Sorel Fitz-Gibbon

University of California, Los Angeles | UCLA · Department of Molecular, Cell, and Developmental Biology (MCDB)

Island oak (Quercus tomentella) is a rare relictual island tree species that exists only on six islands off the coast of California and Mexico, but was once widespread throughout mainland California. Currently, this species is endangered by threats such as non-native plants, and grazing animals, and human removal. Efforts for conservation and resto...

CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolv...

The genus Quercus , which emerged ∼55 million years ago during globally warm temperatures, diversified into ∼450 extant species. We present a high-quality de novo genome assembly of a California endemic oak, Quercus lobata , revealing features consistent with oak evolutionary success. Effective population size remained large throughout history desp...

Ancient introgression can be an important source of genetic variation that shapes the evolution and diversification of many taxa. Here, we estimate the timing, direction and extent of gene flow between two distantly related oak species in the same section (Quercus sect. Quercus). We estimated these demographic events using genotyping by sequencing...

The genus Quercus, which emerged ~55 million years ago during globally warm temperatures, diversified into ~450 species. We present a high-quality de novo genome assembly of a California endemic oak, Quercus lobata , revealing features consistent with oak evolutionary success. Effective population size remained large throughout history despite decl...

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20623-0

Silencing of exogenous DNA can make transgene expression very inefficient. Genetic screens in the model alga Chlamydomonas have demonstrated that transgene silencing can be overcome by mutations in unknown gene(s), thus producing algal strains that stably express foreign genes to high levels. Here, we show that the silencing mechanism specifically...

Understanding how the environment shapes genetic variation provides critical insight about the evolution of local adaptation in natural populations. At multiple spatial scales and multiple geographic contexts within a single species, such information could address a number of fundamental questions about the scale of local adaptation and whether or...

In bacteria, evolution of resistance to one antibiotic is frequently associated with increased resistance (cross‐resistance) or increased susceptibility (collateral sensitivity) to other antibiotics. Cross‐resistance and collateral sensitivity are typically evaluated at the minimum inhibitory concentration (MIC). However, these susceptibility chang...

Climate change over the next century is predicted to cause widespread maladaptation in natural systems. This prediction, as well as many sustainable management and conservation practices, assumes that species are adapted to their current climate. However, this assumption is rarely tested. Using a large-scale common garden experiment combined with g...

The tree of life is highly reticulate, with the history of population divergence emerging from populations of gene phylogenies that reflect histories of introgression, lineage sorting and divergence. In this study, we investigate global patterns of oak diversity and test the hypothesis that there are regions of the oak genome that are broadly infor...

Significance Burkholderia pseudomallei , the etiologic agent of melioidosis, is an environmental organism that inhabits tropical soils and kills an estimated 90,000 people each year. Caused by an intracellular and often drug-resistant pathogen, melioidosis is notoriously difficult to treat, with mortality rates approaching 50% in some settings desp...

The tree of life is highly reticulate, with the history of population divergence buried amongst phylogenies deriving from introgression and lineage sorting. In this study, we test the hypothesis that there are regions of the oak ( Quercus , Fagaceae) genome that are broadly informative about phylogeny and investigate global patterns of oak diversit...

Escherichia coli can derive all essential metabolites and cofactors through a highly evolved metabolic system. Damage of pathways may affect cell growth and physiology, but the strategies by which damaged metabolic pathways can be circumvented remain intriguing. Here, we use a ΔpanD (encoding for aspartate 1-decarboxylase) strain of E. coli that is...

Background: Hybridization and introgression are common phenomena among oak species. These processes can be beneficial by introducing favorable genetic variants across species (adaptive introgression). Given that drought is an important stress, impacting physiological and morphological variation and limiting distributions, our goal was to identify d...

CRISPR/Cas9‐mediated gene editing of human hematopoietic stem cells (hHSCs) is a promising strategy for the treatment of genetic blood diseases through site‐specific correction of identified causal mutations. However, clinical translation is hindered by low ratio of precise gene modification using the corrective donor template (homology‐directed re...

A long‐term debate in evolutionary biology is the extent to which reproductive isolation is a necessary element of speciation. Hybridizing plants in general are cited as evidence against this notion and oaks specifically have been used as the classic example of species maintenance without reproductive isolation. Here, we use thousands of SNPs gener...

