The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a precise and scalable method for intact HIV reservoir quantification1. This duplexed droplet digital PCR (ddPCR) assay simultaneously targets the HIV Packaging Signal (Ψ) and the Rev Responsive Element (RRE) within Envelope (env) to distinguish genomically intact proviruses against a large background of defective ones2

Transcription factors that contain a homeodomain DNA-binding domain have crucial functions in most aspects of cellular function and embryonic development in both animals and plants. Hmx proteins are a sub-family of NK homeodomain-containing proteins that have fundamental roles in development of sensory structures such as the eye and the ear. However, Hmx functions in spinal cord development have not

The site frequency spectrum in human populations is not accurately modeled by an infinite sites model, which assumes that all mutations are unique. Despite the pervasiveness of recurrent mutations, we lack computational methods to identify these events at specific sites in population sequencing data. Rare alleles that are identical-by-descent (IBD) are expected to segregate on a long, shared haplotype

Normal body situs requires precise spatiotemporal expression of the Nodal-Lefty-Pitx2 cascade in the lateral plate mesoderm. The ultimate output of this patterning is establishment of the left-right axis, which provides vital cues for correct organ formation and function. Mutations, deletions and duplications in PITX2 and FOXC1 lead to the rare genetic disease Axenfeld-Rieger syndrome (ARS). While

Recent studies consider lifestyle risk score (LRS), an aggregation of multiple lifestyle exposures, in identifying association of gene-lifestyle interaction with disease traits. However, not all cohorts have data on all lifestyle factors, leading to increased heterogeneity in the environmental exposure in collaborative meta-analyses. We compared and evaluated four approaches (Naïve, Safe, Complete

Chronic pain (CP) is a leading cause of disability worldwide with complex aetiologies that remain elusive. Here we addressed this issue by performing a GWAS on a large UK Biobank sample (N=188,352 cases & N=69,627 controls) which identified two independent loci associated with CP near ADAMTS6 and LEMD2. Gene-based tests revealed additional CP-associated genes (DCAKD, NMT1, MLN, IP6K3). Across 1328

Conventional models of genome evolution are centered around the principle that mutations form independently of each other and build up slowly over time. We characterized the occurrence of bursts of genome-wide loss-of-heterozygosity (LOH) in Saccharomyces cerevisiae, providing support for an additional non-independent and faster mode of mutation accumulation. We initially characterized a yeast clone

The genomic proportion that two relatives share identically by descent—their genetic relatedness—can vary depending on the history of recombination and segregation in their pedigree. This variation is important in many applications of genetics, including pedigree-based estimation of the genetic variance and heritability of traits, and estimation of pedigree relationships from sequence data. Here, we

Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants. While genes under the strongest selective constraint are highly enriched for Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known. Here we show

Zona Pellucida domain (ZP) proteins are critical components of the body's external-most protective layers, apical extracellular matrices (aECMs). Although their loss or dysfunction is associated with many diseases, it remains unclear how ZP proteins assemble in aECMs. Current models suggest that ZP proteins polymerize via their ZPn subdomains, while ZPc subdomains modulate ZPn behavior. Using the model

G protein-coupled receptors (GPCRs) drive an array of critical physiological functions and are an important class of drug targets, though a map of which GPCR genetic variants are associated with phenotypic variation is lacking. We performed a phenome-wide association analysis for 269 common protein-altering variants in 156 GPCRs and 275 phenotypes, including disease outcomes and diverse quantitative

The site frequency spectrum (SFS) is a statistic that summarizes the distribution of derived allele frequencies in a sample of DNA sequences. The SFS provides useful information about genetic variation within and among populations and it can used to make population genetic inferences. Methods for computing the SFS based on the diffusion approximation are computationally efficient when computing all

Background: Genetic connectedness is a critical component of genetic evaluation as it assesses the comparability of predicted genetic values across units. Genetic connectedness also plays an essential role in quantifying the linkage between reference and validation sets in whole-genome prediction. Despite its importance, there is no user-friendly software tool available to calculate connectedness statistics

Inference of admixture proportions is a classical statistical problem in population genetics. Standard methods implicitly assume that both parents of an individual have the same admixture fraction. However, this is rarely the case in real data. In this paper, we show that the distribution of admixture tract lengths in a genome contains information about the admixture proportions of the ancestors of

