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Williams, A. L.

Publications and source records attributed to Williams, A. L..

At least 19 recordsLinked to original sources

Dorsal visual stream development improves symmetry of receptive field coverage and spatial attention

The dorsal visual stream is a large retinotopic network in human visual cortex, involved in attentional and spatial aspects of vision critical for attending to, filtering, and interacting with the visual environment. The visual field maps which comprise the dorsal stream have not been characterized across development; a fundamental gap in human neuroscience given this pathways role in critical childhood behaviors. Here, we designed a gamified task to retinotopically map the dorsal stream in both adults and children for the first time. We found that the dorsal representations of visual space undergo protracted development, increasing the area over which they pool information across the visual field. Children show an asymmetry in the way that receptive fields of each cerebral hemisphere tile visual space, with protracted development predominantly in the right hemisphere serving to balance coverage across the left and right sides of space. This divergence between the hemispheres developmental trajectories has behavioral relevance, with individual variability in visuospatial attention biases correlating with receptive field properties from childhood into adulthood.

neuroscience↗

The rate of identical-by-descent segment sharing between close and distant relatives

Genetic relatives share long stretches of DNA they co-inherited from a common ancestor in identical-by-descent (IBD) segments. Because children inherit half their parents genomes, the expected amount of DNA relatives share drops by [Formula] for each generation that separates them, being 2-d for d-degree relatives. Even so, there is substantial variance in sharing rates, such that most distant relatives share zero IBD segments. We characterized IBD segment sharing between relatives by simulating 100,000 pairs for each of first through eighth cousins, including once-removed and half-cousins, while modeling both crossover interference and sex-specific genetic maps. Our results show that 98.5% of third cousins share at least one IBD segment, while only 32.7% of fifth cousins and 0.961% of eighth cousins have such sharing. These sharing rates are substantially higher than those that arise from models that ignore the more elaborate crossover features. The resulting segment count distributions are available with an interactive segment length threshold at https://hapi-dna.org/ibd-sharing-rates/.

genetics↗

Dynamic responses to rejection in the transplanted human heart revealed through spatial transcriptomics

Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current approaches to diagnosis rely on histology, which exhibits wide diagnostic variability and lacks access to molecular phenotypes that may stratify therapeutic response. Here, we leverage image-based spatial transcriptomics at sub-cellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant (HT) recipients during and following histologically-diagnosed rejection. Across 28 cell types, we identified significant differences in abundance in CD4+ and CD8+ T cells, fibroblasts, and endothelial cells across different biological classes of rejection (cellular, mixed, antibody-mediated). We observed a broad overlap in cellular transcriptional states across histologic rejection severity and biological class and significant heterogeneity within rejection severity grades that would qualify for immunomodulatory treatment. Individuals who had resolved rejection after therapy had a distinct transcriptomic profile relative to those with persistent rejection, including 216 genes across 6 cell types along pathways of inflammation, IL6-JAK-STAT3 signaling, IFN/IFN{gamma} response, and TNF signaling. Spatial transcriptomics also identified genes linked to long-term prognostic outcomes post-HT. These results underscore importance of subtyping immunologic states during rejection to stratify immune-cardiac interactions following HT that are therapeutically relevant to short- and long-term rejection-related outcomes.

genomics↗

Identification of Gene Targets for the Sprouting Inhibitor CIPC

Sprout suppressants are widely used in industry to ensure year-round availability of potato tubers, significantly decreasing wastage by repressing premature growth of buds on the tuber surface during storage. Despite its ban from 2020 in the EU, isopropyl N-(3- chlorophenyl) carbamate (also known as chlorpropham or CIPC) remains the most widely used suppressant world-wide. However, the mechanism of action of CIPC remains obscure. Here we report on a combined targeted transcriptomic and genetic approach to identify components in the tuber bud cell-division machinery that might be involved in CIPCs mode of action. This involved RNAseq analysis of dissected, staged tuber buds during in vitro sprouting with and without CIPC to identify lead genes, followed by the development and application of an Arabidopsis root assay to assess cell division response to CIPC in selected mutants. The ease of use of this model plant, coupled with its immense genetic resources, allowed us to test the functionality of lead genes encoding cell-division associated proteins in the modulation of plant growth response to CIPC. This approach led to the identification of a component of the augmin complex (a core player in mitosis) as a potential target for CIPC.