Engineering a microbial strain for production sometimes entails metabolic modifications that impair essential physiological processes for growth or production. Restoring these functions may require amending a variety of non-obvious physiological networks, and thus, rational design strategies may not be practical. Here we demonstrate that growth and...

Local adaptation is a critical evolutionary process that allows plants to grow better in their local compared to nonnative habitat and results in species‐wide geographic patterns of adaptive genetic variation. For forest tree species with a long generation time, this spatial genetic heterogeneity can shape the ability of trees to respond to rapid c...

X-linked hyper-immunoglobulin M (hyper-IgM) syndrome (XHIM) is a primary immunodeficiency due to mutations in CD40 ligand that affect immunoglobulin class-switch recombination and somatic hypermutation. The disease is amenable to gene therapy using retroviral vectors, but dysregulated gene expression results in abnormal lymphoproliferation in mouse...

Background: A remarkable exception to the large genetic diversity often observed for bacteriophages infecting a specific bacterial host was found for the Cutibacterium acnes (formerly Propionibacterium acnes) phages, which are highly homogeneous. Phages infecting the related species, which is also a member of the Propionibacteriaceae family, Propi...

Chlamydomonas reinhardtii is a unicellular chlorophyte alga that is widely-studied as a reference organism for understanding photosynthesis, sensory and motile cilia, and for development of an algal-based platform for producing biofuels and bio-products. Its highly repetitive, ~205 kbp circular chloroplast genome and ~15.8 kbp linear mitochondrial...

The emergence of next generation sequencing has increased by several orders of magnitude the amount of data available for phylogenetics. Reduced representation approaches, such as restriction-site associated DNA sequencing (RADseq), have proven useful for phylogenetic studies of non-model species at a wide range of phylogenetic depths. However, ana...

Applications of embryonic stem cells (ESCs) require faithful chromatin changes during differentiation, but the fate of the X chromosome state in differentiating ESCs is unclear. Female human ESC lines either carry two active X chromosomes (XaXa), an Xa and inactive X chromosome with or without XIST RNA coating (Xi(XIST+)Xa;XiXa), or an Xa and an er...

Introduction: Site-specific gene correction of the point mutation causing sickle cell disease (SCD) in hematopoietic stem cells (HSCs) constitutes a precise strategy to generate a life-long source of gene-corrected erythrocytes that do not sickle. However, low efficiency of homology-directed repair (HDR) in primitive reconstituting HSCs is currentl...

Oaks represent a valuable natural resource across Northern Hemisphere ecosystems attracting a large research community studying its genetics, ecology, conservation, and management. Here we introduce a draft genome assembly of valley oak (Quercus lobate) using Illumina sequencing of adult leaf tissue of an tree found in an accessible, well-studied,...

Targeted genome editing technology can correct the sickle cell disease (SCD) mutation of the ß-globin gene in hematopoietic stem cells. This correction supports production of red blood cells that synthesize normal hemoglobin proteins. Here, we demonstrate that Transcription Activator-Like Effector Nucleases (TALENs) and the Clustered Regularly Inte...

The selectivity of metal sensors for a single metal ion is critical for cellular metal homeostasis. A suite of metal-responsive regulators is required to maintain a prescribed balance of metal ions ensuring that each apo-protein binds the correct metal. However, there are cases when non-essential metals ions disrupt proper metal sensing. An analysi...

Background The genetic origins of chemotherapy resistance are well established; however, the role of epigenetics in drug resistance is less well understood. To investigate mechanisms of drug resistance, we performed systematic genetic, epigenetic, and transcriptomic analyses of an alkylating agent-sensitive murine lymphoma cell line and a series of...

DNA methylation in plants affects transposon silencing, transcriptional regulation and thus phenotypic variation. One unanswered question is whether DNA methylation could be involved in local adaptation of plant populations to their environments. If methylation alters phenotypes to improve plant response to the environment, then methylation sites o...

The green alga Chlamydomonas reinhardtii is a leading single-celled model for dissecting biological processes in photosynthetic eukaryotes. However, its usefulness has been limited by difficulties in obtaining mutants in genes of interest. To allow generation of large numbers of mapped mutants, we developed high-throughput methods which: (1) Enable...

