A5061833719- CRISPR and Genetic Engineering
- Genomics and Phylogenetic Studies
- DNA Repair Mechanisms
- Evolution and Genetic Dynamics
- Genomics and Rare Diseases
- Cancer Genomics and Diagnostics
- Chromosomal and Genetic Variations
- Plant Virus Research Studies
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Poxvirus research and outbreaks
- Bacteriophages and microbial interactions
- RNA and protein synthesis mechanisms
- Genetic factors in colorectal cancer
- Herpesvirus Infections and Treatments
- RNA Research and Splicing
- Genetic and Kidney Cyst Diseases
- Genetics, Aging, and Longevity in Model Organisms
- Gene expression and cancer classification
- Endoplasmic Reticulum Stress and Disease
- Genetic diversity and population structure
- Genetic Syndromes and Imprinting
- Thallium and Germanium Studies
- Reproductive Health and Technologies
- RNA modifications and cancer
University of Utah
2017-2025
University of Washington
2020-2024
Star Center
2018-2021
Lawrence University
2015-2017
A human genome is sequenced and assembled de novo using a pocket-sized nanopore device. We report the sequencing assembly of reference for GM12878 Utah/Ceph cell line MinION (Oxford Nanopore Technologies) sequencer. 91.2 Gb sequence data, representing ∼30× theoretical coverage, were produced. Reference-based alignment enabled detection large structural variants epigenetic modifications. De reads alone yielded contiguous (NG50 ∼3 Mb). developed protocol to generate ultra-long (N50 > 100 kb,...
The textbook view that most germline mutations in mammals arise from replication errors is indirectly supported by the fact there are both more and cell divisions male than female germline. When analyzing large de novo mutation datasets humans, we find multiple lines of evidence call into question. Notably, despite drastic increase ratio to germ after onset spermatogenesis, even young fathers contribute three times mothers, this barely increases with parental age. This surprising finding...
The number of de novo mutations (DNMs) found in an offspring's genome increases with both paternal and maternal age. But does the rate mutation accumulation human gametes differ across families? Using sequencing data from 33 large, three-generation CEPH families, we observed significant variability parental age effects on DNM counts ranging 0.19 to 3.24 DNMs per year. Additionally, that ~3% originated following primordial germ cell specification a parent, differed non-mosaic germline their...
ABSTRACT Using five complementary short- and long-read sequencing technologies, we phased assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) recombination. From this family, estimate an average 192 DNMs per generation, including 75.5 single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 indels or structural (SVs) originating from tandem repeats, 7.7 centromeric SVs...
Abstract SV-plaudit is a framework for rapidly curating structural variant (SV) predictions. For each SV, we generate an image that visualizes the coverage and alignment signals from set of samples. Images are uploaded to our cloud where users assess quality using client-side web application. Reports can then be generated as tab-delimited file or annotated Variant Call Format (VCF) file. As proof principle, nine researchers collaborated 1 hour evaluate 1,350 SVs each. We anticipate will...
Horizontal gene transfer (HGT) provides a major source of genetic variation. Many viruses, including poxviruses, encode genes with crucial functions directly gained by from hosts. The mechanism to poxvirus genomes is unknown. Using genome analysis and experimental screens infected cells, we discovered central role for Long Interspersed Nuclear Element-1 retrotransposition in HGT virus genomes. process recapitulates processed pseudogene generation, but host messenger RNA directed into...
A substantial fraction of the human genome is difficult to interrogate with short-read DNA sequencing technologies due paralogy, complex haplotype structures, or tandem repeats. Long-read technologies, such as Oxford Nanopore’s MinION, enable direct measurement loci without introducing many biases inherent methods, though they suffer from relatively lower throughput. This limitation has motivated recent efforts develop amplification-free strategies target and enrich interest for subsequent...
Abstract The BXD recombinant inbred (RI) mouse strains are the largest and most deeply phenotyped panel of vertebrate organisms. RIs allow phenotyping isogenic individuals across virtually any environment or treatment. We performed whole genome sequencing generated a compendium SNPs, indels, short tandem repeats, structural variants in these used them to analyze phenomic data accumulated over past 50 years. show that BXDs segregate >6 million with high minor allele which dervied from...
Identifying
Abstract Male infertility is associated with elevated rates of aneuploidy and DNA breaks in spermatozoa germline precursors. This common condition not well understood poor individual familial somatic health relative to fertile men. To further understand the extent source genome instability, we used error-corrected duplex sequencing test whether impaired spermatogenesis relatively poorer oligozoospermic men are linked single nucleotide de novo mutation frequencies their sperm blood,...
Poxvirus adaptation can involve combinations of recombination-driven gene copy number variation and beneficial single nucleotide variants (SNVs) at the same loci. How these distinct mechanisms genetic diversification might simultaneously facilitate to host immune defenses is unknown. We performed experimental evolution with vaccinia virus populations harboring a SNV in actively undergoing amplification. Using long sequencing reads from Oxford Nanopore Technologies platform, we phased SNVs...
