ASU Regents' Professors Open Access Works
The title “Regents’ Professor” is the highest faculty honor awarded at Arizona State University. It is conferred on ASU faculty who have made pioneering contributions in their areas of expertise, who have achieved a sustained level of distinction, and who enjoy national and international recognition for these accomplishments. This collection contains primarily open access works by ASU Regents' Professors.
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- Creators: Stone, Anne
Description
Zoonotic pathogens that cause leprosy (Mycobacterium leprae) and tuberculosis (Mycobacterium tuberculosis complex, MTBC) continue to impact modern human populations. Therefore, methods able to survey mycobacterial infection in potential animal hosts are necessary for proper evaluation of human exposure threats. Here we tested for mycobacterial-specific single- and multi-copy loci using qPCR. In a trial study in which armadillos were artificially infected with M. leprae, these techniques were specific and sensitive to pathogen detection, while more traditional ELISAs were only specific. These assays were then employed in a case study to detect M. leprae as well as MTBC in wild marmosets. All marmosets were negative for M. leprae DNA, but 14 were positive for the mycobacterial rpoB gene assay. Targeted capture and sequencing of rpoB and other MTBC genes validated the presence of mycobacterial DNA in these samples and revealed that qPCR is useful for identifying mycobacterial-infected animal hosts.
ContributorsHousman, Genevieve (Author) / Malukiewicz, Joanna (Author) / Boere, Vanner (Author) / Grativol, Adriana D. (Author) / Pereira, Luiz Cezar M. (Author) / de Oliveira e Silva, Ita (Author) / Ruiz-Miranda, Carlos R. (Author) / Truman, Richard (Author) / Stone, Anne (Author) / College of Liberal Arts and Sciences (Contributor) / School of Human Evolution and Social Change (Contributor) / Biodesign Institute (Contributor) / Personalized Diagnostics (Contributor)
Created2015-11-16
Description
Purpose: To evaluate a new method of measuring ocular exposure in the context of a natural blink pattern through analysis of the variables tear film breakup time (TFBUT), interblink interval (IBI), and tear film breakup area (BUA).
Methods: The traditional methodology (Forced-Stare [FS]) measures TFBUT and IBI separately. TFBUT is measured under forced-stare conditions by an examiner using a stopwatch, while IBI is measured as the subject watches television. The new methodology (video capture manual analysis [VCMA]) involves retrospective analysis of video data of fluorescein-stained eyes taken through a slit lamp while the subject watches television, and provides TFBUT and BUA for each IBI during the 1-minute video under natural blink conditions. The FS and VCMA methods were directly compared in the same set of dry-eye subjects. The VCMA method was evaluated for the ability to discriminate between dry-eye subjects and normal subjects. The VCMA method was further evaluated in the dry eye subjects for the ability to detect a treatment effect before, and 10 minutes after, bilateral instillation of an artificial tear solution.
Results: Ten normal subjects and 17 dry-eye subjects were studied. In the dry-eye subjects, the two methods differed with respect to mean TFBUTs (5.82 seconds, FS; 3.98 seconds, VCMA; P = 0.002). The FS variables alone (TFBUT, IBI) were not able to successfully distinguish between the dry-eye and normal subjects, whereas the additional VCMA variables, both derived and observed (BUA, BUA/IBI, breakup rate), were able to successfully distinguish between the dry-eye and normal subjects in a statistically significant fashion. TFBUT (P = 0.034) and BUA/IBI (P = 0.001) were able to distinguish the treatment effect of artificial tears in dry-eye subjects.
Conclusion: The VCMA methodology provides a clinically relevant analysis of tear film stability measured in the context of a natural blink pattern.
Methods: The traditional methodology (Forced-Stare [FS]) measures TFBUT and IBI separately. TFBUT is measured under forced-stare conditions by an examiner using a stopwatch, while IBI is measured as the subject watches television. The new methodology (video capture manual analysis [VCMA]) involves retrospective analysis of video data of fluorescein-stained eyes taken through a slit lamp while the subject watches television, and provides TFBUT and BUA for each IBI during the 1-minute video under natural blink conditions. The FS and VCMA methods were directly compared in the same set of dry-eye subjects. The VCMA method was evaluated for the ability to discriminate between dry-eye subjects and normal subjects. The VCMA method was further evaluated in the dry eye subjects for the ability to detect a treatment effect before, and 10 minutes after, bilateral instillation of an artificial tear solution.