The taxonomy of oaks (Quercus) is always a challenge because many species exhibit variable phenotypes that overlap with other species. The scrub White Oaks of California are no exception. In California, Quercus section Quercus (i.e., White Oaks) includes six species of scrub oaks plus four tree oak species. Field identification utilizes leaf traits...

Reactive oxygen species (ROS) are produced by and have the potential to be damaging to all aerobic organisms. In photosynthetic organisms, they are an unavoidable byproduct of electron transfer in both the chloroplast and mitochondrion. We employ the reference unicellular green alga, Chlamydomonas reinhardtii, to identify the effect of H2 O2 on gen...

The green alga Chlamydomonas reinhardtii undergoes gametogenesis and mating upon nitrogen starvation. While the steps involved in its sexual reproductive cycle have been extensively characterized, the genome-wide transcriptional and epigenetic changes underlying different life cycle stages have yet to be fully described. Here, we performed transcri...

Alterations in the composition of the intestinal microbiota have been correlated with aging and measures of frailty in the elderly. However, the relationships between microbial dynamics, age-related changes in intestinal physiology, and organismal health remain poorly understood. Here, we show that dysbiosis of the intestinal microbiota, characteri...

Chlamydomonas reinhardtii is a widely used reference organism in studies of photosynthesis, cilia, and biofuels. Most research in this field uses a few dozen standard laboratory strains that are reported to share a common ancestry, but exhibit substantial phenotypic differences. In order to facilitate ongoing Chlamydomonas research and explain the...

Activation of precursor 25-hydroxyvitamin D3 (25D) to hormonal 1,25-dihydroxyvitamin D3 (1,25D) is a pivotal step in vitamin D physiology, catalysed by the enzyme 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase). To establish new models for assessing the physiological importance of the 1α-hydroxylase-25D-axis, we used Danio rerio (zebrafish) to...

Initially using 143 genomes, we developed a method for calculating the pair-wise distance between prokaryotic genomes using a Monte Carlo method to estimate the conservation of gene order. The method was based on repeatedly selecting five or six non-adjacent random orthologs from each of two genomes and determining if the chosen orthologs were in t...

To understand the molecular basis underlying increased triacylglycerol (TAG) accumulation in starchless (sta) Chlamydomonas reinhardtii mutants, we undertook comparative time-course transcriptomics of strains CC-4348 (sta6 mutant), CC-4349, a cell wall-deficient (cw) strain purported to represent the parental STA6 strain, and three independent STA6...

The human skin microbiome plays important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by...

The human skin harbors a diverse community of bacteria, including the Gram-positive, anaerobic bacterium Propionibacterium acnes. P. acnes has historically been linked to the pathogenesis of acne vulgaris, a common skin disease affecting over 80% of all adolescents in the US. To gain insight into potential P. acnes pathogenic mechanisms, we previou...

Unlabelled: Investigation of the human microbiome has revealed diverse and complex microbial communities at distinct anatomic sites. The microbiome of the human sebaceous follicle provides a tractable model in which to study its dominant bacterial inhabitant, Propionibacterium acnes, which is thought to contribute to the pathogenesis of the human...

CRISPR-associated spacer sequences from six P. acnes isolates.

GC content skew and conservation. (Top) GC content skew (C – G/C + G) is shown for 100-nucleotide windows along the multiply aligned genomes. The base counts of the 14 genomes were summed with gaps ignored. The vertical bar indicates the primary switch of the coding strand, which does not seem to affect the GC content skew. (Bottom) Multiple alignm...

P. acnes phage putative origin of replication. (Top) Multiple alignment of noncoding regions of 14 phage genomes. The level of conservation is indicated in the upper track; red indicates low, and green indicates high. (Bottom) Zoom view of the last 150 bases in the noncoding region showing high conservation of regions with unusual base composition....

Genome maps of mycobacteriophages illustrating their genetic diversity. (A) The maps of 25 mycobacteriophage genomes that form subcluster A1 are shown, with the pairwise nucleotide sequence similarities represented between genomes; similarities are spectrum colored, with the most similar being violet and the least similar red. Maps were generated u...

