Biology subjects

Padhi, E. M.

Publications and source records attributed to Padhi, E. M..

3 recordsLinked to original sources

bioRxiv2021

ACES: Analysis of Conservation with Expansive Species

MotivationAn abundance of new reference genomes are becoming available through large-scale sequencing efforts. While the reference FASTA for each genome is available, there is currently no automated mechanism to query a specific sequence across all new reference genomes. ResultsWe developed ACES (Analysis of Conservation with Expansive Species) as a computational workflow to query specific sequences of interest (e.g., enhancers, promoters, exons) against reference genomes with an available reference FASTA. This automated workflow generates BLAST hits against each of the reference genomes, a multiple sequence alignment file, a graphical fragment assembly file, and a phylogenetic tree file. These data files can then be used by the researcher in several ways to provide key insights into conservation of the query sequence. AvailabilityACES is available at https://github.com/TNTurnerLab/ACES Contacttychele@wustl.edu Supplementary informationSupplementary Figure 1 is available on bioRxiv.

bioinformatics↗

bioRxiv2021

de novo variant calling identifies cancer mutation profiles in the 1000 Genomes Project

Detection of de novo variants (DNVs) is critical for studies of disease-related variation and mutation rates. We developed a GPU-based workflow to rapidly call DNVs (HAT) and demonstrated its effectiveness by applying it to 4,216 Simons Simplex Collection (SSC) whole-genome sequenced parent-child trios from DNA derived from blood. In our SSC DNV data, we identified 78 {+/-} 15 DNVs per individual, 18% {+/-} 5% at CpG sites, 75% {+/-} 9% phased to the paternal chromosome of origin, and an average allele balance of 0.49. These calculations are all in line with DNV expectations. We sought to build a control DNV dataset by running HAT on 602 whole-genome sequenced parent-child trios from DNA derived from lymphoblastoid cell lines (LCLs) from the publicly available 1000 Genomes Project (1000G). In our 1000G DNV data, we identified 740 {+/-} 967 DNVs per individual, 14% {+/-} 4% at CpG sites, 61% {+/-} 11% phased to the paternal chromosome of origin, and an average allele balance of 0.41. Of the 602 trios, 80% had > 100 DNVs and we hypothesized the excess DNVs were cell line artifacts. Several lines of evidence in our data suggest that this is true and that 1000G does not appear to be a static reference. By mutation profile analysis, we tested whether these cell line artifacts were random and found that 40% of individuals in 1000G did not have random DNV profiles; rather they had DNV profiles matching B-cell lymphoma. Furthermore, we saw significant excess of protein-coding DNVs in 1000G in the gene IGLL5 that has already been implicated in this cancer. As a result of cell line artifacts, 1000G has variants present in DNA repair genes and at Clinvar pathogenic or likely-pathogenic sites. Our study elucidates important implications of the use of sequencing data from LCLs for both reference building projects as well as disease-related projects whereby these data are used in variant filtering steps.

genomics↗

bioRxiv2020

De Novo Mutation in an Enhancer of EBF3 in simplex autism

Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of de novo protein-coding variants within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2,671 families with autism, with a specific focus on de novo variation in enhancers with previously characterized in vivo activity. We identified three independent de novo mutations limited to individuals with autism in the enhancer hs737. These mutations result in similar phenotypic characteristics, affect enhancer activity in vitro, and preferentially occur in AAT motifs in the enhancer with predicted disruptions of transcription factor binding. We also find that hs737 is enriched for copy number variation in individuals with NDDs, is dosage sensitive in the human population, is brain-specific, and targets the NDD gene EBF3 that is genome-wide significant for protein coding de novo variants, demonstrating the importance of understanding all forms of variation in the genome. One Sentence SummaryWhole-genome sequencing in thousands of families reveals variants relevant to simplex autism in a brain enhancer of the well-established neurodevelopmental disorder gene EBF3.

genomics↗