Alisha K Holloway

University of California, San Francisco, San Francisco, California, United States

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Publications (38)320.21 Total impact

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    ABSTRACT: Mammals have evolved remarkably different sensory, reproductive, metabolic, and skeletal systems. To explore the genetic basis for these differences, we developed a comparative genomics approach to scan whole-genome multiple sequence alignments to identify regions that evolved rapidly in an ancestral lineage but are conserved within extant species. This pattern suggests that ancestral changes in function were maintained in descendants. After applying this test to therian mammals, we identified 4797 accelerated regions, many of which are non-coding and located near developmental transcription factors. We then used mouse transgenic reporter assays to test if non-coding accelerated regions are enhancers and to determine how therian-specific substitutions affect their activity in vivo. We discovered enhancers with expression specific to the therian version in brain regions involved in the hormonal control of milk ejection, uterine contractions, blood pressure, temperature, and visual processing. This work underscores the idea that changes in developmental gene expression are important for mammalian evolution, and it pinpoints candidate genes for unique aspects of mammalian biology.
    Preview · Article · Dec 2015 · Molecular Biology and Evolution
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    R. Sanders Williams · Samad Lotia · Alisha K. Holloway · Alexander R. Pico

    Full-text · Dataset · Dec 2015
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    R. Sanders Williams · Samad Lotia · Alisha K. Holloway · Alexander R. Pico
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    ABSTRACT: We propose that data mining and network analysis utilizing public databases can identify and quantify relationships between scientific discoveries and major advances in medicine (cures). Further development of such approaches could help to increase public understanding and governmental support for life science research and could enhance decision making in the quest for cures.
    Full-text · Article · Sep 2015 · Cell
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    Dataset: nature10530

