Genome Research

Maize phenotypes are plastic, determined by the complex interplay of genetics and environmental variables. Uncovering the genes responsible and understanding how their effects change across a large geographic region are challenging. In this study, we conducted systematic analysis to identify environmental indices that strongly influence 19 traits (including flowering time, plant architecture, and yield component traits) measured in the maize nested association mapping (NAM) population grown in 11 environments...

Mutations in splicing factor 3B subunit 1 ( SF3B1 ) frequently occur in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS). These mutations have different effects on the disease prognosis with beneficial effect in MDS and worse prognosis in CLL patients. A full-length transcriptome approach can expand our knowledge on SF3B1 mutation effects on RNA splicing and its contribution to patient survival and treatment options. We applied long-read transcriptome sequencing (LRTS) to 44 MDS and CLL patients, as well as two pairs of isogenic cell lines with and without SF3B1 mutations, and found >60% of novel isoforms...

Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis -regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved...

Much of the profound interspecific variation in genome content has been attributed to transposable elements (TEs). To explore the extent of TE variation within species, we developed an optimized open-source algorithm, panEDTA, to de novo annotate TEs in a pangenome context. We then generated a unified TE annotation for a maize pangenome derived from 26 reference-quality genomes, which reveals an excess of 35.1 Mb of TE sequences per genome in tropical maize relative to temperate maize. A small number ( n = 216) of TE families, mainly LTR retrotransposons, drive these differences...

The killer-cell immunoglobulin-like receptor (KIR) gene complex, a highly polymorphic region of the human genome that encodes proteins involved in immune responses, poses strong challenges in genotyping owing to its remarkable genetic diversity and structural intricacy. Accurate analysis of KIR alleles, including their structural variations, is crucial for understanding their roles in various immune responses. Leveraging the high-quality genome assemblies from the Human Pangenome Reference Consortium (HPRC), we present a novel bioinformatic tool, the structural KIR annoTator (SKIRT), to investigate gene diversity and facilitate precise KIR allele analysis...

Recently developed protein language models have enabled a variety of applications with the protein contextual embeddings they produce. Per-protein representations (each protein is represented as a vector of fixed dimension) can be derived via averaging the embeddings of individual residues, or applying matrix transformation techniques such as the discrete cosine transformation to matrices of residue embeddings. Such protein-level embeddings have been applied to enable fast searches of similar proteins, however limitations have been found; for example, PROST is good at detecting global homologs but not local homologs, and knnProtT5 excels for proteins of single domains but not multi-domain proteins...

Characterizing cell-cell communication and tracking its variability over time are crucial for understanding the coordination of biological processes mediating normal development, disease progression, and responses to perturbations such as therapies. Existing tools fail to capture time-dependent intercellular interactions, and primarily rely on existing databases compiled from limited contexts. We introduce DIISCO, a Bayesian framework designed to characterize the temporal dynamics of cellular interactions using single-cell RNA sequencing data from multiple time points...

DNA methylation data plays a crucial role in estimating chronological age in mammals, offering real-time insights into an individual's aging process. The Epigenetic Pacemaker (EPM) model allows inference of the biological age as deviations from the population trend. Given the sensitivity of this data, it is essential to safeguard both inputs and outputs of the EPM model. In a recent study, a privacy-preserving approach for EPM computation was introduced, utilizing Fully Homomorphic Encryption (FHE). However, their method had limitations, including having high communication complexity and being impractical for large datasets Our work presents a new privacy preserving protocol for EPM computation, analytically improving both privacy and complexity...

Linear mixed models (LMMs) have been widely used in genome-wide association studies (GWAS) to control for population stratification and cryptic relatedness. However, estimating LMM parameters is computationally expensive, necessitating large-scale matrix operations to build the genetic relatedness matrix (GRM). Over the past 25 years, Randomized Linear Algebra has provided alternative approaches to such matrix operations by leveraging matrix sketching, which often results in provably accurate fast and efficient approximations...

Advances in omics technologies have allowed spatially resolved molecular profiling of single cells, providing a window not only into the diversity and distribution of cell types within a tissue but also into the effects of interactions between cells in shaping the transcriptional landscape. Cells send chemical and mechanical signals which are received by other cells, where they can subsequently initiate context-specific gene regulatory responses. These interactions and their responses shape the individual molecular phenotype of a cell in a given microenvironment...

Embedding methods have emerged as a valuable class of approaches for distilling essential information from complex high-dimensional data into more accessible lower-dimensional spaces. Applications of embedding methods to biological data have demonstrated that gene embeddings can effectively capture physical, structural, and functional relationships between genes. However, this utility has been primarily realized by using gene embeddings for downstream machine learning tasks. Much less has been done to examine the embeddings directly, especially analyses of gene sets in embedding spaces...

Our knowledge of the contribution of genetic interactions (epistasis) to variation in human complex traits remains limited, partly due to the lack of efficient, powerful, and interpretable algorithms to detect interactions. Recently proposed approaches for set-based association tests show promise in improving power to detect epistasis by examining the aggregated effects of multiple variants. Nevertheless, these methods either do not scale to large Biobank datasets or lack interpretability. We propose QuadKAST, a scalable algorithm focused on testing pairwise interaction effects (quadratic effects) within small to medium sized sets of genetic variants (<= 100 SNPs) on a trait and provide quantified interpretation of these effects...

Using k -mers to find sequence matches is increasingly used in many bioinformatic applications, including metagenomic sequence classification. The accuracy of these downstream applications relies on the density of the reference databases, which are rapidly growing. While the increased density provides hope for dramatic improvements in accuracy, scalability is a concern. The k -mers are kept in the memory during the query time, and saving all k -mers of these ever-expanding databases is fast becoming impractical...

There are many gaps in our knowledge of how life cycle variation and organismal body architecture associate with molecular evolution. Using the diverse range of green algal body architectures and life cycle types as a test case, we hypothesize that increases in cytomorphological complexity are likely to be associated with a decrease in the effective population size, since larger-bodied organisms typically have smaller populations, resulting in increased drift. For life cycles, we expect haploid-dominant lineages to evolve under stronger selection intensity relative to diploid-dominant life cycles due to masking of deleterious alleles in heterozygotes...

Transcription Factors (TFs) regulate gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Since TF occupancy is driven in part by recognition of DNA sequence, genetic variation can influence TF-DNA associations and gene regulation. To identify variants that impact TF binding in human brain tissues, we assessed allele specific binding (ASB) at heterozygous variants for 94 TFs in 9 brain regions from two donors. Leveraging graph genomes constructed from phased genomic sequence data, we compared ChIP-seq signals between alleles at heterozygous variants within each brain region and identified thousands of variants exhibiting ASB for at least one TF...

The main way of analyzing genetic sequences is by finding sequence regions that are related to each other. There are many methods to do that, usually based on this idea: find an alignment of two sequence regions, which would be unlikely to exist between unrelated sequences. Unfortunately, it is hard to tell if an alignment is likely to exist by chance. Also, the precise alignment of related regions is uncertain. One alignment does not hold all evidence that they are related. We should consider alternative alignments too...

Colibactin produced primarily by Escherichia coli strains of the B2 phylogroup crosslinks DNA and can promote colon cancer in human hosts. We investigated the toxin's impact on colibactin producers and on bacteria co-cultured with producing cells. Using genome-wide genetic screens and mutation accumulation experiments we uncovered the cellular pathways that mitigate colibactin damage and revealed the specific mutations it induces. We discovered that while colibactin targets A/T rich motifs, as observed in human colon cells, it induces a bacteria-unique mutation pattern...

Natural selection acts ubiquitously on complex human traits, predominantly constraining the occurrence of extreme phenotypes (stabilizing selection). These constraints propagate to DNA sequence variants associated with traits under selection. The genetic imprints of such evolutionary events can thus be detected via combining effect size estimates from genetic association studies and the corresponding allele frequencies. While this approach has been successfully applied to high-level traits, the prevalence and mode of selection acting on molecular traits remains poorly understood...

The lack of population-scale databases hampers research and diagnostics for medically relevant tandem repeats and repeat expansions. We attempt to fill this gap using our pathSTR web tool, which leverages long-read sequencing of large cohorts to determine repeat length and sequence composition in a healthy population. The current version includes 1040 individuals of the 1000 Genomes Project cohort sequenced on the Oxford Nanopore Technologies PromethION. A comprehensive set of medically relevant tandem repeats was genotyped using STRdust and LongTR to determine the tandem repeat length and sequence composition...

Single-cell sequencing methodologies such as scRNA-seq and scATAC-seq have become widespread and effective tools to interrogate tissue composition. Increasingly, variant callers are being applied to these methodologies to resolve the genetic heterogeneity of a sample, especially in the case of detecting the clonal architecture of a tumor. Typically, traditional bulk DNA variant callers are applied to the pooled reads of a single-cell library to detect candidate mutations. Recently, multiple studies have applied such callers on reads from individual cells, with some citing the ability to detect rare variants with higher sensitivity...