Biology subjects

Ramensky, V.

Publications and source records attributed to Ramensky, V..

6 recordsLinked to original sources

bioRxiv2026

kitAb: an automated framework for assay-specific antibody developability modeling and large-scale landscape analysis

Antibody developability is determined by multiple physicochemical properties, and the relevance of individual properties varies among experimental assays. Existing computational approaches, however, often provide fixed assessments or rely on computationally intensive descriptors. We present kitAb, an open-source framework for scalable physicochemical characterization of antibody Fv regions and assay-specific developability modeling. kitAb calculates 59 interpretable sequence- and structure-based descriptors and integrates them with automated feature selection and regression. We evaluated kitAb across ten public datasets comprising 46 experimental endpoints, using sequence-aware or predefined splits where feasible. Predictive performance was strongly assay-dependent. In nested evaluations with sequence-aware or predefined data splits, models using kitAb descriptors achieved predictive performance comparable on average to those using PROPERMAB descriptors, while outperforming models based on TAP or sequence-only features. In a single-structure CPU timing benchmark, kitAb descriptor calculation was approximately 11-fold faster than PROPERMAB. Predictive performance was similar across the three structure-generation backends, and broader AutoML searches did not substantially improve mean performance. We further applied the same descriptor representation to approximately 3.4 million paired natural antibodies and 706 Phase II or later therapeutic antibodies. Repertoire-scale analysis revealed systematic differences in surface charge, hydrophobic and aromatic organization, CDR length and germline-associated physicochemical profiles. The kitAb code and analysis workflows are openly available at https://github.com/katyachemistry/kitAb/.

bioinformatics↗

bioRxiv2019

The burden of deleterious variants in a non-human primate biomedical model

Genome sequencing studies of nonhuman primate (NHP) pedigree and population samples are discovering variants on a large and rapidly growing scale. These studies are increasing the utility of several NHP species as model systems for human disease. In particular, by identifying homozygous protein truncating variants (hPTVs) in genes hypothesized to play a role in causing human diseases, it may be possible to elucidate mechanisms for the phenotypic impact of such variants through investigations that are infeasible in humans. The Caribbean vervet (Chlorocebus aethiops sabaeus) is uniquely valuable for this purpose, as the dramatic expansion of its population following severe bottlenecks has enabled PTVs that passed through the bottleneck to attain a relatively high frequency. Using whole genome sequence (WGS) data from 719 monkeys of the Vervet Research Colony (VRC) extended pedigree, we found 2,802 protein-truncating alleles in 1,747 protein-coding genes present in homozygous state in at least one monkey. Polymorphic sites for 923 SNV hPTVs were also observed in natural Caribbean populations from which the VRC descends. The vervet genome browser (VGB) includes information on these PTVs, together with a catalog of phenotypes and biological samples available for monkeys who carry them. We describe initial explorations of the possible impact of vervet PTVs on early infant mortality.

genetics↗

bioRxiv2018

Exome sequencing identifies high impact trait-associated alleles enriched in Finns

As yet undiscovered rare variants are hypothesized to substantially influence an individuals risk for common diseases and traits, but sequencing studies aiming to identify such variants have generally been underpowered. In isolated populations that have expanded rapidly after a population bottleneck, deleterious alleles that passed through the bottleneck may be maintained at much higher frequencies than in other populations. In an exome sequencing study of nearly 20,000 cohort participants from northern and eastern Finnish populations that exemplify this phenomenon, most novel trait-associated deleterious variants displayed frequencies 10-173 times higher than in other European populations. These enriched alleles underlie 30 novel associations with 20 disease-related quantitative traits and demonstrate a geographical clustering equivalent to that of Mendelian disease mutations characteristic of the Finnish population. Sequencing studies in populations without this unique history would require hundreds of thousands to millions of participants for comparable power.

genomics↗

bioRxiv2018

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To evaluate this hypothesis, we conducted genetic analyses in 26 Colombian (CO) and Costa Rican (CR) pedigrees ascertained for BP1, the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 856 individuals and high-coverage whole-genome sequencing of 454 individuals. Compared to their unaffected relatives, BP1 individuals had higher polygenic risk scores estimated from SNPs associated with BP discovered in independent genome-wide association studies, and also displayed a higher burden of rare deleterious single nucleotide variants (SNVs) and rare copy number variants (CNVs) in genes likely to be relevant to BP1. Parametric and non-parametric linkage analyses identified 15 BP1 linkage peaks, encompassing about 100 genes, although we observed no significant segregation pattern for any particular rare SNVs and CNVs. These results suggest that even in extended pedigrees, genetic risk for BP appears to derive mainly from small to moderate effect rare and common variants.

genetics↗

bioRxiv2016

CpG traffic lights are markers of regulatory regions in humans

DNA methylation is involved in regulation of gene expression. Although modern methods profile DNA methylation at single CpG sites, methylation levels are usually averaged over genomic regions in the downstream analyses. In this study we demonstrate that single CpG methylation can serve as a more accurate predictor of gene expression compared to average promoter / gene body methylation. CpG positions with significant correlation between methylation and expression of a gene nearby (named CpG traffic lights) are evolutionary conserved and enriched for exact TSS positions and active enhancers. Among all promoter types, CpG traffic lights are especially enriched in poised promoters. Genes that harbor CpG traffic lights are associated with development and signal transduction. Methylation levels of individual CpG traffic lights vary between cell types dramatically with the increased frequency of intermediate methylation levels, indicating cell population heterogeneity in CpG methylation levels. Being in line with the concept of the inherited stochastic epigenetic variation, methylation of such CpG positions might contribute to transcriptional regulation. Alternatively, one can hypothesize that traffic lights are markers of absent gene expression resulting from inactivation of their regulatory elements. The CpG traffic lights provide a promising insight into mechanisms of enhancer activity and gene regulation linking methylation of single CpG to expression.

bioinformatics↗

bioRxiv2016

Genetic variation and gene expression across multiple tissues and developmental stages in a non-human primate

By analyzing multi-tissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalogue of expression quantitative trait loci (eQTLs) in a non-human primate model. This catalogue contains more genome-wide significant eQTLs, per sample, than comparable human resources, and reveals sex and age-related expression patterns. Findings include a master regulatory locus that likely plays a role in immune function, and a locus regulating hippocampal long non-coding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

genetics↗