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Search Results: 1 - 10 of 194034 matches for " David B Goldstein "
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The Importance of Synthetic Associations Will Only Be Resolved Empirically
David B. Goldstein
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001008
Abstract:
The Importance of Synthetic Associations Will Only Be Resolved Empirically
David B. Goldstein
PLOS Biology , 2011, DOI: 10.1371/journal.pbio.1001008
Abstract:
Editorial
Li Jin, David B Goldstein
Human Genomics , 2003, DOI: 10.1186/1479-7364-1-1-5
Abstract:
Host Genetics and HIV-1: The Final Phase?
Jacques Fellay ,Kevin V. Shianna,Amalio Telenti,David B. Goldstein
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001033
Abstract: This is a crucial transition time for human genetics in general, and for HIV host genetics in particular. After years of equivocal results from candidate gene analyses, several genome-wide association studies have been published that looked at plasma viral load or disease progression. Results from other studies that used various large-scale approaches (siRNA screens, transcriptome or proteome analysis, comparative genomics) have also shed new light on retroviral pathogenesis. However, most of the inter-individual variability in response to HIV-1 infection remains to be explained: genome resequencing and systems biology approaches are now required to progress toward a better understanding of the complex interactions between HIV-1 and its human host.
Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans
Matthew V. Rockman,Matthew W. Hahn,Nicole Soranzo,Fritz Zimprich,David B. Goldstein,Gregory A. Wray
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0030387
Abstract: Changes in the cis-regulation of neural genes likely contributed to the evolution of our species' unique attributes, but evidence of a role for natural selection has been lacking. We found that positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory. Independent lines of phylogenetic and population genetic evidence support a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee–human hybrid promoters, the selected sequence increases transcriptional inducibility. The evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.
Rare Variants Create Synthetic Genome-Wide Associations
Samuel P. Dickson,Kai Wang,Ian Krantz,Hakon Hakonarson,David B. Goldstein
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000294
Abstract: Genome-wide association studies (GWAS) have now identified at least 2,000 common variants that appear associated with common diseases or related traits (http://www.genome.gov/gwastudies), hundreds of which have been convincingly replicated. It is generally thought that the associated markers reflect the effect of a nearby common (minor allele frequency >0.05) causal site, which is associated with the marker, leading to extensive resequencing efforts to find causal sites. We propose as an alternative explanation that variants much less common than the associated one may create “synthetic associations” by occurring, stochastically, more often in association with one of the alleles at the common site versus the other allele. Although synthetic associations are an obvious theoretical possibility, they have never been systematically explored as a possible explanation for GWAS findings. Here, we use simple computer simulations to show the conditions under which such synthetic associations will arise and how they may be recognized. We show that they are not only possible, but inevitable, and that under simple but reasonable genetic models, they are likely to account for or contribute to many of the recently identified signals reported in genome-wide association studies. We also illustrate the behavior of synthetic associations in real datasets by showing that rare causal mutations responsible for both hearing loss and sickle cell anemia create genome-wide significant synthetic associations, in the latter case extending over a 2.5-Mb interval encompassing scores of “blocks” of associated variants. In conclusion, uncommon or rare genetic variants can easily create synthetic associations that are credited to common variants, and this possibility requires careful consideration in the interpretation and follow up of GWAS signals.
A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans
Anna C Need, Dalia Kasperavi?iūt?, Elizabeth T Cirulli, David B Goldstein
Genome Biology , 2009, DOI: 10.1186/gb-2009-10-1-r7
Abstract: Using a principal components analysis, we found that the individuals with full Jewish ancestry formed a clearly distinct cluster from those individuals with no Jewish ancestry. Using the position on the first principal component axis, every single individual with self-reported full Jewish ancestry had a higher score than any individual with no Jewish ancestry.Here we show that within Americans of European ancestry there is a perfect genetic corollary of Jewish ancestry which, in principle, would permit near perfect genetic inference of Ashkenazi Jewish ancestry. In fact, even subjects with a single Jewish grandparent can be statistically distinguished from those without Jewish ancestry. We also found that subjects with Jewish ancestry were slightly more heterozygous than the subjects with no Jewish ancestry, suggesting that the genetic distinction between Jews and non-Jews may be more attributable to a Near-Eastern origin for Jewish populations than to population bottlenecks.Many genetic and non-genetic lines of evidence make clear that there are differences amongst the Jewish and non-Jewish peoples of Europe. There are both specific genetic diseases (for example, Tay-Sachs) and particular mutations (for example, the breast cancer BRCA1 185delAG mutation) that have considerably higher incidences in Jewish populations, and both Y chromosome and mitochondrial DNA lineages show associations with Jewish heritage [1-5]. No study, however, has directly addressed the question of whether Jewish individuals form a consistently identifiable group on the basis of genetic data alone, as has been documented for other racial/ethnic groups [6]. Recently, Price et al. [7] showed that self-described Jewish ancestry was a major determinant of population genetic structure in European populations, but they did not address the question of whether genetic data might be able to accurately identify which individuals do and do not have Jewish ancestry. Here we investigate whether it is poss
A simple technique for quantifying apoptosis in 96-well plates
Deborah Ribble, Nathaniel B Goldstein, David A Norris, Yiqun G Shellman
BMC Biotechnology , 2005, DOI: 10.1186/1472-6750-5-12
Abstract: We compared our method and the conventional EB/AO method for quantifying apoptosis of suspension cells (Jurkat) and adherent cells (A375) under normal growth and apoptosis-inducing conditions. We found that our new EB/AO method achieved quantification results comparable to those produced using the conventional EB/AO method for both suspension and adherent cells.By eliminating the detaching and washing steps, our method drastically reduces the time needed to perform the test, minimizes damage to adherent cells, and decreases the possibility of losing floating cells. Overall, our method is an improvement over the currently available techniques especially for adherent cells.Apoptosis, a type of programmed cell death, is an active process. It is a normal component of the development and health of multicellular organisms. The study of apoptosis is an important field of biological inquiry since a deficiency or an excess of apoptosis is one of the causes for cancers, autoimmune disorders, diabetes, Alzheimer's, organ and bone marrow transplant rejection, and many other diseases. Accordingly, a quick and easy assay for quantification of apoptosis would be very useful for many biological researchers.Currently, methods available to help detect apoptosis in vitro include several morphological staining methods (such as ethidium bromide and acridine orange (EB/AO) [1,2], DAPI (4; 6-diamidino-2phenylidole) [2], Hoechst staining [2], and etc), Annexin V staining [3-6], DNA ladder [7,8], TUNEL (Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling) [9-11], Caspase-3/7 activity [12-16], and ssDNA staining [17-22]. However, these methods have at least one of the following limitations:All current staining methods, Annexin V, and DNA laddering assays require detaching, washing and transferring the cells. These procedures might damage the cell membranes and change the cell population distribution of live, apoptotic and/or necrotic cells. Procedures with multiple steps al
Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans
Matthew V Rockman ,Matthew W Hahn,Nicole Soranzo,Fritz Zimprich,David B Goldstein,Gregory A Wray
PLOS Biology , 2005, DOI: 10.1371/journal.pbio.0030387
Abstract: Changes in the cis-regulation of neural genes likely contributed to the evolution of our species' unique attributes, but evidence of a role for natural selection has been lacking. We found that positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory. Independent lines of phylogenetic and population genetic evidence support a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee–human hybrid promoters, the selected sequence increases transcriptional inducibility. The evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.
Rare Variants Create Synthetic Genome-Wide Associations
Samuel P. Dickson,Kai Wang,Ian Krantz,Hakon Hakonarson,David B. Goldstein
PLOS Biology , 2010, DOI: 10.1371/journal.pbio.1000294
Abstract: Genome-wide association studies (GWAS) have now identified at least 2,000 common variants that appear associated with common diseases or related traits (http://www.genome.gov/gwastudies), hundreds of which have been convincingly replicated. It is generally thought that the associated markers reflect the effect of a nearby common (minor allele frequency >0.05) causal site, which is associated with the marker, leading to extensive resequencing efforts to find causal sites. We propose as an alternative explanation that variants much less common than the associated one may create “synthetic associations” by occurring, stochastically, more often in association with one of the alleles at the common site versus the other allele. Although synthetic associations are an obvious theoretical possibility, they have never been systematically explored as a possible explanation for GWAS findings. Here, we use simple computer simulations to show the conditions under which such synthetic associations will arise and how they may be recognized. We show that they are not only possible, but inevitable, and that under simple but reasonable genetic models, they are likely to account for or contribute to many of the recently identified signals reported in genome-wide association studies. We also illustrate the behavior of synthetic associations in real datasets by showing that rare causal mutations responsible for both hearing loss and sickle cell anemia create genome-wide significant synthetic associations, in the latter case extending over a 2.5-Mb interval encompassing scores of “blocks” of associated variants. In conclusion, uncommon or rare genetic variants can easily create synthetic associations that are credited to common variants, and this possibility requires careful consideration in the interpretation and follow up of GWAS signals.
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