Single-cell RNA sequencing (scRNA-seq) has led to remarkable progress in our understanding of tissue heterogeneity in health and disease. Recently, the need for scRNA-seq sample fixation has emerged in many scenarios, such as when samples need long-term transportation, or when experiments need to be temporally synchronized. Methanol fixation is a simple and gentle method that has been routinely applied

Biallelic variants in TBC1-domain containing kinase (TBCK) cause intellectual disability in children. It remains unclear how variants in TBCK lead to a neurodevelopmental disorder and what biological factors modulate the variability of clinical severity. Previous studies showed increased autophagosomes in patients sharing the truncating (p.R126X) Boricua homozygous TBCK variant, who exhibit a severe

Yeast cells survive in stationary phase culture by entering quiescence, which is measured by colony forming capacity upon nutrient re-exposure. Yeast chronological lifespan (CLS) studies, employing the comprehensive collection of gene knockout strains, have correlated weakly between independent laboratories, which is hypothesized to reflect differential interaction between the deleted genes, auxotrophy

The winged insects of the order Diptera are colloquially named for their most recognizable phenotype: flight. These insects rely on flight for a number of important life history traits, like dispersal, foraging, and courtship. Despite the importance of flight, relatively little is known about the genetic architecture of variation for flight performance. Accordingly, we sought to uncover the genetic

Transcriptional enhancers have been defined by their ability to operate independent of distance and orientation in plasmid-based reporter assays of gene expression. Currently, histone marks are used heavily to identify and define enhancers but both methods do not consider the endogenous role of an enhancer in the context of native chromatin. We employed a combination of genomic editing, single cell

Genetic variation is of crucial importance for selection and genetic improvement of crops. Landraces are valuable sources of diversity for germplasm improvement, but for quantitative traits efficient strategies for their targeted utilization are lacking. Here, we propose a genome-based strategy for making native diversity accessible for traits with limited genetic variation in elite germplasm. We generated

The 1.6Mb 3q29 deletion (3q29Del) confers >40-fold increased risk for schizophrenia (SZ) and is also a risk factor for intellectual disability (ID) and autism spectrum disorders (ASD). No single gene in this interval is definitively associated with SZ, ID, or ASD, prompting the hypothesis that neurodevelopmental sequelae emerge upon loss of multiple functionally-connected genes. However, 3q29 interval

Human mesenchymal stem cells (hMSCs) can be differentiated into adipocytes and osteoblasts. While the transcriptomic and epigenomic changes during adipogenesis and osteogenesis have been characterized, what happens to the chromatin loops is hardly known. Here we induced hMSCs to adipogenic and osteogenic differentiation, and performed 2 kb resolution Hi-C experiments for loop detection and generated

Site-specific recombinases are widely used tools for analysis of genetics, development and cell biology, and many schemes have been devised to alter gene expression by recombinase-mediated DNA rearrangements. Because the FRT and lox target sites for the commonly used FLP and Cre recombinases are asymmetrical, and must pair in the same direction to recombine, construct design must take into account

Precision genome editing for model organisms has revolutionized functional analysis and validation of a wide variety of molecular systems. To date, the capacity to insert transgenes into the model nematode Caenorhabditis elegans has focused on utilizing either transposable elements or CRISPR-based safe harbor strategies. These methods require laborious screening processes that often result in false

Adaptation to nutrient scarcity involves an orchestrated response of metabolic and signaling pathways to maintain homeostasis. We provide evidence that lysosomal export of cystine coordinates remobilization of internal nutrient stores with reactivation of the growth regulator TORC1 signaling upon fasting in the Drosophila fat body. Mechanistically, cystine is reduced to cysteine and metabolized to

Behavioral genetics in non-model organisms is currently gated by technological limitations. However, with the growing availability of genome editing and functional genomic tools, complex behavioral traits such as social behavior can now be explored in diverse organisms. Here we present a minimally invasive neurosurgical procedure for a classic behavioral, ecological and evolutionary system: threespine

The principle and the techniques applied in DNA extraction play a pivotal role in the obtention of a purified genetic material. The present study investigates the efficiency of eight protocols in the DNA extraction of Hypostomus commersoni, an essential component of South American freshwater ichthyofauna. The quality of samples was assessed through spectrophotometry, gel electrophoresis, and PCR-RAPD

The gram-negative bacterium Coxiella burnetii is the causative agent of Query (Q) fever in humans and coxiellosis in livestock. Association between host genetic background and Coxiella burnetii pathogenesis has been demonstrated both in humans and animals; however, specific genes associated with severity of infection remain unknown. We employed the Drosophila Genetics Reference Panel to perform a genome-wide

