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  Rare disease genetics

  We develop and apply new software for identifying causal genetic variants in studies of rare familial disease. The University of Utah has a long history of expertise in this area and we work closely with many clinical collaborators to solve rare disease. Our GEMINI software is central to these efforts, and our laboratory collaborates with other members of the Utah Center for Genetic Discovery to study familial disease among the large pedigrees in the Utah Genome Project.

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  Structural variation

  Human chromosomes harbor hundreds of structural differences including deletions, insertions, duplications, inversions, and translocations. Collectively, these differences are known as "structural variation" (or, "SV"). Any two humans differ by thousands of structural variants which vary greatly in size and phenotypic consequence. However, we are just beginning to understand the contribution of SV to evolution, development, and complex disease. Our laboratory continues to develop new methods such as LUMPY for detecting and understanding structural variation using modern DNA sequencing techniques.

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  Cancer genomics and genome evolution

  Massively parallel DNA sequencing has yielded detailed maps of clonal variation in human cancer, through an inference of clonal substructure by analysis of variant allele frequencies in bulk tumor cell populations and direct sequencing of single cells. Dynamic changes in clonal structure over time and under the selective pressure of treatment have been extensively studied in hematologic malignancies, but are less well characterized in solid cancers. Our understanding of the dynamics of clonal change and its role in therapeutic response and the emergence of resistance is in its infancy. However, deeper insight is accessible via significant advances in sequencing and new algorithms. We are developing new methods to identify genomic changes that are responsible for clonal evolution, chemoresistance, and relapse.

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  Algorithm and Software Development

  Broadly speaking, the research in my laboratory marries genetics with genomics technologies, computer science, and machine learning techniques to develop new strategies for gaining insight into genome biology. We try to tackle challenging problems with practical importance to understanding genome variation in the context of human disease. We actively maintain a broad range of widely used tools for genome research including: BEDTOOLS, GEMINI, LUMPY, VCFANNO, PEDDY, and GQT.

somalier

Extract informative sites, evaluate relatedness, and perform quality-control on BAM, CRAM, BCF, VCF, and GVCF. somalier makes checking any number of samples for identity easy directly from the alignments.

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slivar

slivar is a set of command-line tools that enables rapid querying and filtering of VCF files. It facilitates operations on trios and groups and allows arbitrary expressions using simple javascript.

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ggd

Search, and install genomic data packages. Build and check new ggd data packages. ggd provides easy access to processed genomic data. It removes the difficulties and complexities with finding and processing the data sets and annotations germane to your experiments and/or analyses. You can quickly and easily search and install data package using ggd. ggd also offers tools to easily create and contribute data packages to ggd.

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d4-format

The D4 Quantatative Data Format. We sought to improve on existing formats such as BigWig and compressed BED files by creating the Dense Depth Data Dump (D4) format and tool suite. The D4 format is adaptive in that it profiles a random sample of aligned sequence depth from the input BAM or CRAM file to determine an optimal encoding that minimizes file size, while also enabling fast data access. We show that D4 uses less disk space for both RNA-Seq and whole-genome sequencing and offers 3 to 440 fold speed improvements over existing formats for random access, aggregation and summarization for scalable downstream analyses that would be otherwise intractable.

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smoove-nf

Nextflow implementation of the smoove workflow, integrating several other tools meant to facilate variant calling and quality control of discovered variants.

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seqcover

seqcover is a tool for viewing and evaluating depth-of-coverage with the following aims...

• show a global view where it's easy to see problematic samples and genes
• offer an interactive gene-wise view to explore coverage characteristics of individual samples within each gene
• not require a server (single html page)
• be responsive for up to 20 samples * 200 genes and be useful for a single-sample see how we do this
• highlight outlier samples based on any number of (summarized) background samples

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samplot

samplot is a command line tool for rapid, multi-sample structural variant visualization. samplot takes SV coordinates and bam files and produces high-quality images that highlight any alignment and depth signals that substantiate the SV.

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oncogemini

OncoGEMINI is an adaptation of GEMINI intended for the improved identification of biologically and clincally relevant tumor variants from multi-sample and longitudinal tumor sequencing data. Using a GEMINI-compatible database (generated from an annotated VCF file), OncoGEMINI is able to filter tumor variants based on included genomic annotations and various allele frequency signatures.

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mosdepth

Fast BAM/CRAM depth calculation for WGS, exome, or targeted sequencing. mosdepth can output...

• per-base depth about 2x as fast samtools depth--about 25 minutes of CPU time for a 30X genome.
• mean per-window depth given a window size--as would be used for CNV calling.
• the mean per-region given a BED file of regions.
• the mean or median per-region cumulative coverage histogram given a window size
• a distribution of proportion of bases covered at or above a given threshold for each chromosome and genome-wide.
• quantized output that merges adjacent bases as long as they fall in the same coverage bins e.g. (10-20)
• threshold output to indicate how many bases in each region are covered at the given thresholds.
• A summary of mean depths per chromosome and within specified regions per chromosome.
• a d4 file (better than bigwig).

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jigv

igv.js server and automatic configuration to view bam/cram/vcf/bed. igv.js requires that the files are hosted on a server, like apache or nginx and it requires writing html and javascript. In a single binary, jigv provides a server and some default configuration, javascript, and HTML enabling a simple entrypoint...

jigv --open-browser --region chr1:34566-34999 *.bam /path/to/some.cram my.vcf.gz

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idplot

Designed to accelerate SARS-CoV-2 research, idplot allows one to quickly compare similar sequences (*.fasta) to a reference (.fasta) with options to inspect recombination and similarity within an interactive report.

