Browsing by Author "Cirulli, Elizabeth T"

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    Common genetic variation and the control of HIV-1 in humans.
    (PLoS Genet, 2009-12) Fellay, Jacques; Ge, Dongliang; Shianna, Kevin V; Colombo, Sara; Ledergerber, Bruno; Cirulli, Elizabeth T; Urban, Thomas J; Zhang, Kunlin; Gumbs, Curtis E; Smith, Jason P; Castagna, Antonella; Cozzi-Lepri, Alessandro; De Luca, Andrea; Easterbrook, Philippa; Günthard, Huldrych F; Mallal, Simon; Mussini, Cristina; Dalmau, Judith; Martinez-Picado, Javier; Miro, José M; Obel, Niels; Wolinsky, Steven M; Martinson, Jeremy J; Detels, Roger; Margolick, Joseph B; Jacobson, Lisa P; Descombes, Patrick; Antonarakis, Stylianos E; Beckmann, Jacques S; O'Brien, Stephen J; Letvin, Norman L; McMichael, Andrew J; Haynes, Barton F; Carrington, Mary; Feng, Sheng; Telenti, Amalio; Goldstein, David B; NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
    To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.
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    Factors affecting pitch discrimination performance in a cohort of extensively phenotyped healthy volunteers.
    (Scientific reports, 2017-11-28) Smith, Lauren M; Bartholomew, Alex J; Burnham, Lauren E; Tillmann, Barbara; Cirulli, Elizabeth T
    Despite efforts to characterize the different aspects of musical abilities in humans, many elements of this complex area remain unknown. Musical abilities are known to be associated with factors like intelligence, training, and sex, but a comprehensive evaluation of the simultaneous impact of multiple factors has not yet been performed. Here, we assessed 918 healthy volunteers for pitch discrimination abilities-their ability to tell two tones close in pitch apart. We identified the minimal threshold that the participants could detect, and we found that better performance was associated with higher intelligence, East Asian ancestry, male sex, younger age, formal music training-especially before age 6-and English as the native language. All these factors remained significant when controlling for the others, with general intelligence, musical training, and male sex having the biggest impacts. We also performed a small GWAS and gene-based collapsing analysis, identifying no significant associations. Future genetic studies of musical abilities should involve large sample sizes and an unbiased genome-wide approach, with the factors highlighted here included as important covariates.
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    Individual Variation in Contagious Yawning Susceptibility Is Highly Stable and Largely Unexplained by Empathy or Other Known Factors
    (PLoS One, 2014-03-14) Bartholomew, Alex J; Cirulli, Elizabeth T
    The contagious aspect of yawning is a well-known phenomenon that exhibits variation in the human population. Despite the observed variation, few studies have addressed its intra-individual reliability or the factors modulating differences in the susceptibility of healthy volunteers. Due to its obvious biological basis and impairment in diseases like autism and schizophrenia, a better understanding of this trait could lead to novel insights into these conditions and the general biological functioning of humans. We administered 328 participants a 3-minute yawning video stimulus, a cognitive battery, and a comprehensive questionnaire that included measures of empathy, emotional contagion, circadian energy rhythms, and sleepiness. Individual contagious yawning measurements were found to be highly stable across testing sessions, both in a lab setting and if administered remotely online, confirming that certain healthy individuals are less susceptible to contagious yawns than are others. Additionally, most individuals who failed to contagiously yawn in our study were not simply suppressing their reaction, as they reported not even feeling like yawning in response to the stimulus. In contrast to previous studies indicating that empathy, time of day, or intelligence may influence contagious yawning susceptibility, we found no influence of these variables once accounting for the age of the participant. Participants were less likely to show contagious yawning as their age increased, even when restricting to ages of less than 40 years. However, age was only able to explain 8% of the variability in the contagious yawn response. The vast majority of the variability in this extremely stable trait remained unexplained, suggesting that studies of its inheritance are warranted.
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    Screening the human exome: a comparison of whole genome and whole transcriptome sequencing.
    (Genome Biol, 2010) Cirulli, Elizabeth T; Singh, Abanish; Shianna, Kevin V; Ge, Dongliang; Smith, Jason P; Maia, Jessica M; Heinzen, Erin L; Goedert, James J; Goldstein, David B; Center for HIV/AIDS Vaccine Immunology (CHAVI)
    BACKGROUND: There is considerable interest in the development of methods to efficiently identify all coding variants present in large sample sets of humans. There are three approaches possible: whole-genome sequencing, whole-exome sequencing using exon capture methods, and RNA-Seq. While whole-genome sequencing is the most complete, it remains sufficiently expensive that cost effective alternatives are important. RESULTS: Here we provide a systematic exploration of how well RNA-Seq can identify human coding variants by comparing variants identified through high coverage whole-genome sequencing to those identified by high coverage RNA-Seq in the same individual. This comparison allowed us to directly evaluate the sensitivity and specificity of RNA-Seq in identifying coding variants, and to evaluate how key parameters such as the degree of coverage and the expression levels of genes interact to influence performance. We find that although only 40% of exonic variants identified by whole genome sequencing were captured using RNA-Seq; this number rose to 81% when concentrating on genes known to be well-expressed in the source tissue. We also find that a high false positive rate can be problematic when working with RNA-Seq data, especially at higher levels of coverage. CONCLUSIONS: We conclude that as long as a tissue relevant to the trait under study is available and suitable quality control screens are implemented, RNA-Seq is a fast and inexpensive alternative approach for finding coding variants in genes with sufficiently high expression levels.
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    The characterization of twenty sequenced human genomes.
    (PLoS Genet, 2010-09-09) Pelak, Kimberly; Shianna, Kevin V; Ge, Dongliang; Maia, Jessica M; Zhu, Mingfu; Smith, Jason P; Cirulli, Elizabeth T; Fellay, Jacques; Dickson, Samuel P; Gumbs, Curtis E; Heinzen, Erin L; Need, Anna C; Ruzzo, Elizabeth K; Singh, Abanish; Campbell, C Ryan; Hong, Linda K; Lornsen, Katharina A; McKenzie, Alexander M; Sobreira, Nara LM; Hoover-Fong, Julie E; Milner, Joshua D; Ottman, Ruth; Haynes, Barton F; Goedert, James J; Goldstein, David B
    We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.
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    Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene
    (PLoS Genetics, 2010-06-17) Sobreira, Nara LM; Cirulli, Elizabeth T; Avramopoulos, Dimitrios; Wohler, Elizabeth; Oswald, Gretchen L; Stevens, Eric L; Ge, Dongliang; Shianna, Kevin V; Smith, Jason P; Maia, Jessica M; Gumbs, Curtis E; Pevsner, Jonathan; Thomas, George; Valle, David; Hoover-Fong, Julie E; Goldstein, David B