Genome maps of mycobacteriophages illustrating their genetic diversity. (B) The broad diversity of the mycobacteriophages is illustrated by the genome maps of 15 mycobacteriophages representing different clusters or singleton genomes. Maps are represented as in panel A. Download Figure S2B, PDF file, 0.3 MB.

Supplemental methods. Download Text S1, DOCX file, 0.1 MB.

Dot plot nucleotide sequence comparisons of randomly chosen subsets of 14 mycobacteriophages. Six randomly chosen subsets of 14 mycobacteriophages were generated using a Research Randomizer (http://www.randomizer.org/form.htm), and the concatenated genomes were compared to themselves using Gepard (J. Krumsiek, R. Arnold, and T. Rattei, Bioinformati...

P. acnes strains used in this study.

Objectives: To examine the subgingival metagenome associated with chronic periodontitis we are using a longitudinal human model. The goal of this investigation was to conduct a preliminary characterization of the subgingival microbiome in these subjects before and after initial periodontal therapy using 16S rRNA clone libraries. Methods: Generally...

The increase of the acidic nature of proteins as an adaptation to hypersalinity has been well documented within halophile isolates. Here we explore the effect of salinity on amino acid preference on an environmental scale. Via pyrosequencing, we have obtained two distinct metagenomic data sets from the Dead Sea, one from a 1992 archaeal bloom and o...

We investigate the genes associated with lateral gene transfer in thermal and saline environments on an environmental scale and present a novel approach to identify transfer events into haloarchaea utilizing their preference for acidic amino acids.

We have attempted to use a Monte Carlo approach to look for small genome-wide instances of gene order conservation. Our trees show the actinobacteria as a sister group to the bulk of the firmicutes. The results are supportive of a single origin for the gram-positive cell.

Metagenomic approaches can offer a broad overview of the microbial diversity in and environment and the metabolic processes performed within. At the most general level, knowing merely the GC content of an environment is enough to yield valuable insights as to the makeup of a microbial community. It has been documented that various environmental str...

The subseafloor marine biosphere may be one of the largest reservoirs of microbial biomass on Earth and has recently been the subject of debate in terms of the composition of its microbial inhabitants, particularly on sediments from the Peru Margin. A metagenomic analysis was made by using whole-genome amplification and pyrosequencing of sediments...

We examine terminal addition, the process of addition of serial elements in a posterior subterminal growth zone during animal development, across modern taxa and fossil material. We argue that terminal addition was the basal condition in Bilateria, and that modification of terminal addition was an important component of the rapid Cambrian evolution...

The architecture of single-stranded DNA-binding proteins, which play key roles in DNA metabolism, is based on different combinations of the oligonucleotide/oligosaccharide binding (OB) fold. Whereas the polypeptide serving this function in bacteria contains one OB fold, the eukaryotic functional homolog comprises a complex of three proteins, each h...

Phylogenetic profiling involves the study of the occurrence of gene families across fully sequenced genomes. For any gene, it is possible to create a phylogenetic profile, which encodes the presence or absence of homologs of the gene across organisms. Phylogenetic profiles may be used to measure the evolutionary distance between organisms, leading...

We constructed genomic trees based on the presence and absence of families of protein-encoding genes observed in 55 prokaryotic and five eukaryotic genomes. There are features of the genomic trees that are not congruent with typical rRNA phylogenetic trees. In the bacteria, for example, Deinococcus radiodurans associ-ates with the Gram-positive bac...

Uracil-DNA glycosylases (UDGs) catalyse the removal of uracil by flipping it out of the double helix into their binding pockets, where the glycosidic bond is hydrolysed by a water molecule activated by a polar amino acid. Interestingly, the four known UDG families differ in their active site make-up. The activating residues in UNG and SMUG enzymes...

Proliferating cell nuclear antigen (PCNA) acts as a sliding clamp on duplex DNA. Its homologs, present in Eukarya and Archaea, are part of protein complexes that are indispensable for DNA replication and DNA repair. In Eukarya, PCNA is known to interact with more than a dozen different proteins, including a human major nuclear uracil-DNA glycosylas...

Genomic trees have been constructed based on the presence and absence of families of protein-encoding genes observed in 27 complete genomes, including genomes of 15 free-living organisms. This method does not rely on the identification of suspected orthologs in each genome, nor the specific alignment used to compare gene sequences because the prote...

