Identification and comparative analysis of sixteen fungal peptidyl-prolyl cis/trans isomerase repertoires

BACKGROUND: The peptidyl-prolyl cis/trans isomerase (PPIase) class of proteins is present in all known eukaryotes, prokaryotes, and archaea, and it is comprised of three member families that share the ability to catalyze the cis/trans isomerisation of a prolyl bond. Some fungi have been used as model systems to investigate the role of PPIases within the cell, however how representative these repertoires are of other fungi or humans has not been fully investigated. RESULTS: PPIase numbers within these fungal repertoires appears associated with genome size and orthology between repertoires was found to be low. Phylogenetic analysis showed the single-domain FKBPs to evolve prior to the multi-domain FKBPs, whereas the multi-domain cyclophilins appear to evolve throughout cyclophilin evolution. A comparison of their known functions has identified, besides a common role within protein folding, multiple roles for the cyclophilins within pre-mRNA splicing and cellular signalling, and within transcription and cell cycle regulation for the parvulins. However, no such commonality was found with the FKBPs. Twelve of the 17 human cyclophilins and both human parvulins, but only one of the 13 human FKBPs, identified orthologues within these fungi. hPar14 orthologues were restricted to the Pezizomycotina fungi, and R. oryzae is unique in the known fungi in possessing an hCyp33 orthologue and a TPR-containing FKBP. The repertoires of Cryptococcus neoformans, Aspergillus fumigatus, and Aspergillus nidulans were found to exhibit the highest orthology to the human repertoire, and Saccharomyces cerevisiae one of the lowest. CONCLUSION: Given this data, we would hypothesize that: (i) the evolution of the fungal PPIases is driven, at least in part, by the size of the proteome, (ii) evolutionary pressures differ both between the different PPIase families and the different fungi, and (iii) whilst the cyclophilins and parvulins have evolved to perform conserved functions, the FKBPs have evolved to perform more variable roles. Also, the repertoire of Cryptococcus neoformans may represent a better model fungal system within which to study the functions of the PPIases as its genome size and genetic tractability are equal to those of Saccharomyces cerevisiae, whilst its repertoires exhibits greater orthology to that of humans. However, further experimental investigations are required to confirm this

Sequence determinants of human microsatellite variability

<p>Abstract</p> <p>Background</p> <p>Microsatellite loci are frequently used in genomic studies of DNA sequence repeats and in population studies of genetic variability. To investigate the effect of sequence properties of microsatellites on their level of variability we have analyzed genotypes at 627 microsatellite loci in 1,048 worldwide individuals from the HGDP-CEPH cell line panel together with the DNA sequences of these microsatellites in the human RefSeq database.</p> <p>Results</p> <p>Calibrating PCR fragment lengths in individual genotypes by using the RefSeq sequence enabled us to infer repeat number in the HGDP-CEPH dataset and to calculate the mean number of repeats (as opposed to the mean PCR fragment length), under the assumption that differences in PCR fragment length reflect differences in the numbers of repeats in the embedded repeat sequences. We find the mean and maximum numbers of repeats across individuals to be positively correlated with heterozygosity. The size and composition of the repeat unit of a microsatellite are also important factors in predicting heterozygosity, with tetra-nucleotide repeat units high in G/C content leading to higher heterozygosity. Finally, we find that microsatellites containing more separate sets of repeated motifs generally have higher heterozygosity.</p> <p>Conclusions</p> <p>These results suggest that sequence properties of microsatellites have a significant impact in determining the features of human microsatellite variability.</p