Dystonia is a debilitating hyperkinetic movement disorder, frequently transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants in TSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented

White matter keeps human brain globally connected and shapes communication and connectivity patterns among brain regions. White matter microstructure influences brain structural integrity and may underpin brain functions and disorders. Although under strong genetic control, a large number of genetic variants of white matter remain undiscovered. Here we analyzed the genetic architecture of white matter

How long could a chromatin loop be stabilized inside the nucleus? Such a time is crucial for chromatin organization maintenance and stability. To answer this question, we explore several physical scenarios, where the loop maintenance is due to diffusing cross-linkers such as cohesin and CTCF that can bind and unbind at the base of chromatin loops. We find that this mechanism is sufficient to guarantee

Facioscapulohumeral dystrophy (FSHD) is linked to misexpression of the transcription factor, DUX4. Although DUX4 target gene expression is often readily detectable, analysis of DUX4 expression has been limited due to its low expression in patient samples. Recently, single cell/nucleus RNA-sequencing was used to detect the native expression of DUX4 for the first time, but important spatial relationships

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of X-linked retinitis pigmentosa (RP). Herein we used whole-exome sequencing to screen possible novel RPGR mutations in RP patients, and identified a novel missense mutation E585K in a patient with early onset but slow disease progression, and a frameshift deletion E998Gfs*78 in a patient with RP sine pigmento and

Hybrid crop breeding programs using a two-part strategy produced the most genetic gain, but a maximum avoidance of inbreeding crossing scheme was required to increase long-term genetic gain. The two-part strategy uses outbred parents to complete multiple generations per year to reduce the generation interval of hybrid crop breeding programs. The maximum avoidance of inbreeding crossing scheme manages

Cowpea is one of the most important legume grain in the SubSaharian region of Africa used for human consumption and animal feeding but its production is hampered by biotic and abiotic constraints raising the need to broaden its genetic basis. For this purpose, the seeds of two cowpea varieties Melakh and Yacine were respectively irradiated with 300 and 340 Gy. The developed mutant populations were

Endoglin (ENG) forms a receptor complex with ALK1 in endothelial cells (ECs) to promote BMP9/10 signalling. Loss of function mutations in either ENG or ALK1 genes lead to the inherited vascular disorder Hereditary Haemorrhagic Telangiectasia (HHT), characterised by arteriovenous malformations (AVMs). However, the vessel-specific role of ENG and ALK1 proteins in protecting against AVMs is unclear. For

Multiparental populations (MPPs) are experimental populations in which the genome of every individual is a mosaic of known founder haplotypes. These populations are useful for detecting quantitative trait loci (QTL) because tests of association can leverage inferred founder haplotype descent. It is difficult, however, to determine how haplotypes at a locus group into distinct functional alleles, termed

The majority of polygenic risk scores (PRS) have been developed and optimized in individuals of European ancestry, and may have limited generalizability across other ancestral populations. Understanding aspects of PRS that contribute to this issue and determining solutions is complicated by disease-specific genetic architecture and limited knowledge of trans-ethnic sharing of causal variants and effect

Accurate understanding of the global spread of emerging viruses is critically important for public health response and for anticipating and preventing future outbreaks. Here, we elucidate when, where and how the earliest sustained SARS-CoV-2 transmission networks became established in Europe and the United States (US). Our results refute prior findings erroneously linking cases in January 2020 with

Purple corn offers an attractive source of economical natural anthocyanin-based colorant for use in foods and beverages. Yet to maximize the scalability and meet growing demands, both anthocyanin concentrations and agronomic performance must improve in purple corn varieties. We studied flux through the flavonoid biosynthesis pathway using GWAS data derived from a diverse purple corn landrace with anthocyanin-rich

Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently

The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate

Ciliopathies are a large class of inherited disorders caused by defects in cilia. Variants in ciliopathy genes are highly pleiotropic and represent excellent case studies for interrogating genotype-phenotype correlation. However, in most cell and animal studies, ciliopathy mechanisms are not investigated using alleles as they occur in patients. We have employed Caenorhabditis elegans to model and characterise

Antimicrobial resistance (AMR) is a global threat, including in sub-Saharan Africa. However, little is known about the genetics of resistant bacteria in the region. In Malawi, there is growing concern about increasing rates of antimicrobial resistance to most empirically used antimicrobials. The highly drug resistant Escherichia coli sequence type (ST) 131, which is associated with the extended spectrum

