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Detecting clusters of mutations.

ABSTRACT: Positive selection for protein function can lead to multiple mutations within a small stretch of DNA, i.e., to a cluster of mutations. Recently, Wagner proposed a method to detect such mutation clusters. His method, however, did not take into account that residues with high solvent accessibility are inherently more variable than residues with low solvent accessibility. Here, we propose a new algorithm to detect clustered evolution. Our algorithm controls for different substitution probabilities at buried and exposed sites in the tertiary protein structure, and uses random permutations to calculate accurate P values for inferred clusters. We apply the algorithm to genomes of bacteria, fly, and mammals, and find several clusters of mutations in functionally important regions of proteins. Surprisingly, clustered evolution is a relatively rare phenomenon. Only between 2% and 10% of the genes we analyze contain a statistically significant mutation cluster. We also find that not controlling for solvent accessibility leads to an excess of clusters in terminal and solvent-exposed regions of proteins. Our algorithm provides a novel method to identify functionally relevant divergence between groups of species. Moreover, it could also be useful to detect artifacts in automatically assembled genomes.

SUBMITTER: Zhou T

PROVIDER: S-EPMC2582452 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Detecting clusters of mutations.

Zhou Tong T Enyeart Peter J PJ Wilke Claus O CO

PloS one 20081119 11

Positive selection for protein function can lead to multiple mutations within a small stretch of DNA, i.e., to a cluster of mutations. Recently, Wagner proposed a method to detect such mutation clusters. His method, however, did not take into account that residues with high solvent accessibility are inherently more variable than residues with low solvent accessibility. Here, we propose a new algorithm to detect clustered evolution. Our algorithm controls for different substitution probabilities ...[more]

PMID: 19018282

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Project description:BackgroundPeople with HIV infection in the United States are often affected by chronic viral hepatitis. These coinfected people with either HBV or HCV are at increased risk for serious, life-threatening complications. Coinfections with viral hepatitis may also complicate the delivery of anti-retroviral therapy (ART) by escalating the risk of drug-related hepatoxicity. According to the Centers for Disease Control and Prevention (CDC), approximately 10 percent of people with HIV in the United States also have HBV, and 25 percent also have HCV coinfection. With the advent of highly active antiretroviral therapy (HAART) and the increased life-expectancy of HIV patients, clinicians are more likely to be confronted with issues related to co-infection and the management challenges that they present, especially in resource-limited settings. The purpose of this analysis was to identify geographical clusters of HIV- (HBV/HCV) co-infection and compared to the geographical clusters of not co-infected using DC, Department of Health surveillance data. The results of the analysis will be used to target resources to areas at risk.MethodsHIV and Hepatitis surveillance data were matched among cases diagnosed between 1980 and 2016. HIV-hepatitis co-infected and the not co-infected spatial clusters were detected using discrete Poisson model. Kulldorff's spatial scan statistic method was implemented in the free software tool called SaTScan which has been widely adopted for detecting disease cluster. The analysis was conducted by tracts, but for visualization, ease of interpretation and assist in policy making the tract map was overlaid with the ward map using ArcGIS 10.5.1.ResultsBetween 1980 and 2016, there were 12,965 diagnosed cases of HIV, of which 2,316 HIV/Hepatitis matches were identified. Of the 2316 co-infected people living in DC, 25 percent (N = 590) of people had HBV, and 75 percent (N = 1,726) had HCV. Out of 12,965 diagnosed cases, remaining 10,649 did not have any co-infections (not co-infected). IDU (27.16 percent) and MSM (32.86 percent) were the highest mode of transmission for co-infected population. African-American were reported 83.64 percent (N = 1,937) among co-infection population. Three clusters were identified for both co-infected population in DC. The largest cluster radius for co-infected analysis covers wards 6, 7 and 8 as well as large parts of 2 and 5 (p < 0.001). Multiple clusters were identified for not co-infected population (p < 0.001). IDU (n = 450) was the highest mode of transmission for the co-infected clusters. For all clusters combined of not co-infected population highest mode of transmission were MSM (n = 2,534). This analysis also showed racial disparity, economic deprivation and lack of education were prominent in the co-infected clusters.ConclusionWe identified locations of high risk clusters where enhanced hepatitis and HIV prevention, treatment, and care can help combat the epidemic. The clusters radius expands into the neighboring state of Maryland as well. The findings from this analysis will be used to target area based public health policy and healthcare interventions for HIV-hepatitis. It is recommended based on the analysis that needle exchange programs can successfully control new HIV infections as well as hepatitis co-infections.

Project description:Rapid advance in single-cell RNA sequencing (scRNA-seq) allows measurement of the expression of genes at single-cell resolution in complex disease or tissue. While many methods have been developed to detect cell clusters from the scRNA-seq data, this task currently remains a main challenge. We proposed a multi-objective optimization-based fuzzy clustering approach for detecting cell clusters from scRNA-seq data. First, we conducted initial filtering and SCnorm normalization. We considered various case studies by selecting different cluster numbers ( c l = 2 to a user-defined number), and applied fuzzy c-means clustering algorithm individually. From each case, we evaluated the scores of four cluster validity index measures, Partition Entropy ( P E ), Partition Coefficient ( P C ), Modified Partition Coefficient ( M P C ), and Fuzzy Silhouette Index ( F S I ). Next, we set the first measure as minimization objective (?) and the remaining three as maximization objectives (?), and then applied a multi-objective decision-making technique, TOPSIS, to identify the best optimal solution. The best optimal solution (case study) that had the highest TOPSIS score was selected as the final optimal clustering. Finally, we obtained differentially expressed genes (DEGs) using Limma through the comparison of expression of the samples between each resultant cluster and the remaining clusters. We applied our approach to a scRNA-seq dataset for the rare intestinal cell type in mice [GEO ID: GSE62270, 23,630 features (genes) and 288 cells]. The optimal cluster result (TOPSIS optimal score= 0.858) comprised two clusters, one with 115 cells and the other 91 cells. The evaluated scores of the four cluster validity indices, F S I , P E , P C , and M P C for the optimized fuzzy clustering were 0.482, 0.578, 0.607, and 0.215, respectively. The Limma analysis identified 1240 DEGs (cluster 1 vs. cluster 2). The top ten gene markers were Rps21, Slc5a1, Crip1, Rpl15, Rpl3, Rpl27a, Khk, Rps3a1, Aldob and Rps17. In this list, Khk (encoding ketohexokinase) is a novel marker for the rare intestinal cell type. In summary, this method is useful to detect cell clusters from scRNA-seq data.

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Detecting clusters of mutations.

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Detecting clusters of mutations.

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