plant biology↗

Reconstructing parent genomes using siblings and other relatives

Reconstructing the DNA of ancestors from their descendants has the potential to empower phenotypic analyses (including association and genetic nurture studies), improve pedigree reconstruction, and shed light on the ancestral population and phenotypes of ancestors. We developed HAPI-RECAP, a method that reconstructs the DNA of parents from full siblings and their relatives. This tool leverages HAPI2s output, a new phasing approach that applies to siblings (and optionally one or both parents) and reliably infers parent haplotypes but does not link the ungenotyped parents DNA across chromosomes or between segments flanking ambiguities. By combining IBD between the reconstructed parents and the relatives, HAPI-RECAP resolves the source parent of these segments. Moreover, the method exploits crossovers the children inherited and sex-specific genetic maps to infer the reconstructed parents sexes. We validated these methods on research participants from both 23andMe, Inc. and the San Antonio Mexican American Family Studies. Given data for one parent, HAPI2 reconstructs large fractions of the missing parents DNA, between 77.6% and 99.97% among all families, and 90.3% on average in three- and four-child families. When reconstructing both parents, HAPI-RECAP inferred between 33.2% and 96.6% of the parents genotypes, averaging 70.6% in four-child families. Reconstructed genotypes have average error rates < 10-3, or comparable to those from direct genotyping. HAPI-RECAP inferred the parent sexes 100% correctly given IBD-linked segments and can also reconstruct parents without any IBD. As datasets grow in size, more families will be implicitly collected; HAPI-RECAP holds promise to enable high quality parent genotype reconstruction.

bioinformatics↗

Phasing millions of samples achieves near perfect accuracy, enabling parent-of-origin classification of variants

Haplotype phasing, the process of determining which genetic variants are physically located on the same chromosome, is crucial for various genetic analyses. In this study, we first benchmark SHAPEIT and Beagle, two state-of-the-art phasing methods, on two large datasets: > 8 million diverse, research-consented 23andMe, Inc. customers and the UK Biobank (UKB). We find that both perform exceptionally well. Beagles median switch error rate (SER) (after excluding single SNP switches) in white British trios from UKB is 0.026% compared to 0.00% for European ancestry 23andMe research participants; 55.6% of European ancestry 23andMe research participants have zero non-single SNP switches, compared to 42.4% of white British trios. South Asian ancestry 23andMe research participants have the highest median SER amongst the 23andMe populations, but it is still remarkably low at 0.46%. We also investigate the relationship between identity-by-descent (IBD) and SER, finding that switch errors tend to occur in regions of little or no IBD segment coverage. SHAPEIT and Beagle excel at intra-chromosomal phasing, but lack the ability to phase across chromosomes, motivating us to develop an inter-chromosomal phasing method, called HAPTIC (HAPlotype TIling and Clustering), that assigns paternal and maternal variants discretely genome-wide. Our approach uses identity-by-descent (IBD) segments to phase blocks of variants on different chromosomes. HAPTIC represents the segments a focal individual shares with their relatives as nodes in a signed graph and performs bipartite clustering on the signed graph using spectral clustering. We test HAPTIC on 1022 UKB trios, yielding a median phase error of 0.08% in regions covered by IBD segments (33.5% of sites). We also ran HAPTIC in the 23andMe database and found a median phase error rate (the rate of mismatching alleles between the inferred and true phase) of 0.92% in Europeans (93.8% of sites) and 0.09% in admixed Africans (92.7% of sites). HAPTICs precision depends heavily on data from relatives, so will increase as datasets grow larger and more diverse. HAPTIC enables analyses that require the parent-of-origin of variants, such as association studies and ancestry inference of untyped parents.