Common genetic variants can have profound effects on cellular function, but studying these effects in primary human tissue samples and during development is challenging. Human induced pluripotent stem cell (iPSC) technology holds great promise for assessing these effects across different differentiation contexts. Here, we use an efficient pooling strategy to differentiate 215 iPS cell lines towards

Ciliary microtubules are subject to post-translational modifications that act as a Tubulin Code to regulate motor traffic, binding proteins and stability. In humans, loss of CCP1, a cytosolic carboxypeptidase and tubulin deglutamylating enzyme, causes infantile-onset neurodegeneration. In C.elegans, mutations in ccpp-1, the homolog of CCP1, result in progressive degeneration of neuronal cilia and loss

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and also identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identify 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology across the life course, including

Hybridization has resulted in the origin and variation in extant species, and hybrids continue to arise despite pre- and post-zygotic barriers that limit their formation and evolutionary success. One important system that maintains species boundaries in prokaryotes and eukaryotes is the mismatch repair pathway, which blocks homeologous recombination between divergent DNA sequences. Previous studies

Alteration of the lipid composition of biological membranes interferes with their function and can cause tissue damage by triggering apoptosis. Upon lipid bilayer stress, the endoplasmic reticulum mounts a stress response that is similar to the unfolded protein response. However, only a few genes are known to regulate lipid bilayer stress. Here, we performed a suppressor screen that combined the auxin-inducible

Genetic and environmental manipulations, such as dietary restriction (DR), can improve both health span and lifespan in a wide range of organisms, including humans. Changes in nutrient intake trigger often overlapping metabolic pathways that can generate distinct or even opposite outputs depending on several factors, such as when DR occurs in the lifecycle of the organism or the nature of the changes

Many diseases and complex traits exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We developed a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and applied S-LDXR to genome-wide association summary statistics for 31 diseases and

Objective: Due to the allergic nature of the pollen of Cryptomeria japonica, the most important Japanese forestry conifer, a pollen-free cultivar is preferred. Mutant trees detected in nature have been used for the production of a pollen-free cultivar. In order to reduce the time and cost needed for the production and breeding, we aimed to develop simple diagnostic molecular markers for mutant alleles

Genetic diversity and maternal ancestry line relationships amongst a sample of 96 Cleveland Bay horses were investigated using a 479bp length of mitochondrial D-loop sequence. The analysis yielded at total of 11 haplotypes with 27 variable positions, all of which have been described in previous equine mitochondrial DNA d-loop studies. Four main haplotype clusters were present in the Cleveland Bay breed

To better understand molecular pathways underlying liver health and disease, we performed genome-wide association studies (GWAS) on circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) across 408,300 subjects from four ethnic groups in the UK Biobank, focusing on variants associating with both enzymes. Of these variants, the strongest effect is a rare (MAF in White

Despite the strong genetic basis of psychiatric disorders, the molecular origins of these diseases are still largely unmapped. RNA-binding proteins (RBPs) are responsible for most post- transcriptional regulation, from splicing to translational to localization. RBPs thus act as key gatekeepers of cellular homeostasis, especially in the brain. Here, we leverage a deep learning approach to interrogate

Phenotypes of sessile organisms rely not only on their own genotype but also on the genotypes of neighboring individuals. Previously, we incorporated such neighbor effects into a single-marker regression using the Ising model of ferromagnetism. However, little is known about how to incorporate neighbor effects in quantitative trait locus (QTL) mapping. In this study, we propose a new method for interval

Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, novel multiOMICs approaches are needed for deciphering the underlying molecular networks. Here, we integrated genomics, transcriptomics, and proteomics of

Since spilling over into humans, SARS-CoV-2 has rapidly spread across the globe, accumulating significant genetic diversity. The structure of this genetic diversity, and whether it reveals epidemiological insights, are fundamental questions for understanding the evolutionary trajectory of this virus. Here we use a recently developed phylodynamic approach to uncover phylogenetic structures underlying

Gene-environment (GxE) interactions are one of the least studied aspects of the genetic architecture of human traits and diseases. The environment of an individual is inherently high dimensional, evolves through time and can be expensive and time consuming to measure. The UK Biobank study, with all 500,000 participants having undergone an extensive baseline questionnaire, represents a unique opportunity

Obesity is a growing societal scourge responsible for approximately 4 million deaths worldwide. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain