Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.

/pdf/gut-brain-axis-and-the-microbiota-3ksluuopxy.pdf

Gut/brain axis and the microbiota

The effective population sizes of ancestral as well as modern species are important parameters in models of population genetics and human evolution. The commonly used method for estimating ancestral population sizes, based on counting mismatches between the species tree and the inferred gene trees, is highly biased as it ignores uncertainties in gene tree reconstruction. In this article, we develop a Bayes method for simultaneous estimation of the species divergence times and current and ancestral population sizes. The method uses DNA sequence data from multiple loci and extracts information about conflicts among gene tree topologies and coalescent times to estimate ancestral population sizes. The topology of the species tree is assumed known. A Markov chain Monte Carlo algorithm is implemented to integrate over uncertain gene trees and branch lengths (or coalescence times) at each locus as well as species divergence times. The method can handle any species tree and allows different numbers of sequences at different loci. We apply the method to published noncoding DNA sequences from the human and the great apes. There are strong correlations between posterior estimates of speciation times and ancestral population sizes. With the use of an informative prior for the human-chimpanzee divergence date, the population size of the common ancestor of the two species is estimated to be ∼20,000, with a 95% credibility interval (8000, 40,000). Our estimates, however, are affected by model assumptions as well as data quality. We suggest that reliable estimates have yet to await more data and more realistic models.

/pdf/bayes-estimation-of-species-divergence-times-and-ancestral-37hkcsc1uc.pdf

Bayes Estimation of Species Divergence Times and Ancestral Population Sizes Using DNA Sequences From Multiple Loci

Saliva is a readily accessible and informative biofluid, making it ideal for the early detection of a wide range of diseases including cardiovascular, renal, and autoimmune diseases, viral and bacterial infections and, importantly, cancers. Saliva-based diagnostics, particularly those based on metabolomics technology, are emerging and offer a promising clinical strategy, characterizing the association between salivary analytes and a particular disease. Here, we conducted a comprehensive metabolite analysis of saliva samples obtained from 215 individuals (69 oral, 18 pancreatic and 30 breast cancer patients, 11 periodontal disease patients and 87 healthy controls) using capillary electrophoresis time-of-flight mass spectrometry (CE-TOF-MS). We identified 57 principal metabolites that can be used to accurately predict the probability of being affected by each individual disease. Although small but significant correlations were found between the known patient characteristics and the quantified metabolites, the profiles manifested relatively higher concentrations of most of the metabolites detected in all three cancers in comparison with those in people with periodontal disease and control subjects. This suggests that cancer-specific signatures are embedded in saliva metabolites. Multiple logistic regression models yielded high area under the receiver-operating characteristic curves (AUCs) to discriminate healthy controls from each disease. The AUCs were 0.865 for oral cancer, 0.973 for breast cancer, 0.993 for pancreatic cancer, and 0.969 for periodontal diseases. The accuracy of the models was also high, with cross-validation AUCs of 0.810, 0.881, 0.994, and 0.954, respectively. Quantitative information for these 57 metabolites and their combinations enable us to predict disease susceptibility. These metabolites are promising biomarkers for medical screening.

/pdf/capillary-electrophoresis-mass-spectrometry-based-saliva-tgrf48vj19.pdf

Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles

Human DNA sequence variation data are useful for studying the origin, evolution, and demographic history of modern humans and the mechanisms of maintenance of genetic variability in human populations, and for detecting linkage association of disease. Here, we report worldwide variation data from a approximately 10-kilobase noncoding autosomal region. We identified 75 variant sites in 64 humans (128 sequences) and 463 variant sites among the human, chimpanzee, and orangutan sequences. Statistical tests suggested that the region is selectively neutral. The average nucleotide diversity (pi) across the region was 0.088% among all of the human sequences obtained, 0.085% among African sequences, and 0.082% among non-African sequences, supporting the view of a low nucleotide diversity ( approximately 0.1%) in humans. The comparable pi value in non-Africans to that in Africans indicates no severe bottleneck during the evolution of modern non-Africans; however, the possibility of a mild bottleneck cannot be excluded because non-Africans showed considerably fewer variants than Africans. The present and two previous large data sets all show a strong excess of low frequency variants in comparison to that expected from an equilibrium population, indicating a relatively recent population expansion. The mutation rate was estimated to be 1.15 x 10(-9) per nucleotide per year. Estimates of the long-term effective population size N(e) by various statistical methods were similar to those in other studies. The age of the most recent common ancestor was estimated to be approximately 1.29 million years ago among all of the sequences obtained and approximately 634,000 years ago among the non-African sequences, providing the first evidence from a noncoding autosomal region for ancient human histories, even among non-Africans.

https://www.pnas.org/content/pnas/97/21/11354.full.pdf

Worldwide DNA sequence variation in a 10-kilobase noncoding region on human chromosome 22

Structure of the omega-aminocarboxylic acid-binding sites of human plasminogen. Arginine 70 and aspartic acid 56 are essential for binding of ligand by kringle 4.

Here we show that Lgl1 protein, cub-1-related proteins, coch-5b2-related proteins, coagulation factor C of horse-shoe crab and a predicted protein of Plasmodium falciparum share a homologous domain. Since this domain-type was first identified in Limulus factor C, Coch-5b2 and Lgl1 we propose the name LCCL for this domain-family. The LCCL module of coch-5b2 is of special biological interest because it has been shown recently that mutations affecting this module cause the deafness disorder DFNA9 in humans. With a view to defining the structure and function of the LCCL domain of human coch-5b2 protein, we have expressed it in Escherichia coli and subjected it to preliminary structural characterization. Structure prediction and circular dichroism studies on the recombinant protein indicate that the domain possesses both alpha helices and beta strands. It is shown that the mutations which cause hearing loss in humans affect residues that are critical for the integrity of the LCCL module of the coch-5b2 protein.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1432-1327.2000.01641.x

The LCCL module.

By using sensitive homology-search and gene-finding programs, we have found that a genomic region from the tip of the short arm of human chromosome 16 (16p13.3) encodes a putative secreted protein consisting of a domain related to the whey acidic protein (WAP) domain, a domain homologous with follistatin modules of the Kazal-domain family (FS module), an immunoglobulin-related domain (Ig domain), two tandem domains related to Kunitz-type protease inhibitor modules (KU domains), and a domain belonging to the recently defined NTR-module family (NTR domain). The gene encoding these WAP, FS, Ig, KU, and NTR modules (hereafter referred to as the WFIKKN gene) is intron-depleted--its single 1,157-bp intron splits the WAP module. The validity of our gene prediction was confirmed by sequencing a WFIKKN cDNA cloned from a lung cDNA library. Studies on the tissue-expression pattern of the WFIKKN gene have shown that the gene is expressed primarily in pancreas, kidney, liver, placenta, and lung. As to the function of the WFIKKN protein, it is noteworthy that it contains FS, WAP, and KU modules, i.e., three different module types homologous with domains frequently involved in inhibition of serine proteases. The protein also contains an NTR module, a domain type implicated in inhibition of zinc metalloproteinases of the metzincin family. On the basis of its intriguing homologies, we suggest that the WFIKKN protein is a multivalent protease inhibitor that may control the action of multiple types of serine proteases as well as metalloproteinase(s).

https://www.pnas.org/content/pnas/98/7/3705.full.pdf

A human protein containing multiple types of protease-inhibitory modules

Kringle 4, an 88-residue plasminogen fragment carrying a lysine-binding site, loses its affinity for lysine-Sepharose upon reductive cleavage of its disulfide bridges. Aerobic incubation of the reduced, denatured fragment results in the rapid restoration of the disulfide bonds with concomitant recovery of lysine-Sepharose affinity. The ability of the unfolded fragment to regain its native conformation suggests that the kringle structure is an autonomous folding domain. During refolding of kringle 4 the native disulfide bonds, (formula; see text) and (formula; see text), appears first. The folding intermediate possessing these two disulfide bridges already binds to lysine-Sepharose, indicating that the third native bridge, which in native kringle 4 connects residues Cys1 and Cys79, is not essential for the maintenance of the biologically active conformation of kringle 4. Comparison of the sequences of human prothrombin, urokinase, and plasminogen kringles revealed that the residues surrounding the (formula; see text) and (formula; see text) bridges constitute the most conservative segments of kringles, whereas the residues neighboring the (formula; see text) bridge are not highly conserved. We propose that conservation of various residues in the different kringles reflects their importance for the folding autonomy of kringles.

Folding autonomy of the kringle 4 fragment of human plasminogen

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