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freebayes-nf

A simplified version of freebayes-parallel written in Nextflow to handle job distribution on HPC resources. Intervals can be supplied by the user or created automatically to optimize compute utilization.

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covviz

A many-sample coverage browser. The aim of covviz is to highlight regions of significant and sustained deviation of coverage depth from the majority of samples.

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duphold

Uphold your DUP and DEL calls. SV callers like lumpy look at split-reads and pair distances to find structural variants. This tool is a fast way to add depth information to those calls. This can be used as additional information for filtering variants; for example we will be skeptical of deletion calls that do not have lower than average coverage compared to regions with similar gc-content.

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smoove

smoove simplifies and speeds calling and genotyping SVs for short reads. It also improves specificity by removing many spurious alignment signals that are indicative of low-level noise and often contribute to spurious calls.

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STRling

STRling (pronounced like "sterling") is a method to detect large STR expansions from short-read sequencing data. It is capable of detecting novel STR expansions, that is expansions where there is no STR in the reference genome at that position (or a different repeat unit from what is in the reference). It can also detect STR expansions that are annotated in the reference genome. STRling uses kmer counting to recover mis-mapped STR reads. It then uses soft-clipped reads to precisely discover the position of the STR expansion in the reference genome.

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indexcov

Crazy fast genome coverage estimates! The BAM and CRAM formats provide a supplementary linear index that facilitates rapid access to sequence alignments in arbitrary genomic regions. Comparing consecutive entries in a BAM or CRAM index allows one to infer the number of alignment records per genomic region for use as an effective proxy of sequence depth in each genomic region. Based on these properties, we have developed indexcov, an efficient estimator of whole-genome sequencing coverage to rapidly identify samples with aberrant coverage profiles, reveal large scale chromosomal anomalies, recognize potential batch effects, and infer the sex of a sample.

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bedtools

Collectively, the bedtools utilities are a swiss-army knife of tools for a wide-range of genomics analysis tasks. The most widely-used tools enable genome arithmetic. That is, set theory on the genome. For example, bedtools allows one to intersect, merge, count, complement, and shuffle genomic intervals from multiple files in widely-used genomic file formats such as BAM, BED, GFF, VCF. While each individual tool is designed to do a relatively simple task (e.g., intersect two interval files), quite sophisticated analyses can be conducted by combining multiple bedtools operations on the UNIX command line.

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lumpy

LUMPY is a novel and general probabilistic SV discovery framework that naturally integrates multiple SV detection signals, including those generated from read alignments or prior evidence, and that can readily adapt to any additional source of evidence that may become available with future technological advances.

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gemini

GEMINI (GEnome MINIng) is a flexible framework for exploring genetic variation in the context of the wealth of genome annotations available for the human genome. By placing genetic variants, sample phenotypes and genotypes, as well as genome annotations into an integrated database framework, GEMINI provides a simple, flexible, and powerful system for exploring genetic variation for rare disease and population genetics.

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gqt

Genotype Query Tools (GQT) is command line software and a C API for indexing and querying large-scale genotype data sets like those produced by 1000 Genomes, the UK100K, and forthcoming datasets involving millions of genomes. GQT represents genotypes as compressed bitmap indices, which reduce computational burden of variant queries based on sample genotypes, phenotypes, and relationships by orders of magnitude over standard "variant-centric" indexing strategies. This index can significantly expand the capabilities of population-scale analyses by providing interactive-speed queries to data sets with millions of individuals.

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poretools

Poretools is a flexible toolkit for exploring datasets generated by nanopore sequencing devices from MinION for the purposes of quality control and downstream analysis. Poretools operates directly on the native FAST5 (an application of the HDF5 standard) file format produced by ONT and provides a wealth of format conversion utilities and data exploration and visualization tools.

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speedseq

SpeedSeq is an open-source genome analysis platform that accomplishes alignment, variant detection and functional annotation of a 50× human genome in 13 h on a low-cost server and alleviates a bioinformatics bottleneck that typically demands weeks of computation with extensive hands-on expert involvement. SpeedSeq offers performance competitive with or superior to current methods for detecting germline and somatic single-nucleotide variants, structural variants, insertions and deletions, and it includes novel functionality for streamlined interpretation.

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vcfanno

vcfanno annotates a VCF with any number of sorted and tabixed input BED, BAM, and VCF files in parallel. It does this by finding overlaps as it streams over the data and applying user-defined operations on the overlapping annotations.

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peddy

pedagree is a python library for querying, QC'ing, and manipulating pedigree files.

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Giggle

Giggle is Google for genomic features and intervals. That is, scalable, multi-file index for fast queries of genomic intervals.

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Duphold: scalable, depth-based annotation and curation of high-confidence structural variant calls.

Brent S. Pedersen, Aaron R. Quinlan.

GigaScience, https://doi.org/10.1093/gigascience/giz040

Overlooked roles of DNA damage and maternal age in generating human germline mutations.

Ziyue Gao, Priya Moorjani, Thomas A. Sasani, Brent S. Pedersen, Aaron R. Quinlan, Lynn B. Jorde, Guy Amster, Molly Przeworski.

PNAS, https://doi.org/10.1073/pnas.1901259116

Coexpression patterns define epigenetic regulators associated with neurological dysfunction.

Leandros Boukas, James M. Havrilla, Peter F. Hickey, Aaron R. Quinlan, Hans T. Bjornsson, Kasper D. Hansen.

Genome Research, https://doi.org/10.1101/gr.239442.118

Salt Lake Learners of Biostats (SLLOBS)

Applied Computational Genomics

Tutorials

Lectures

Eccles Institute for Human Genetics
15 North 2030 East, Room 7160B

aquinlan at genetics dot utah dot edu