Results: Ten normal subjects and 17 dry-eye subjects were studied. In the dry-eye subjects, the two methods differed with respect to mean TFBUTs (5.82 seconds, FS; 3.98 seconds, VCMA; P = 0.002). The FS variables alone (TFBUT, IBI) were not able to successfully distinguish between the dry-eye and normal subjects, whereas the additional VCMA variables, both derived and observed (BUA, BUA/IBI, breakup rate), were able to successfully distinguish between the dry-eye and normal subjects in a statistically significant fashion. TFBUT (P = 0.034) and BUA/IBI (P = 0.001) were able to distinguish the treatment effect of artificial tears in dry-eye subjects.
Conclusion: The VCMA methodology provides a clinically relevant analysis of tear film stability measured in the context of a natural blink pattern.
ContributorsAbelson, Richard (Author) / Lane, Keith J. (Author) / Angjeli, Endri (Author) / Johnston, Patrick (Author) / Ousler, George (Author) / Montgomery, Douglas (Author) / Ira A. Fulton Schools of Engineering (Contributor) / School of Computing, Informatics and Decision Systems Engineering (Contributor)
Created2011-09-21
Description
Purpose: To investigate use of an improved ocular tear film analysis protocol (OPI 2.0) in the Controlled Adverse Environment (CAE[superscript SM]) model of dry eye disease, and to examine the utility of new metrics in the identification of subpopulations of dry eye patients.
Methods: Thirty-three dry eye subjects completed a single-center, single-visit, pilot CAE study. The primary endpoint was mean break-up area (MBA) as assessed by the OPI 2.0 system. Secondary endpoints included corneal fluorescein staining, tear film break-up time, and OPI 2.0 system measurements. Subjects were also asked to rate their ocular discomfort throughout the CAE. Dry eye endpoints were measured at baseline, immediately following a 90-minute CAE exposure, and again 30 minutes after exposure.
Results: The post-CAE measurements of MBA showed a statistically significant decrease from the baseline measurements. The decrease was relatively specific to those patients with moderate to severe dry eye, as measured by baseline MBA. Secondary endpoints including palpebral fissure size, corneal staining, and redness, also showed significant changes when pre- and post-CAE measurements were compared. A correlation analysis identified specific associations between MBA, blink rate, and palpebral fissure size. Comparison of MBA responses allowed us to identify subpopulations of subjects who exhibited different compensatory mechanisms in response to CAE challenge. Of note, none of the measures of tear film break-up time showed statistically significant changes or correlations in pre-, versus post-CAE measures.
Conclusion: This pilot study confirms that the tear film metric MBA can detect changes in the ocular surface induced by a CAE, and that these changes are correlated with other, established measures of dry eye disease. The observed decrease in MBA following CAE exposure demonstrates that compensatory mechanisms are initiated during the CAE exposure, and that this compensation may provide the means to identify and characterize clinically relevant subpopulations of dry eye patients.
Methods: Thirty-three dry eye subjects completed a single-center, single-visit, pilot CAE study. The primary endpoint was mean break-up area (MBA) as assessed by the OPI 2.0 system. Secondary endpoints included corneal fluorescein staining, tear film break-up time, and OPI 2.0 system measurements. Subjects were also asked to rate their ocular discomfort throughout the CAE. Dry eye endpoints were measured at baseline, immediately following a 90-minute CAE exposure, and again 30 minutes after exposure.
Results: The post-CAE measurements of MBA showed a statistically significant decrease from the baseline measurements. The decrease was relatively specific to those patients with moderate to severe dry eye, as measured by baseline MBA. Secondary endpoints including palpebral fissure size, corneal staining, and redness, also showed significant changes when pre- and post-CAE measurements were compared. A correlation analysis identified specific associations between MBA, blink rate, and palpebral fissure size. Comparison of MBA responses allowed us to identify subpopulations of subjects who exhibited different compensatory mechanisms in response to CAE challenge. Of note, none of the measures of tear film break-up time showed statistically significant changes or correlations in pre-, versus post-CAE measures.