bioinformatics↗

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

The human lung is structurally complex, with a diversity of specialized epithelial, stromal and immune cells playing specific functional roles in anatomically distinct locations, and large-scale changes in the structure and cellular makeup of this distal lung is a hallmark of pulmonary fibrosis (PF) and other progressive chronic lung diseases. Single-cell transcriptomic studies have revealed numerous disease-emergent/enriched cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using sub-cellular resolution image-based spatial transcriptomics, we analyzed the gene expression of more than 1 million cells from 19 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell-types, established the cellular and molecular basis of classical PF histopathologic disease features, and identified a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Using machine-learning and trajectory analysis methods to segment and rank airspaces on a gradient from normal to most severely remodeled, we identified a sequence of compositional and molecular changes that associate with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially-resolved characterization of the cellular and molecular programs of PF and control lungs, provide new insights into the heterogeneous pathobiology of PF, and establish analytical approaches which should be broadly applicable to other imaging-based spatial transcriptomic studies.

genomics↗

Phase-free local ancestry inference mitigates the impact of switch errors on phase-based methods

Local ancestry inference (LAI) is an indispensable component of a variety of analyses in medical and population genetics, from admixture mapping to characterizing demographic history. However, the accuracy of LAI depends on a number of factors such as phase quality (for phase-based LAI methods), time since admixture of the population under study, and other factors. Here we present an empirical analysis of four LAI methods using simulated individuals of mixed African and European ancestry, examining the impact of variable phase quality and a range of demographic scenarios. We found that regardless of phasing options, calls from LAI methods that operate on unphased genotypes (phase-free LAI) have 2.6-4.6% higher Pearson correlation with the ground truth than methods that operate on phased genotypes (phase-based LAI). Applying the TRACTOR phase-correction algorithm led to modest improvements in phase-based LAI, but despite this, the Pearson correlation of phase-free LAI remained 2.4-3.8% higher than phase-corrected phase-based approaches (considering the best performing methods in each category). Phase-free and phase-based LAI accuracy differences can dramatically impact downstream analyses: estimates of the time since admixture using phase-based LAI tracts are upwardly biased by {approx}10 generations using our highest quality phased data but have virtually no bias using phase-free LAI calls. Our study underscores the strong dependence of phase-based LAI accuracy on phase quality and highlights the merits of LAI approaches that analyze unphased genetic data.

genetics↗

Identifying Biomarkers of Retinal Pigment Epithelial Cell Stem Cell-derived RPE Cell Heterogeneity and Transplantation Efficacy

Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single cell RNA sequencing (sc-RNA-seq), assessing functional cell integration in vitro into a mature RPE monolayer and in vivo efficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated with in vivo efficacy and increased cell integration capability. Gene expression analysis revealed a lncRNA (TREX) as a predictive marker of in vivo efficacy. TREX knockdown decreased cell integration while overexpression increased integration in vitro and improved vision rescue in the RCS rats.

cell biology↗

Simultaneous inference of parental admixture proportions and admixture times from unphased local ancestry calls

Population genetic analyses of local ancestry tracts routinely assume that the ancestral admixture process is identical for both parents of an individual, an assumption that may be invalid when considering recent admixture. Here we present Parental Admixture Proportion Inference (PAPI), a Bayesian tool for inferring the admixture proportions and admixture times for each parent of a single admixed individual. PAPI analyzes unphased local ancestry tracts and has two components models: a binomial model that exploits the informativeness of homozygous ancestry regions to infer parental admixture proportions, and a hidden Markov model (HMM) that infers admixture times from tract lengths. Crucially, the HMM employs an approximation to the pedigree crossover dynamics that accounts for unobserved within-ancestry recombination, enabling inference of parental admixture times. We compared the accuracy of PAPIs admixture proportion estimates with those of ANCESTOR in simulated admixed individuals and found that PAPI outperforms ANCESTOR by an average of 46% in a representative set of simulation scenarios, with PAPIs estimates deviating from the ground truth by 0.047 on average. Moreover, PAPIs admixture time estimates were strongly correlated with the ground truth in these simulations (R = 0.76), but have an average downward bias of 1.01 generations that is partly attributable to inaccuracies in local ancestry inference. As an illustration of its utility, we ran PAPI on real African Americans from the PAGE study (N = 5, 786) and found strong evidence of assortative mating by ancestry proportion: couples ancestry proportions are closer to each other than expected by chance (P < 10-6), and are highly correlated (R = 0.87). We anticipate that PAPI will be useful in studying the population dynamics of admixture and will also be of interest to individuals seeking to learn about their personal genealogies.