    Full-text · Dataset · Jun 2015
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    Alexander G Williams · Sean Thomas · Stacia K Wyman · Alisha K Holloway
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    ABSTRACT: RNA-seq is widely used to determine differential expression of genes or transcripts as well as identify novel transcripts, identify allele-specific expression, and precisely measure translation of transcripts. Thoughtful experimental design and choice of analysis tools are critical to ensure high-quality data and interpretable results. Important considerations for experimental design include number of replicates, whether to collect paired-end or single-end reads, sequence length, and sequencing depth. Common analysis steps in all RNA-seq experiments include quality control, read alignment, assigning reads to genes or transcripts, and estimating gene or transcript abundance. Our aims are two-fold: to make recommendations for common components of experimental design and assess tool capabilities for each of these steps. We also test tools designed to detect differential expression, since this is the most widespread application of RNA-seq. We hope that these analyses will help guide those who are new to RNA-seq and will generate discussion about remaining needs for tool improvement and development. Curr. Protoc. Hum. Genet. 83:11.13.1-11.13.20. © 2014 by John Wiley & Sons, Inc.
    Preview · Article · Oct 2014 · Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.]
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    Sean Thomas · Jason G Underwood · Elizabeth Tseng · Alisha K Holloway
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    ABSTRACT: The chicken has long served as an important model organism in many fields, and continues to aid our understanding of animal development. Functional genomics studies aimed at probing the mechanisms that regulate development require high-quality genomes and transcript annotations. The quality of these resources has improved dramatically over the last several years, but many isoforms and genes have yet to be identified. We hope to contribute to the process of improving these resources with the data presented here: a set of long cDNA sequencing reads, and a curated set of new genes and transcript isoforms not currently represented in the most up-to-date genome annotation currently available to the community of researchers who rely on the chicken genome.
    Full-text · Article · Apr 2014 · PLoS ONE
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    Dennis Kostka · Tara Friedrich · Alisha K. Holloway · Katherine S. Pollard
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    ABSTRACT: Next-generation sequencing technology enables the identification of thousands of gene regulatory sequences in many cell types and organisms. We consider the problem of testing if two such sequences differ in their number of binding site motifs for a given transcription factor (TF) protein. Binding site motifs impart regulatory function by providing TFs the opportunity to bind to genomic elements and thereby affect the expression of nearby genes. Evolutionary changes to such functional DNA are hypothesized to be major contributors to phenotypic diversity within and between species; but despite the importance of TF motifs for gene expression, no method exists to test for motif loss or gain. Assuming that motif counts are Binomially distributed, and allowing for dependencies between motif instances in evolutionarily related sequences, we derive the probability mass function of the difference in motif counts between two nucleotide sequences. We provide a method to numerically estimate this distribution from genomic data and show through simulations that our estimator is accurate. Finally, we introduce the R package {\tt motifDiverge} that implements our methodology and illustrate its application to gene regulatory enhancers identified by a mouse developmental time course experiment. While this study was motivated by analysis of regulatory motifs, our results can be applied to any problem involving two correlated Bernoulli trials.
    Preview · Article · Jan 2014 · Statistics and its interface
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    ABSTRACT: Large-scale annotation efforts have improved our ability to coarsely predict regulatory elements throughout vertebrate genomes. However, it is unclear how complex spatiotemporal patterns of gene expression driven by these elements emerge from the activity of short, transcription factor binding sequences. We describe a comprehensive promoter extension assay in which the regulatory potential of all 6 base-pair (bp) sequences was tested in the context of a minimal promoter. To enable this large-scale screen, we developed algorithms that use a reverse-complement aware decomposition of the de Bruijn graph to design a library of DNA oligomers incorporating every 6-bp sequence exactly once. Our library multiplexes all 4,096 unique 6-mers into 184 double-stranded 15-bp oligomers, which is sufficiently compact for in vivo testing. We injected each multiplexed construct into zebrafish embryos and scored GFP expression in 15 tissues at two developmental time points. Twenty-seven constructs produced consistent expression patterns, with the majority doing so in only one tissue. Functional sequences are enriched near biologically relevant genes, match motifs for developmental transcription factors, and are required for enhancer activity. By concatenating tissue-specific functional sequences, we generated completely synthetic enhancers for the notochord, epidermis, spinal cord, forebrain and otic lateral line, and show that short regulatory sequences do not always function modularly. This work introduces a unique in vivo catalog of short, functional regulatory sequences and demonstrates several important principles of regulatory element organization. Furthermore, we provide resources for designing compact, reverse-complement aware k-mer libraries.
    Full-text · Article · Jul 2013 · Genome biology
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    ABSTRACT: Background: We describe the genome of the western painted turtle, Chrysemys picta bellii, one of the most widespread, abundant, and well-studied turtles. We place the genome into a comparative evolutionary context, and focus on genomic features associated with tooth loss, immune function, longevity, sex differentiation and determination, and the species' physiological capacities to withstand extreme anoxia and tissue freezing. Results: Our phylogenetic analyses confirm that turtles are the sister group to living archosaurs, and demonstrate an extraordinarily slow rate of sequence evolution in the painted turtle. The ability of the painted turtle to withstand complete anoxia and partial freezing appears to be associated with common vertebrate gene networks, and we identify candidate genes for future functional analyses. Tooth loss shares a common pattern of pseudogenization and degradation of tooth-specific genes with birds, although the rate of accumulation of mutations is much slower in the painted turtle. Genes associated with sex differentiation generally reflect phylogeny rather than convergence in sex determination functionality. Among gene families that demonstrate exceptional expansions or show signatures of strong natural selection, immune function and musculoskeletal patterning genes are consistently over-represented. Conclusions: Our comparative genomic analyses indicate that common vertebrate regulatory networks, some of which have analogs in human diseases, are often involved in the western painted turtle's extraordinary physiological capacities. As these regulatory pathways are analyzed at the functional level, the painted turtle may offer important insights into the management of a number of human health disorders.
    Full-text · Article · Mar 2013 · Genome biology
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    Bin Z He · Alisha K Holloway · Sebastian J Maerkl · Martin Kreitman