Conclusion: This pilot study confirms that the tear film metric MBA can detect changes in the ocular surface induced by a CAE, and that these changes are correlated with other, established measures of dry eye disease. The observed decrease in MBA following CAE exposure demonstrates that compensatory mechanisms are initiated during the CAE exposure, and that this compensation may provide the means to identify and characterize clinically relevant subpopulations of dry eye patients.
ContributorsAbelson, Richard (Author) / Lane, Keith J. (Author) / Rodriguez, John (Author) / Johnston, Patrick (Author) / Angjeli, Endri (Author) / Ousler, George (Author) / Montgomery, Douglas (Author) / Ira A. Fulton Schools of Engineering (Contributor) / School of Computing, Informatics and Decision Systems Engineering (Contributor)
Created2012-11-12
Description
Recent efforts have attempted to describe the population structure of common chimpanzee, focusing on four subspecies: Pan troglodytes verus, P. t. ellioti, P. t. troglodytes, and P. t. schweinfurthii. However, few studies have pursued the effects of natural selection in shaping their response to pathogens and reproduction. Whey acidic protein (WAP) four-disulfide core domain (WFDC) genes and neighboring semenogelin (SEMG) genes encode proteins with combined roles in immunity and fertility. They display a strikingly high rate of amino acid replacement (dN/dS), indicative of adaptive pressures during primate evolution. In human populations, three signals of selection at the WFDC locus were described, possibly influencing the proteolytic profile and antimicrobial activities of the male reproductive tract. To evaluate the patterns of genomic variation and selection at the WFDC locus in chimpanzees, we sequenced 17 WFDC genes and 47 autosomal pseudogenes in 68 chimpanzees (15 P. t. troglodytes, 22 P. t. verus, and 31 P. t. ellioti). We found a clear differentiation of P. t. verus and estimated the divergence of P. t. troglodytes and P. t. ellioti subspecies in 0.173 Myr; further, at the WFDC locus we identified a signature of strong selective constraints common to the three subspecies in WFDC6—a recent paralog of the epididymal protease inhibitor EPPIN. Overall, chimpanzees and humans do not display similar footprints of selection across the WFDC locus, possibly due to different selective pressures between the two species related to immune response and reproductive biology.
ContributorsFerreira, Zelia (Author) / Hurle, Belen (Author) / Andres, Aida M. (Author) / Kretzschmar, Warren W. (Author) / Mullikin, James C. (Author) / Cherukuri, Praveen F. (Author) / Cruz, Pedro (Author) / Gonder, Mary Katherine (Author) / Stone, Anne (Author) / Tishkoff, Sarah (Author) / Swanson, Willie J. (Author) / Green, Eric D. (Author) / Clark, Andrew G. (Author) / Seixas, Susana (Author) / NISC Comparative Sequencing Program (Author) / College of Liberal Arts and Sciences (Contributor) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor)
Created2013-12-19
Description
Animal hybridization is well documented, but evolutionary outcomes and conservation priorities often differ for natural and anthropogenic hybrids. Among primates, an order with many endangered species, the two contexts can be hard to disentangle from one another, which carries important conservation implications. Callithrix marmosets give us a unique glimpse of genetic hybridization effects under distinct natural and human-induced contexts. Here, we use a 44 autosomal microsatellite marker panel to examine genome-wide admixture levels and introgression at a natural C. jacchus and C. penicillata species border along the Sao Francisco River in NE Brazil and in an area of Rio de Janeiro state where humans introduced these species exotically. Additionally, we describe for the first time autosomal genetic diversity in wild C. penicillata and expand previous C. jacchus genetic data. We characterize admixture within the natural zone as bimodal where hybrid ancestry is biased toward one parental species or the other. We also show evidence that Sao Francisco River islands are gateways for bidirectional gene flow across the species border. In the anthropogenic zone, marmosets essentially form a hybrid swarm with intermediate levels of admixture, likely from the absence of strong physical barriers to interspecific breeding. Our data show that while hybridization can occur naturally, the presence of physical, even if leaky, barriers to hybridization is important for maintaining species genetic integrity. Thus, we suggest further study of hybridization under different contexts to set well informed conservation guidelines for hybrid populations that often fit somewhere between "natural" and "man-made."
ContributorsMalukiewicz, Joanna (Author) / Boere, Vanner (Author) / Fuzessy, Lisieux F. (Author) / Grativol, Adriana D. (Author) / de Oliveira e Silva, Ita (Author) / Pereira, Luiz C. M. (Author) / Ruiz-Miranda, Carlos R. (Author) / Valenca, Yuri M. (Author) / Stone, Anne (Author) / College of Liberal Arts and Sciences (Contributor) / School of Human Evolution and Social Change (Contributor)
Created2015-06-10
Description
Background
Improvements in sequencing technology now allow easy acquisition of large datasets; however, analyzing these data for phylogenetics can be challenging. We have developed a novel method to rapidly obtain homologous genomic data for phylogenetics directly from next-generation sequencing reads without the use of a reference genome. This software, called SISRS, avoids the time consuming steps of de novo whole genome assembly, multiple genome alignment, and annotation.
Results
For simulations SISRS is able to identify large numbers of loci containing variable sites with phylogenetic signal. For genomic data from apes, SISRS identified thousands of variable sites, from which we produced an accurate phylogeny. Finally, we used SISRS to identify phylogenetic markers that we used to estimate the phylogeny of placental mammals. We recovered eight phylogenies that resolved the basal relationships among mammals using datasets with different levels of missing data. The three alternate resolutions of the basal relationships are consistent with the major hypotheses for the relationships among mammals, all of which have been supported previously by different molecular datasets.
Conclusions
SISRS has the potential to transform phylogenetic research. This method eliminates the need for expensive marker development in many studies by using whole genome shotgun sequence data directly. SISRS is open source and freely available at https://github.com/rachelss/SISRS/releases.
Improvements in sequencing technology now allow easy acquisition of large datasets; however, analyzing these data for phylogenetics can be challenging. We have developed a novel method to rapidly obtain homologous genomic data for phylogenetics directly from next-generation sequencing reads without the use of a reference genome. This software, called SISRS, avoids the time consuming steps of de novo whole genome assembly, multiple genome alignment, and annotation.
Results
For simulations SISRS is able to identify large numbers of loci containing variable sites with phylogenetic signal. For genomic data from apes, SISRS identified thousands of variable sites, from which we produced an accurate phylogeny. Finally, we used SISRS to identify phylogenetic markers that we used to estimate the phylogeny of placental mammals. We recovered eight phylogenies that resolved the basal relationships among mammals using datasets with different levels of missing data. The three alternate resolutions of the basal relationships are consistent with the major hypotheses for the relationships among mammals, all of which have been supported previously by different molecular datasets.
Conclusions
SISRS has the potential to transform phylogenetic research. This method eliminates the need for expensive marker development in many studies by using whole genome shotgun sequence data directly. SISRS is open source and freely available at https://github.com/rachelss/SISRS/releases.
ContributorsSchwartz, Rachel (Author) / Harkins, Kelly (Author) / Stone, Anne (Author) / Cartwright, Reed (Author) / Biodesign Institute (Contributor) / Center for Evolution and Medicine (Contributor) / College of Liberal Arts and Sciences (Contributor) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor)
Created2015-06-11
Description
Background
The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers.
Results
To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection.
Conclusions
While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.
The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers.
Results
To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection.
Conclusions
While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.
ContributorsLou, Dianne I. (Author) / McBee, Ross M. (Author) / Le, Uyen Q. (Author) / Stone, Anne (Author) / Wilkerson, Gregory K. (Author) / Demogines, Ann M. (Author) / Sawyer, Sara L. (Author) / College of Liberal Arts and Sciences (Contributor) / School of Human Evolution and Social Change (Contributor) / School of Life Sciences (Contributor)
Created2014-07-11