genetics↗

Sexual dimorphism and the effect of wild introgressions on recombination in cassava (Manihot esculenta Crantz) breeding germplasm

Recombination has essential functions in meiosis, evolution, and breeding. The frequency and distribution of crossovers dictate the generation of new allele combinations and can vary across species and between sexes. Here, we examine recombination landscapes across the 18 chromosomes of cassava (Manihot esculenta Crantz) with respect to male and female meioses and known introgressions from the wild relative Manihot glaziovii. We used SHAPEIT2 and duoHMM to infer crossovers from genotyping-by-sequencing (GBS) data and a validated multi-generational pedigree from the International Institute of Tropical Agriculture (IITA) cassava breeding germplasm consisting of 7,020 informative meioses. We then constructed new genetic maps and compared them to an existing map previously constructed by the International Cassava Genetic Map Consortium (ICGMC). We observed higher recombination rates in females compared to males, and lower recombination rates in M. glaziovii introgression segments on chromosomes 1 and 4, with suppressed recombination along the entire length of the chromosome in the case of the chromosome 4 introgression. Finally, we discuss hypothesized mechanisms underlying our observations of heterochiasmy and crossover suppression and discuss the broader implications for plant breeding.

genomics↗

Evaluating the utility of identity-by-descent segment numbers for relatedness inference via information theory and classification

Despite decades of methods development for classifying relatives in genetic studies, pairwise relatedness methods recalls are above 90% only for first through third degree relatives. The top-performing approaches, which leverage identity-by-descent (IBD) segments, often use only kinship coefficients, while others, including ERSA, use the number of segments relatives share. To quantify the potential for using segment numbers in relatedness inference, we leveraged information theory measures to analyze exact (i.e., produced by a simulator) IBD segments from simulated relatives. Over a range of settings, we found that the mutual information between the relatives degree of relatedness and a tuple of their kinship coefficient and segment number is on average 4.6% larger than between the degree and the kinship coefficient alone. We further evaluated IBD segment number utility by building a Bayes classifier to predict first through sixth degree relationships using different feature sets. When trained and tested with exact segments, the inclusion of segment numbers improves the recall by between 0.0028 and 0.030 for second through sixth degree relatives. However, the recalls improve by less than 0.018 per degree when using inferred segments, suggesting limitations due to IBD detection accuracy. Lastly, we compared our Bayes classifier that includes segment numbers with ERSA and IBIS and found comparable results, with the Bayes classifier and ERSA slightly outperforming each other across different degrees. Overall, this study shows that IBD segment numbers can improve relatedness inference but that errors from current SNP array-based detection methods yield dampened signals in practice.

genetics↗

FFA and OFA encode distinct types of face identity information

Faces of different people elicit distinct functional MRI (fMRI) patterns in several face-selective brain regions. Here we used representational similarity analysis to investigate what type of identity-distinguishing information is encoded in three face-selective regions: fusiform face area (FFA), occipital face area (OFA), and posterior superior temporal sulcus (pSTS). We used fMRI to measure brain activity patterns elicited by naturalistic videos of famous face identities, and compared their representational distances in each region with models of the differences between identities. Models included low-level to high-level image-computable properties and complex human-rated properties. We found that the FFA representation reflected perceived face similarity, social traits, and gender, and was well accounted for by the OpenFace model (deep neural network, trained to cluster faces by identity). The OFA encoded low-level image-based properties (pixel-wise and Gabor-jet dissimilarities). Our results suggest that, although FFA and OFA can both discriminate between identities, the FFA representation is further removed from the image, encoding higher-level perceptual and social face information.

neuroscience↗

Sexual dimorphism and the effect of wild introgressions on recombination in Manihot esculenta

Recombination has essential functions in evolution, meiosis, and breeding. Here, we use the multi-generational pedigree, consisting of 7,165 informative meioses (3,679 female; 3,486 male), and genotyping-by-sequencing (GBS) data from the International Institute of Tropical Agriculture (IITA) to study recombination in cassava (Manihot esculenta). We detected recombination events using SHAPEIT2 and duoHMM, examined the recombination landscape across the 18 chromosomes of cassava and in regions with known introgressed segments from cassavas wild relative Manihot glaziovii, constructed a genetic map and compared it to an existing map constructed by the International Cassava Genetic Map Consortium (ICGMC), and inspected patterns of recombination placement in male and female meioses to see if there is evidence of sexual dimorphism in crossover distribution and frequency. We found that the placement of crossovers along chromosomes did not vary between the two sexes but that females undergo more meiotic recombination than males. We also observed that introgressions from M. glaziovii decreased recombination in the introgressed region and, in the case of chromosome 4, along the entire length of the chromosome that the introgression is on. We observed a dosage effect on chromosome 1, possibly suggesting the presence of a variant on the M. glaziovii haplotype that leads to lower overall recombination in the introgressed region.

genomics↗

Distinguishing pedigree relationships using multi-way identical by descent sharing and sex-specific genetic maps

The proportion of samples with one or more close relatives in a genetic dataset increases rapidly with sample size, necessitating relatedness modeling and enabling pedigree-based analyses. Despite this, relatives are generally unreported and current inference methods typically detect only the degree of relatedness of sample pairs and not pedigree relationships. We developed CREST, an accurate and fast method that identifies the pedigree relationships of close relatives. CREST utilizes identical by descent (IBD) segments shared between a pair of samples and their mutual relatives, leveraging the fact that sharing rates among these individuals differ across pedigree configurations. Furthermore, CREST exploits the profound differences in sex-specific genetic maps to classify pairs as maternally or paternally related--e.g., paternal half-siblings--using the locations of autosomal IBD segments shared between the pair. In simulated data, CREST correctly classifies 91.5-99.5% of grandparent-grandchild (GP) pairs, 70.5-97.0% of avuncular (AV) pairs, and 79.0-98.0% of half-siblings (HS) pairs compared to PADREs rates of 38.5-76.0% of GP, 60.5-92.0% of AV, 73.0-95.0% of HS pairs. Turning to the real 20,032 sample Generation Scotland (GS) dataset, CREST correctly determines the relationship of 99.0% of GP, 85.7% of AV, and 95.0% of HS pairs that have sufficient mutual relative data, completing this analysis in 10.1 CPU hours including IBD detection. CRESTs maternal and paternal relationship inference is also accurate, as it flagged five pairs as incorrectly labeled in the GS pedigrees-- three of which we confirmed as mistakes, and two with an uncertain relationship--yielding 99.7% of HS and 93.5% of GP pairs correctly classified.

genetics↗

Mapping gene flow between ancient hominins through demography-aware inference of the ancestral recombination graph

The sequencing of Neanderthal and Denisovan genomes has yielded many new insights about interbreeding events between extinct hominins and the ancestors of modern humans. While much attention has been paid to the relatively recent gene flow from Neanderthals and Denisovans into modern humans, other instances of introgression leave more subtle genomic evidence and have received less attention. Here, we present an extended version of the ARGweaver algorithm, ARGweaver-D, which can infer local genetic relationships under a user-defined demographic model that includes population splits and migration events. This Bayesian algorithm probabilistically samples ancestral recombination graphs (ARGs) that specify not only tree topology and branch lengths along the genome, but also indicate migrant lineages. The sampled ARGs can therefore be parsed to produce probabilities of introgression along the genome. We show that this method is well powered to detect the archaic migration into modern humans, even with only a few samples. We then show that the method can also detect introgressed regions stemming from older migration events, or from unsampled populations. We apply it to human, Neanderthal, and Denisovan genomes, looking for signatures of older proposed migration events, including ancient humans into Neanderthal, and unknown archaic hominins into Denisovans. We identify 3% of the Neanderthal genome that is putatively introgressed from ancient humans, and estimate that the gene flow occurred between 200-300kya. We find no convincing evidence that negative selection acted against these regions. We also identify 1% of the Denisovan genome which was likely introgressed from an unsequenced hominin ancestor, and note that 15% of these regions have been passed on to modern humans through subsequent gene flow.