    Full-text · Dataset · Dec 2012
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    ABSTRACT: Heart development is exquisitely sensitive to the precise temporal regulation of thousands of genes that govern developmental decisions during differentiation. However, we currently lack a detailed understanding of how chromatin and gene expression patterns are coordinated during developmental transitions in the cardiac lineage. Here, we interrogated the transcriptome and several histone modifications across the genome during defined stages of cardiac differentiation. We find distinct chromatin patterns that are coordinated with stage-specific expression of functionally related genes, including many human disease-associated genes. Moreover, we discover a novel preactivation chromatin pattern at the promoters of genes associated with heart development and cardiac function. We further identify stage-specific distal enhancer elements and find enriched DNA binding motifs within these regions that predict sets of transcription factors that orchestrate cardiac differentiation. Together, these findings form a basis for understanding developmentally regulated chromatin transitions during lineage commitment and the molecular etiology of congenital heart disease.
    Full-text · Article · Sep 2012 · Cell
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    ABSTRACT: This report of independent genome sequences of two natural populations of Drosophila melanogaster (37 from North America and 6 from Africa) provides unique insight into forces shaping genomic polymorphism and divergence. Evidence of interactions between natural selection and genetic linkage is abundant not only in centromere- and telomere-proximal regions, but also throughout the euchromatic arms. Linkage disequilibrium, which decays within 1 kbp, exhibits a strong bias toward coupling of the more frequent alleles and provides a high-resolution map of recombination rate. The juxtaposition of population genetics statistics in small genomic windows with gene structures and chromatin states yields a rich, high-resolution annotation, including the following: (1) 5'- and 3'-UTRs are enriched for regions of reduced polymorphism relative to lineage-specific divergence; (2) exons overlap with windows of excess relative polymorphism; (3) epigenetic marks associated with active transcription initiation sites overlap with regions of reduced relative polymorphism and relatively reduced estimates of the rate of recombination; (4) the rate of adaptive nonsynonymous fixation increases with the rate of crossing over per base pair; and (5) both duplications and deletions are enriched near origins of replication and their density correlates negatively with the rate of crossing over. Available demographic models of X and autosome descent cannot account for the increased divergence on the X and loss of diversity associated with the out-of-Africa migration. Comparison of the variation among these genomes to variation among genomes from D. simulans suggests that many targets of directional selection are shared between these species.
    Full-text · Article · Jun 2012 · Genetics
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    E Patterson · R Webb · A Weisbrod · B Bian · M He · L Zhang · AK Holloway · R Krishna · N Nilubol · K Pacak · E Kebebew
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    ABSTRACT: Currently, the diagnosis of malignant pheochromocytoma can only be made when there is clinical evidence of metastasis or extensive local invasion. Thus, there is a need for new diagnostic marker(s) to identify tumors with malignant potential. The purpose of this study was to identify microRNAs (miRNAs) that are differentially expressed between benign and malignant pheochromocytomas and assess their diagnostic accuracy. Toward this aim, we analyzed miRNA expression in benign and malignant pheochromocytoma tumor samples using whole genome microarray profiling. Microarray analysis identified eight miRNAs that were significantly differentially expressed between benign and malignant pheochromocytomas. We measured a subset of these miRNAs directly by RT-PCR and found that miR-483-5p, miR-183, and miR-101 had significantly higher expression in malignant tumors as compared to their benign counterparts. Area under the receiver operating curve (AUC) analysis indicated that miR-483-5p, miR-101, and miR-183 could be useful diagnostic markers for distinguishing malignant from benign pheochromocytomas. In addition, these miRNAs could be detected in pheochromocytoma patient serum. Overall our data suggest that misexpression of miR-483-5p, miR-101, and miR-183 is associated with malignant pheochromocytoma.
    Preview · Article · Jan 2012 · Endocrine Related Cancer
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    ABSTRACT: The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.
    Full-text · Article · Oct 2011 · Nature
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    Yin Xiong · Lisa Zhang · Alisha K Holloway · Xiaolin Wu · Ling Su · Electron Kebebew
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    ABSTRACT: The molecular basis and characteristics of familial non-medullary thyroid cancer are poorly understood. In this study, we performed microRNA (miRNA) profiling of familial and sporadic papillary thyroid cancer tumor samples. Genome wide miRNA profiling of sporadic and familial papillary thyroid cancer was performed. Differentially expressed miRNAs were validated by quantitative RT-PCR. Ectopic expression of miR-886-3p in thyroid cancer lines was performed to identify pathways targeted by the miRNA, as well as, to determine its effect on tumor cell biology. We found four differentially expressed miRNAs between familial and sporadic papillary thyroid cancer tumor samples. MiR-886-3p and miR-20a were validated to be differentially expressed by 3- and 4-fold, respectively. Pathway analysis of genome-wide expression data on cells overexpressing miR-886-3p and target prediction analysis showed genes involved in DNA replication and focal adhesion pathways were regulated by miR-886-3p. Overexpression of miR-886-3p in thyroid cancer cell lines significantly inhibited cellular proliferation, the number and size of spheroids and cellular migration. Additionally, overexpression of miR-886-3p increased the number of cells in S phase. Our findings for the first time suggest that miR-886-3p plays an important role in thyroid cancer tumor cell biology and regulates genes involved in DNA replication and focal adhesion. Thus, miR-886-3p may play a role in the initiation and or progression of papillary thyroid cancer.
    Preview · Article · Oct 2011 · PLoS ONE
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    ABSTRACT: Assignment of alleles to haplotypes for nearly all the variants on all chromosomes can be performed by genetic analysis of a nuclear family with three or more children. Whole-genome sequence data enable deterministic phasing of nearly all sequenced alleles by permitting assignment of recombinations to precise chromosomal positions and specific meioses. We demonstrate this process of genetic phasing on two families each with four children. We generate haplotypes for all of the children and their parents; these haplotypes span all genotyped positions, including rare variants. Misassignments of phase between variants (switch errors) are nearly absent. Our algorithm can also produce multimegabase haplotypes for nuclear families with just two children and can handle families with missing individuals. We implement our algorithm in a suite of software scripts (Haploscribe). Haplotypes and family genome sequences will become increasingly important for personalized medicine and for fundamental biology.
    Full-text · Article · Aug 2011 · The American Journal of Human Genetics
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    Dataset: Figure S7
    Bin Z. He · Alisha K. Holloway · Sebastian J. Maerkl · Martin Kreitman
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    ABSTRACT: PWM derived from mel footprints (PWMmel) or their aligned sequences in sim (PWMsim) produce consistent results under our classification method. On the scatter plot each point represents a single nucleotide mutation with its x, y values being the estimates of its effect on binding affinity using either the mel PWM or the sim PWM, respectively. Green and red triangles are mutations occurring on mel or sim lineages. From the figure, the PWM have very little biases with respect to scoring mutations from the species where it is derived or the other species. (PDF)
    Preview · Dataset · Apr 2011
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    Dataset: Figure S3
    Bin Z. He · Alisha K. Holloway · Sebastian J. Maerkl · Martin Kreitman
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    ABSTRACT: PWM based on mel footprints and SELEX PWM produce consistent results. Each point represents one substitution and its x, y values are the estimates of its effect on binding affinity using the footprint PWM or the SELEX PWM, respectively. 33/34 strong-effect substitutions are consistently assigned by the two sets of PWM into either affinity-increasing or affinity-decreasing categories. (PDF)
    Preview · Dataset · Apr 2011
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    Dataset: Figure S4
    Bin Z. He · Alisha K. Holloway · Sebastian J. Maerkl · Martin Kreitman
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    ABSTRACT: Impact of ascertainment on the detectability of a mutation in mel. Each box represents a TFBS, where orange indicates relatively strong binding affinity while greens indicates weak affinity. Each column is an alignment of a sample of six mel alleles with the inferred ancestral allele. In the first column, a fixed affinity-decreasing mutation in mel with a relatively large effect makes the TFBS not detectable as a footprint. In column 2 and 3, the affinity-decreasing mutations are not fixed but segregating, therefore the probability of not detecting the TFBS is proportional to the derived allele frequency (assuming a random mel allele is used in the footprint assay). Column 3–6 illustrate the situation for affinity-increasing mutations, where the substitutions are always detectable but the segregating mutations are detected with higher probability when the derived allele frequency is low. The last two columns represent cases where both alleles are detectable. To incorporate the uncertainty in the detectability of the low-affinity allele, we define a parameter f for the probability that the weak allele is not detectable. (PDF)
    Preview · Dataset · Apr 2011
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    Dataset: Figure S8
    Bin Z. He · Alisha K. Holloway · Sebastian J. Maerkl · Martin Kreitman
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    ABSTRACT: A geneaology tree based on 10 kb CRM sequences for 162 lines from DGRP and the Berkeley reference sequencing strain. The tree is built in MEGA using maximum likelihood method, based on 10 kb sequence alignments. It is rooted with one sequence from a closely related species D. sechellia as an outgroup (bold and blue). The reference sequencing strain (referred to as lab, bold and red) is obviously inter-mingled with the other 162 lines. A similar procedure on 3 different 10 kb sequences sampled from the genome produced similar shaped trees with the lab line embedded among the 162 lines, although the exact orders of branches are not the same, reflecting different geneaologies between regions in the genome. (PDF)
    Preview · Dataset · Apr 2011

Publication Stats

2k Citations
320.21 Total Impact Points

Top Journals

Institutions

  • 2010-2015
    • University of California, San Francisco
      • Gladstone Institute
      San Francisco, California, United States
    • J. David Gladstone Institutes
      San Francisco, California, United States
  • 2014
    • CSU Mentor
      Long Beach, California, United States
  • 2012
    • University of California, Berkeley
      • Department of Statistics
      Berkeley, California, United States
  • 2011
    • San Francisco Estuary Institute
      San Francisco, California, United States
  • 2004-2010
    • University of California, Davis
      • • Center for Population Biology
      • • Department of Evolution & Ecology
      Davis, California, United States
  • 2006
    • University of Texas at Austin
      • Department of Integrative Biology
      Texas City, TX, United States