Cardiff University

About: Cardiff University is a education organization based out in Cardiff, United Kingdom. It is known for research contribution in the topics: Population & Context (language use). The organization has 34188 authors who have published 82643 publications receiving 3046531 citations. The organization is also known as: University of Cardiff & University College of South Wales and Monmouthshire.

A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes

Abstract: Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

The Ehrlich Pathway for Fusel Alcohol Production : a Century of Research on Saccharomyces cerevisiae Metabolism

Abstract: Saccharomyces cerevisiae has been used for at least eight millennia in the production of alcoholic beverages (41). Along with ethanol and carbon dioxide, fermenting cultures of this yeast produce many low-molecular-weight flavor compounds. These alcohols, aldehydes, organic acids, esters, organic sulfides, and carbonyl compounds have a strong impact on product quality. Indeed, the subtle aroma balance of these compounds in fermented foods and beverages is often used as an organoleptic fingerprint for specific products and brands (42). Food fermentation by yeast and lactic acid bacteria is accompanied by the formation of the aliphatic and aromatic alcohols known as fusel alcohols. Fusel oil, which derives its name from the German word fusel (bad liquor), is obtained during the distillation of spirits and is enriched with these higher alcohols. While fusel alcohols at high concentrations impart off-flavors, low concentrations of these compounds and their esters make an essential contribution to the flavors and aromas of fermented foods and beverages. Fusel alcohols are derived from amino acid catabolism via a pathway that was first proposed a century ago by Ehrlich (13). Amino acids represent the major source of the assimilable nitrogen in wort and grape must, and these amino acids are taken up by yeast in a sequential manner (23, 32). Amino acids that are assimilated by the Ehrlich pathway (valine, leucine, isoleucine, methionine, and phenylalanine) are taken up slowly throughout the fermentation time (32). After the initial transamination reaction (Fig. ​(Fig.1),1), the resulting α-keto acid cannot be redirected into central carbon metabolism. Before α-keto acids are excreted into the growth medium, yeast cells convert them into fusel alcohols or acids via the Ehrlich pathway. FIG. 1. The Ehrlich pathway. Catabolism of branched-chain amino acids (leucine, valine, and isoleucine), aromatic amino acids (phenylalanine, tyrosine, and trytophan), and the sulfur-containing amino acid (methionine) leads to the formation of fusel acids and ... Current scientific interest in the Ehrlich pathway is supported by increased demands for natural flavor compounds such as isoamyl alcohol and 2-phenylethanol, which can be produced from amino acids in yeast-based bioconversion processes (14), as well as by the need to control flavor profiles of fermented food products. The goal of this paper is to present a concise centenary overview of the biochemistry, molecular biology, and physiology of this important pathway in S. cerevisiae.

Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder

Abstract: To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution

Abstract: The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia

Abstract: Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.