Exploration of the role of diquarks in hadrons using lattice QCD

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Physics, 2006.Includes bibliographical references (p. 76-78).We perform a number of measurements relevant to nuclear and particle physics by using the tools of lattice QCD. We verify our lattice calculations by reproducing published meson masses. We then study the light quark distribution in a meson with one heavy quark. After improving our methods in the meson case, we conclude by looking at the correlation between the two light quarks in a baryon. We find evidence for these quarks binding into spatially extended diquarks.by Patrick S. Varilly.S.B

A general theory of DNA-mediated and other valence-limited interactions

We present a general theory for predicting the interaction potentials between DNA-coated colloids, and more broadly, any particles that interact via valence-limited ligand-receptor binding. Our theory correctly incorporates the configurational and combinatorial entropic factors that play a key role in valence-limited interactions. By rigorously enforcing self-consistency, it achieves near-quantitative accuracy with respect to detailed Monte Carlo calculations. With suitable approximations and in particular geometries, our theory reduces to previous successful treatments, which are now united in a common and extensible framework. We expect our tools to be useful to other researchers investigating ligand-mediated interactions. A complete and well-documented Python implementation is freely available at http://github.com/patvarilly/DNACC .Comment: 18 pages, 10 figure

The Case for Selection at CCR5-Δ32

The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Δ32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Δ32 arose within the past 1,000 y and rose to its present high frequency (5%–14%) in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Δ32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Δ32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5), they imply that the pattern of genetic variation seen atCCR5-Δ32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome

Genome-wide detection and characterization of positive selection in human populations

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used ‘long-range haplotype’ methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population: LARGE and DMD, both related to infection by the Lassa virus3, in West Africa; SLC24A5 and SLC45A2, both involved in skin pigmentation in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia

Sitting at the edge: How biomolecules use hydrophobicity to tune their interactions and function

Water near hydrophobic surfaces is like that at a liquid-vapor interface, where fluctuations in water density are substantially enhanced compared to that in bulk water. Here we use molecular simulations with specialized sampling techniques to show that water density fluctuations are similarly enhanced, even near hydrophobic surfaces of complex biomolecules, situating them at the edge of a dewetting transition. Consequently, water near these surfaces is sensitive to subtle changes in surface conformation, topology, and chemistry, any of which can tip the balance towards or away from the wet state, and thus significantly alter biomolecular interactions and function. Our work also resolves the long-standing puzzle of why some biological surfaces dewet and other seemingly similar surfaces do not.Comment: 12 pages, 4 figure

Searching for signals of evolutionary selection in 168 genes related to immune function.

Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing immune function. We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency (MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH). Six of the 168 genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent data from the International HapMap Project. These analyses identify two loci involved in immune function that are candidates for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection in genome-wide polymorphism data

Searching for Signals of Evolutionary Selection in 168 Genes Related to Immune Function

Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing immune function. We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency (MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH). Six of the 168 genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent data from the International HapMap Project. These analyses identify two loci involved in immune function that are candidates for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection in genome-wide polymorphism data

Comparisons with Empirical and Simulation Data

<div><p>(A) and (B) Plots of relative EHH versus frequency for <i>CCR5</i> in comparison to HapMap data (release 16) for Chromosome 3 in European-Americans (A) and 1,000 simulations of 400 chromosomes in European-Americans (B). Green dots represent the comparison haplotypes and the lines represent, from bottom to top, the 50th, 75th, 95th, and 99th percentiles. The red dots represent the results for eight <i>CCR5-</i>Δ<i>32</i>-bearing chromosomes in (A) and 32 <i>CCR5-</i>Δ<i>32</i>-bearing chromosomes in (B) for the centromere-proximal side, and the blue dots represent results for the centromere-distal side.</p> <p>(C) EHL of the haplotypes of frequency 6%–10% from the HapMap (solid green line) and from simulations (dotted green line) in comparison to <i>CCR5-</i>Δ<i>32</i> (red line).</p></div

Model of Haplotype-Based Selection Approach

<p>The image compares this approach, where the variants at the gene being studied are fully elaborated, to a model where the variants are not fully elaborated. At the top, multiple SNPs are genotyped to fully define the variants that exist in the gene. The resultant observed haplotype structure is shown in both bifurcation diagram and EHH plot formats (see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030378#s3" target="_blank">Materials and Methods</a>). At the bottom, only one SNP is genotyped, collapsing all other variants into a seemingly diverse super-haplotype and creating an impression of extension for the remaining haplotype.</p