evolutionary biology↗

Surprising impacts of crossover interference and sex-specific genetic maps on identical by descent distributions

Simulations of close relatives and identical by descent (IBD) segments are common in genetic studies, yet most past efforts have utilized sex averaged genetic maps and ignored crossover interference, thus omitting features known to affect the breakpoints of IBD segments. We developed Ped-sim, a method for simulating relatives that can utilize either sex-specific or sex averaged genetic maps and also either a model of crossover interference or the traditional Poisson model for inter-crossover distances. To characterize the impact of previously ignored mechanisms, we simulated data for all four combinations of these factors. We found that modeling crossover interference decreases the standard deviation of the IBD proportion by 10.4% on average in full siblings through second cousins. By contrast, sex-specific maps increase this standard deviation by 4.2% on average, and also impact the number of segments relatives share. Most notably, using sex-specific maps, the number of segments half-siblings share is bimodal; and when combined with interference modeling, the probability that sixth cousins have non-zero IBD ranges from 9.0 to 13.1%, depending on the sexes of the individuals through which they are related. We present new analytical results for the distributions of IBD segments under these models and show they match results from simulations. Finally, we compared IBD sharing rates between simulated and real relatives and find that the combination of sex-specific maps and interference modeling most accurately captures IBD rates in real data. Ped-sim is open source and available from https://github.com/williamslab/ped-sim.\n\nAuthor summarySimulations are ubiquitous throughout statistical genetics in order to generate data with known properties, enabling tests of inference methods and analyses of real world processes in settings where experimental data are challenging to collect. Simulating genetic data for relatives in a pedigree requires the synthesis of chromosomes parents transmit to their children. These chromosomes form as a mosaic of a given parents two chromosomes, with the location of switches between the two parental chromosomes known as crossovers. Detailed information about crossover generation based on real data from humans now exists, including the fact that men and women have overall different rates (women produce ~1.6 times more crossovers) and that real crossovers are subject to interference--whereby crossovers are further apart from one another than expected under a model that selects their locations randomly. Our new method, Ped-sim, can simulate pedigree data using these less commonly modeled crossover features, and we used it to evaluate the importance of sex-specific rates and interference in real data. These comparisons show that both factors shape the amount of DNA two relatives share identically, and that their inclusion in models of crossover better fit data from real relatives.

genetics↗

Inferring identical by descent sharing of sample ancestors promotes high resolution relative detection

As genetic datasets increase in size, the fraction of samples with one or more close relatives grows rapidly, resulting in sets of mutually related individuals. We present DRUID--Deep Relatedness Utilizing Identity by Descent--a method that works by inferring the identical by descent (IBD) sharing profile of an ungenotyped ancestor of a set of close relatives. Using this IBD profile, DRUID infers relatedness between unobserved ancestors and more distant relatives, thereby combining information from multiple samples to remove one or more generations between the deep relationships to be identified. DRUID constructs sets of close relatives by detecting full siblings and also uses a novel approach to identify the aunts/uncles of two or more siblings, recovering 92.2% of real aunts/uncles with zero false positives. In real and simulated data, DRUID correctly infers up to 10.5% more relatives than PADRE when using data from two sets of distantly related siblings, and 10.7-31.3% more relatives given two sets of siblings and their aunts/uncles. DRUID frequently infers relationships either correctly or within one degree of the truth, with PADRE classifying 43.3-58.3% of tenth degree relatives in this way compared to 79.6-96.7% using DRUID.

genetics↗