The complete genome sequence of Pyrobaculum aerophilum reveals clues to how organisms can adapt to extreme temperatures

We determined and annotated the complete 2.2-megabase genome sequence of Pyrobaculum aerophilum, a facultatively aerobic nitrate-reducing hyperthermophilic (T(opt) = 100 degrees C) crenarchaeon. Clues were found suggesting explanations of the organism's surprising intolerance to sulfur, which may aid in the development of methods for genetic studie...

Deamination of cytosine to uracil and 5-methylcytosine to thymine represents a major mutagenic threat particularly at high temperatures. In double-stranded DNA, these spontaneous hydrolytic reactions give rise to G·U and G·T mispairs, respectively, that must be restored to G·C pairs prior to the next round of DNA replication; if left unrepaired, 50...

We mapped transcription start sites for ten unrelated protein-encoding Pyrobaculum aerophilum genes by primer extension and S(1) nuclease mapping. All of the mapped transcripts start at the computationally predicted translation start codons, two of which were supported by N-terminal protein sequencing. A whole genome computational analysis of the r...

Pyrimidine adducts in cellular DNA arise from modification of the pyrimidine 5,6-double bond by oxidation, reduction or hydration. The biological outcome includes increased mutation rate and potential lethality. A major DNA N:-glycosylase responsible for the excision of modified pyrimidine bases is the base excision repair (BER) glycosylase endonuc...

Proteins containing the Nudix box "GX(5)EX(7)REUXEEXGU" (where U is usually Leu, Val, or Ile) are Nudix hydrolases, which catalyze the hydrolysis of a variety of nucleoside diphosphate derivatives. Here we report cloning and characterization of a human cDNA encoding a novel nudix hydrolase NUDT5 for the hydrolysis of ADP-sugars. The deduced amino a...

Three-dimensional protein folds were assigned to all ORFs of the recently sequenced genome of the hyperthermophilic archaeon Pyrobaculum aerophilum. Binary hypothesis testing was used to estimate a confidence level for each assignment. A separate test was conducted to assign a probability for whether each sequence has a novel fold-i.e., one that is...

U/G and T/G mismatches commonly occur due to spontaneous deamination of cytosine and 5-methylcytosine in double-stranded DNA. This mutagenic effect is particularly strong for extreme thermophiles, since the spontaneous deamination reaction is much enhanced at high temperature. Previously, a U/G and T/G mismatch-specific glycosylase (Mth-MIG) was fo...

Vacuolar-type H(+)-translocating pyrophosphatases (V-PPases) have been considered to be restricted to plants, a few species of phototrophic proteobacteria and protists. Here, we describe PVP, a thermostable, sequence-divergent V-PPase from the facultatively aerobic hyperthermophilic archaeon Pyrobaculum aerophilum. PVP shares only 38% sequence iden...

A phylogenetic ‘tree of life’ has been constructed based on the observed presence and absence of families of protein-encoding genes observed in 11 complete genomes of free-living microorganisms. Past attempts to reconstruct the evolutionary relationships of microorganisms have been limited to sets of genes rather than complete genomes. Despite appa...

The crenarchaeon Pyrobaculum aerophilum is with an optimal growth temperature of 100 degrees C one of the most thermophilic organisms known to possess an aerobic respiratory chain. The analysis of DNA sequences from the Pyrobaculum genome project lead to the identification of an open reading frame potentially coding for a Rieske iron-sulfur protein...

We have constructed a physical map of the approximately 1.7-Mb genome of the hyperthermophilic archaeon Pyrobaculum aerophilum. Derived from a 12× coverage genomic fosmid library with an average insert size of 36 Kb, the map consists of a single circular contig of 96 overlapping fosmid clones with 211 markers ordered along them. One hundred of the...

The hyperthermophilic archaeum, Pyrobaculum aerophilum, grows optimally at 100°C with a doubling time of 180 min. It is a member of the phylogenetically ancient Thermoproteales order, but differs significantly from all other members by its facultatively aerobic metabolism. Due to its simple cultivation requirements and its nearly 100% plating effic...

Thesis (Ph. D.)--University of California, Los Angeles, 1998. Typescript (photocopy). Vita. Includes bibliographical references.