Search results for: Expectation Maximization (EM) clustering

Authors: Nadezhda M. Usmanova, Nikolai V. Tomilin

Abstract:

Mammalian genomes contain large number of retroelements (SINEs, LINEs and LTRs) which could affect expression of protein coding genes through associated transcription factor binding sites (TFBS). Activity of the retroelement-associated TFBS in many genes is confirmed experimentally but their global functional impact remains unclear. Human SINEs (Alu repeats) and mouse SINEs (B1 and B2 repeats) are known to be clustered in GCrich gene rich genome segments consistent with the view that they can contribute to regulation of gene expression. We have shown earlier that Alu are involved in formation of cis-regulatory modules (clusters of TFBS) in human promoters, and other authors reported that Alu located near promoter CpG islands have an increased frequency of CpG dinucleotides suggesting that these Alu are undermethylated. Human Alu and mouse B1/B2 elements have an internal bipartite promoter for RNA polymerase III containing conserved sequence motif called B-box which can bind basal transcription complex TFIIIC. It has been recently shown that TFIIIC binding to B-box leads to formation of a boundary which limits spread of repressive chromatin modifications in S. pombe. SINEassociated B-boxes may have similar function but conservation of TFIIIC binding sites in SINEs located near mammalian promoters has not been studied earlier. Here we analysed abundance and distribution of retroelements (SINEs, LINEs and LTRs) in annotated sequences of the Database of mammalian transcription start sites (DBTSS). Fractions of SINEs in human and mouse promoters are slightly lower than in all genome but >40% of human and mouse promoters contain Alu or B1/B2 elements within -1000 to +200 bp interval relative to transcription start site (TSS). Most of these SINEs is associated with distal segments of promoters (-1000 to -200 bp relative to TSS) indicating that their insertion at distances >200 bp upstream of TSS is tolerated during evolution. Distribution of SINEs in promoters correlates negatively with the distribution of CpG sequences. Using analysis of abundance of 12-mer motifs from the B1 and Alu consensus sequences in genome and DBTSS it has been confirmed that some subsegments of Alu and B1 elements are poorly conserved which depends in part on the presence of CpG dinucleotides. One of these CpG-containing subsegments in B1 elements overlaps with SINE-associated B-box and it shows better conservation in DBTSS compared to genomic sequences. It has been also studied conservation in DBTSS and genome of the B-box containing segments of old (AluJ, AluS) and young (AluY) Alu repeats and found that CpG sequence of the B-box of old Alu is better conserved in DBTSS than in genome. This indicates that Bbox- associated CpGs in promoters are better protected from methylation and mutation than B-box-associated CpGs in genomic SINEs. These results are consistent with the view that potential TFIIIC binding motifs in SINEs associated with human and mouse promoters may be functionally important. These motifs may protect promoters from repressive histone modifications which spread from adjacent sequences. This can potentially explain well known clustering of SINEs in GC-rich gene rich genome compartments and existence of unmethylated CpG islands.

Keywords: Retroelement, promoter, CpG island, DNAmethylation.

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Authors: Chau-Kuang Chen, Juanita Buford, Colette Davis, Raisha Allen, John Hughes, Jr., James Tyus, Dexter Samuels

Abstract:

During the post-Civil War era, the city of Nashville, Tennessee, had the highest mortality rate in the United States. The elevated death and disease rates among former slaves were attributable to lack of quality healthcare. To address the paucity of healthcare services, Meharry Medical College, an institution with the mission of educating minority professionals and serving the underserved population, was established in 1876. Purpose: The social ecological framework and partial least squares (PLS) path modeling were used to quantify the impact of socioeconomic status and adverse health outcome on primary care professionals serving the disadvantaged community. Thus, the study results could demonstrate the accomplishment of the College’s mission of training primary care professionals to serve in underserved areas. Methods: Various statistical methods were used to analyze alumni data from 1975 – 2013. K-means cluster analysis was utilized to identify individual medical and dental graduates in the cluster groups of the practice communities (Disadvantaged or Non-disadvantaged Communities). Discriminant analysis was implemented to verify the classification accuracy of cluster analysis. The independent t-test was performed to detect the significant mean differences of respective clustering and criterion variables. Chi-square test was used to test if the proportions of primary care and non-primary care specialists are consistent with those of medical and dental graduates practicing in the designated community clusters. Finally, the PLS path model was constructed to explore the construct validity of analytic model by providing the magnitude effects of socioeconomic status and adverse health outcome on primary care professionals serving the disadvantaged community. Results: Approximately 83% (3,192/3,864) of Meharry Medical College’s medical and dental graduates from 1975 to 2013 were practicing in disadvantaged communities. Independent t-test confirmed the content validity of the cluster analysis model. Also, the PLS path modeling demonstrated that alumni served as primary care professionals in communities with significantly lower socioeconomic status and higher adverse health outcome (p < .001). The PLS path modeling exhibited the meaningful interrelation between primary care professionals practicing communities and surrounding environments (socioeconomic statues and adverse health outcome), which yielded model reliability, validity, and applicability. Conclusion: This study applied social ecological theory and analytic modeling approaches to assess the attainment of Meharry Medical College’s mission of training primary care professionals to serve in underserved areas, particularly in communities with low socioeconomic status and high rates of adverse health outcomes. In summary, the majority of medical and dental graduates from Meharry Medical College provided primary care services to disadvantaged communities with low socioeconomic status and high adverse health outcome, which demonstrated that Meharry Medical College has fulfilled its mission. The high reliability, validity, and applicability of this model imply that it could be replicated for comparable universities and colleges elsewhere.

Keywords: Disadvantaged Community, K-means Cluster Analysis, PLS Path Modeling, Primary care.

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