Prevalence of common disease-associated variants in Asian Indians

<p>Abstract</p> <p>Background</p> <p>Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i) Indians constitute a distinct population-genetic cluster, and (ii) despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity.</p> <p>Results</p> <p>We investigated the prevalence of common polymorphisms that have been associated with diseases, such as atherosclerosis (<it>ALOX5</it>), hypertension (<it>CYP3A5</it>, <it>AGT</it>, <it>GNB3</it>), diabetes (<it>CAPN10</it>, <it>TCF7L2</it>, <it>PTPN22</it>), prostate cancer (DG8S737, rs1447295), Hirschsprung disease (<it>RET</it>), and age-related macular degeneration (<it>CFH</it>, <it>LOC387715</it>). In addition, we examined polymorphisms associated with skin pigmentation (<it>SLC24A5</it>) and with the ability to taste phenylthiocarbamide (<it>TAS2R38</it>). All polymorphisms were studied in a cohort of 576 India-born Asian Indians sampled in the United States. This sample consisted of individuals whose mother tongue is one of 14 of the 22 "official" languages recognized in India as well as individuals whose mother tongue is Parsi, a cultural group that has resided in India for over 1000 years. Analysis of the data revealed that allele frequency differences between the different Indian language groups were small, and interestingly the variant alleles of <it>ALOX5 </it>g.8322G>A and g.50778G>A, and <it>PTPN22 </it>g.36677C>T were present only in a subset of the Indian language groups. Furthermore, a latitudinal cline was identified both for the allele frequencies of the SNPs associated with hypertension (<it>CYP3A5</it>, <it>AGT</it>, <it>GNB3</it>), as well as for those associated with the ability to taste phenylthiocarbamide (<it>TAS2R38</it>).</p> <p>Conclusion</p> <p>Although caution is warranted due to the fact that this US-sampled Indian cohort may not represent a random sample from India, our results will hopefully assist in the design of future studies that investigate the genetic causes of these diseases in India. Our results also support the inclusion of the Indian population in disease-related genetic studies, as it exhibits unique genotype as well as phenotype characteristics that may yield new insights into the underlying causes of common diseases that are not available in other populations.</p

Using Population Mixtures to Optimize the Utility of Genomic Databases: Linkage Disequilibrium and Association Study Design in India

When performing association studies in populations that have not been the focus of large-scale investigations of haplotype variation, it is often helpful to rely on genomic databases in other populations for study design and analysis – such as in the selection of tag SNPs and in the imputation of missing genotypes. One way of improving the use of these databases is to rely on a mixture of database samples that is similar to the population of interest, rather than using the single most similar database sample. We demonstrate the effectiveness of the mixture approach in the application of African, European, and East Asian HapMap samples for tag SNP selection in populations from India, a genetically intermediate region underrepresented in genomic studies of haplotype variation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65949/1/j.1469-1809.2008.00457.x.pd

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Hypodontia: genetics and future perspectives

evelopment is a complex process of reciprocal interactions that we have only recently begun to understand. With the large number of genes involved in the odontogenic process, the opportunity for mutations to disrupt this process is high. Tooth agenesis (hypodontia) is the most common craniofacial malformation with patients missing anywhere from one tooth to their entire dentition. Hypodontia can occur in association with other developmental anomalies (syndromic) or as an isolated condition (non-syndromic). Recent advances in genetic techniques have allowed us to begin understanding the genetic processes that underlie the odontogenic process and to identify the mechanisms responsible for tooth agenesis. Thus far two genes have been identified by mutational analysis as the major causes of non-syndromic hypodontia; PAX9 and MSX1. Haploinsufficiency of either has been observed to cause the more severe forms of hypodontia whilst point mutations cause hypodontia to varying degrees of severity. With the prevalence of hypodontia having been observed to have increased during the 20th century, the future identification and analysis of its genetic basis is essential to allow us to better treat the condition. The clinician can facilitate this process by collaborating with the human geneticist and referring patients/families with familial hypodontia for investigative research

Hypodontia: genetics and future Hypodontia: genetics and future Hypodontia: genetics and future Hypodontia: genetics and future Hypodontia: genetics and future perspectives perspectives perspectives perspectives perspectives Parimal Das Parimal Das Parima

Abstract Abstract Abstract Abstract Abstract Tooth development is a complex process of reciprocal interactions that we have only recently begun to understand. With the large number of genes involved in the odontogenic process, the opportunity for mutations to disrupt this process is high. Tooth agenesis (hypodontia) is the most common craniofacial malformation with patients missing anywhere from one tooth to their entire dentition. Hypodontia can occur in association with other developmental anomalies (syndromic) or as an isolated condition (non-syndromic). Recent advances in genetic techniques have allowed us to begin understanding the genetic processes that underlie the odontogenic process and to identify the mechanisms responsible for tooth agenesis. Thus far two genes have been identified by mutational analysis as the major causes of non-syndromic hypodontia; PAX9 and MSX1. Haploinsufficiency of either has been observed to cause the more severe forms of hypodontia whilst point mutations cause hypodontia to varying degrees of severity. With the prevalence of hypodontia having been observed to have increased during the 20 th century, the future identification and analysis of its genetic basis is essential to allow us to better treat the condition. The clinician can facilitate this process by collaborating with the human geneticist and referring patients/families with familial hypodontia for investigative research