ethnic groups, together with information on individuals birthplaces, linguistic/religious practices and 31 cultural practices, we disentangle the effects of geographic distance, elevation, and social factors upon shaping the genetic structure of Ethiopians today. We provide evidence of associations between social behaviours and increased genetic differences among present-day peoples. We show that genetic similarity is broadly associated with linguistic classifications, but indicate pronounced genetic similarity among groups from disparate language classifications that may in part be attributable to recent intermixing. We also illustrate how groups reporting the same culture traits are more genetically similar on average and show evidence of recent intermixing, suggesting how shared cultural traits may promote admixture. In addition to providing insights into the genetic structure and history of Ethiopia, these results identify the most important cultural and geographic proxies for genetic differentiation and provide a resource for designing sampling protocols for future genetic studies involving Ethiopians.

genetics↗

bioRxiv2019

New insights into malaria susceptibility from the genomes of 17,000 individuals from Africa, Asia, and Oceania

We conducted a genome-wide association study of host resistance to severe Plasmodium falciparum malaria in over 17,000 individuals from 11 malaria-endemic countries, undertaking a wide ranging analysis which identifies five replicable associations with genome-wide levels of evidence. Our findings include a newly implicated variant on chromosome 6 associated with risk of cerebral malaria, and the discovery of an erythroid-specific transcription start site underlying the association in ATP2B4. Previously reported HLA associations cannot be replicated in this dataset. We estimate substantial heritability of severe malaria (h2 ~ 23%), of which around 10% is explained by the currently identified associations. Our dataset will provide a major building block for future research on the genetic determinants of disease in these diverse human populations.

genetics↗

bioRxiv2018

Bayesian meta-analysis across genome-wide association studies of diverse phenotypes

Genome-wide association studies (GWAS) are a powerful tool for understanding the genetic basis of diseases and traits, but most studies have been conducted in isolation, with a focus on either a single or a set of closely related phenotypes. We describe MetABF, a simple Bayesian framework for performing integrative meta-analysis across multiple GWAS using summary statistics. The approach is applicable across a wide range of study designs and can increase the power by 50% compared to standard frequentist tests when only a subset of studies have a true effect. We demonstrate its utility in a meta-analysis of 20 diverse GWAS which were part of the Wellcome Trust Case-Control Consortium 2. The novelty of the approach is its ability to explore, and assess the evidence for, a range of possible true patterns of association across studies in a computationally efficient framework.

genetics↗

bioRxiv2018

BGEN: a binary file format for imputed genotype and haplotype data

The impact of modern technology on genetic epidemiology has been significant, with studies comprising millions of individuals assessed at tens of millions of genetic variants now becoming common. Studies on this scale provide logistical and analytic challenges starting with the issue of efficiently storing, transmitting, and accessing underlying data. Here we present a binary file format (the BGEN format) that can store both directly-typed and statistically imputed genotype data, and achieves substantial space savings by data compression and the use of an efficient representation for probabilities. We investigate the properties of this format using imputed data from the UK BiLEVE study, demonstrating both storage efficiency, and fast data loading performance on the order of hundreds of millions of imputed genotypes per second. To make using BGEN as easy as possible, we provide a detailed specification and a freely available reference implementation, and we leverage this by developing additional tools including an indexing tool (bgenix) and an R package (rbgen) that permits loading of BGEN-encoded data into the R statistical programming environment. The UK Biobank is one of a number of projects that have used BGEN for release of imputed data, and we expect the format to continue to be widely implemented and used.

bioinformatics↗

bioRxiv2017

Inferring adaptive gene-flow in recent African history

Gene-flow from an ancestrally differentiated group has been shown to be a powerful source of selectively advantageous variants. To understand whether recent gene-flow may have contributed to adaptation among humans in sub-Saharan Africa, we applied a novel method to identify deviations in ancestry inferred from genome-wide data in 48 populations. Among the signals of ancestry deviation that we find in the Fula, an historically pastoralist ethnic group from the Gambia, are the region that encodes the lactose persistence phenotype, LCT/MCM6, which has the highest proportion of Eurasian ancestry in the genome. The region with the lowest proportion of non-African ancestry is across DARC, which encodes the Duffy null phenotype and is protective for Plasmodium vivax malaria. In the Jola from the Gambia and a Khoesan speaking group from Namibia we find multiple regions with inferred ancestry deviation including the Major Histocompatibility Complex. Our analysis shows the potential for adaptive gene-flow in recent human history.

evolutionary biology↗

bioRxiv2017

Genome-wide genetic data on ~500,000 UK Biobank participants

The UK Biobank project is a large prospective cohort study of ~500,000 individuals from across the United Kingdom, aged between 40-69 at recruitment. A rich variety of phenotypic and health-related information is available on each participant, making the resource unprecedented in its size and scope. Here we describe the genome-wide genotype data (~805,000 markers) collected on all individuals in the cohort and its quality control procedures. Genotype data on this scale offers novel opportunities for assessing quality issues, although the wide range of ancestries of the individuals in the cohort also creates particular challenges. We also conducted a set of analyses that reveal properties of the genetic data - such as population structure and relatedness - that can be important for downstream analyses. In addition, we phased and imputed genotypes into the dataset, using computationally efficient methods combined with the Haplotype Reference Consortium (HRC) and UK10K haplotype resource. This increases the number of testable variants by over 100-fold to ~96 million variants. We also imputed classical allelic variation at 11 human leukocyte antigen (HLA) genes, and as a quality control check of this imputation, we replicate signals of known associations between HLA alleles and many common diseases. We describe tools that allow efficient genome-wide association studies (GWAS) of multiple traits and fast phenome-wide association studies (PheWAS), which work together with a new compressed file format that has been used to distribute the dataset. As a further check of the genotyped and imputed datasets, we performed a test-case genome-wide association scan on a well-studied human trait, standing height.

genetics↗

bioRxiv2016

A structural variant encoding hybrid glycophorins is associated with resistance to severe malaria

Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. Here we analyse whole genome sequence data from worldwide human populations, including 765 new genomes from across sub-Saharan Africa, and identify a diverse array of large copy number variants affecting the host invasion receptor genes GYPA and GYPB. We find that a nearby reported association with severe malaria is explained by a complex structural variant that involves the loss of GYPB and gain of two hybrid genes, each with a GYPB extracellular domain and GYPA intracellular domain. This variant reduces the risk of severe malaria by 40% and has recently risen in frequency in parts of Kenya. We show that the structural variant encodes the Dantu blood group antigen, and therefore a serologically distinct red cell phenotype. These findings demonstrate that structural variation of red blood cell invasion receptors is associated with natural resistance to P. falciparum malaria.

genomics↗