Ageing may be due to mutation accumulation across the lifespan, leading tissue dysfunction, disease, and death. We tested whether germline autosomal rates in young adults predict their remaining survival, and, for women, reproductive lifespans. Age-adjusted (AAMRs) 61 women men from Utah CEPH (Centre d'Etude du Polymorphisme Humain) families were determined. Age at death, cause of all-site cancer incidence, histories provided by Population Database, Cancer Registry, Genetic Reference...
Maintaining germline genome integrity is essential and enormously complex. Although many proteins are involved in DNA replication, proofreading, repair, mutator alleles have largely eluded detection mammals. replication repair often recognize sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum of de novo mutations - frequencies C>T, A>G, etc. will differ between genomes harbor either a wild-type allele. Previously, used quantitative trait locus...
Abstract The number of de novo mutations (DNMs) found in an offspring’s genome is known to increase with both paternal and maternal age. But does the rate mutation accumulation parental gametes differ across families? To answer this question, we analyzed DNMs 33 large, three-generation families collected Utah by Centre d’Etude du Polymorphisme Humain (CEPH) consortium. We observed significant variability age effects on DNM counts families, ranging from 0.24 3.33 additional per year. Using up...
Abstract Although the textbook view is that most germline mutations arise from replication errors, when analyzing large de novo mutation datasets in humans, we find multiple lines of evidence call understanding into question. Notably, despite drastic increase ratio male to female germ cell divisions after onset spermatogenesis, even young fathers contribute three times more than mothers, and this barely increases with parental ages. This surprising finding points a substantial contribution...
Summary Paragraph Although germline mutation rates and spectra can vary within between species, genetic modifiers of these traits have long eluded detection. In this study, we searched for loci that influence mutagenesis using a uniquely powerful resource: panel recombinant inbred mouse lines known as the B X D , descended from laboratory strains C57BL/6J ( ) DBA/2J ). Each BXD lineage has been maintained by brother-sister mating in near absence natural selection, accumulating de novo...
Polymorphic human Alu elements are excellent tools for assessing population structure, and new retrotransposition events can contribute to disease. Next-generation sequencing has greatly increased the potential discover in populations, various bioinformatics methods have been designed tackle problem of detecting these highly repetitive elements. However, current techniques discovery may miss rare, polymorphic Combining multiple approaches provide a better profile mobilome. AluYb8/9 focus our...
Abstract Summary Unfazed is a command-line tool to determine the parental gamete of origin for de novo mutations from paired-end Illumina DNA sequencing reads. uses variant information sequenced trio identify by linking phase-informative inherited variants using read-based phasing. It achieves high success rate chaining reads into haplotype groups, thus increasing search space informative sites. provides simple interface and scales well large inputs, determining parent-of-origin nearly 30...
Cilia are conserved cellular structures that facilitate sensory‐based processes, including those required for neuronal and kidney functions. Here, we show the human mitogen activated kinase‐15 (MAPK‐15) ortholog in Caenorhabditis elegans encodes a ciliary protein. A strain harboring mutation catalytic site of kinase domain results ciliary‐specific defects tail neurons both hermaphrodite male worms, manifesting dye uptake, dendrite extension, mating behavior defects. Transgenic‐fusion...
Abstract Horizontal gene transfer (HGT) provides a major source of genetic variation. Many viruses, including poxviruses, encode genes with crucial functions directly gained by from hosts. The mechanism to poxvirus genomes is unknown. Using genome analysis and experimental screens infected cells, we discovered central role for Long Interspersed Nuclear Element-1 (LINE-1) retrotransposition in HGT virus genomes. process recapitulates processed pseudogene generation, but host messenger RNA...
ABSTRACT SV-plaudit is a framework for rapidly curating structural variant (SVs) predictions. For each SV, we generate an image that visualizes the coverage and alignment signals from set of samples. Images are uploaded to our cloud where users assess quality using client-side web application. Reports can then be generated as tab-delimited file or annotated VCF. As proof principle, nine researchers collaborated one hour evaluate 1,350 SVs each. We anticipate will become standard step in...
Abstract Large DNA viruses rapidly evolve to defeat host defenses. Poxvirus adaptation can involve combinations of recombination-driven gene copy number variation and beneficial single nucleotide variants (SNVs) at the same locus, yet how these distinct mechanisms genetic diversification might simultaneously facilitate immune blocks is unknown. We performed experimental evolution with a vaccinia virus population harboring SNV in actively undergoing amplification. Comparisons genomes using...
Maintaining germline genome integrity is essential and enormously complex. Although many proteins are involved in DNA replication, proofreading, repair [1], mutator alleles have largely eluded detection mammals.DNA replication often recognize sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum of de novo mutations — frequencies C>T, A>G, etc. will differ between genomes harbor either a wild-type allele. Previously, used quantitative trait...