Genomic rearrangements can result in losses, amplifications, translocations and inversions of DNA fragments thereby modifying genome architecture, and potentially having clinical consequences. Many ...genomic disorders caused by structural variation have initially been uncovered by early cytogenetic methods. The last decade has seen significant progression in molecular cytogenetic techniques, allowing rapid and precise detection of structural rearrangements on a whole-genome scale. The high resolution attainable with these recently developed techniques has also uncovered the role of structural variants in normal genetic variation alongside single-nucleotide polymorphisms (SNPs). We describe how array-based comparative genomic hybridisation, SNP arrays, array painting and next-generation sequencing analytical methods (read depth, read pair and split read) allow the extensive characterisation of chromosome rearrangements in human genomes.
Objective: To describe the systematic analysis of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes, characterise the structural chromosome ...rearrangements, map the translocation breakpoints, and report detectable genomic imbalances. Methods: DNA microarrays were used with a resolution of 1 Mb for the detailed genome-wide analysis of the patients. Array CGH was used to screen for genomic imbalance and array painting to map chromosome breakpoints rapidly. These two methods facilitate rapid analysis of translocation breakpoints and screening for cryptic chromosome imbalance. Breakpoints of rearrangements were further refined (to the level of spanning clones) using fluorescence in situ hybridisation where appropriate. Results: Unexpected additional complexity or genome imbalance was found in six of 10 patients studied. The patients could be grouped according to the general nature of the karyotype rearrangement as follows: (A) three cases with complex multiple rearrangements including deletions, inversions, and insertions at or near one or both breakpoints; (B) three cases in which, while the translocations appeared to be balanced, microarray analysis identified previously unrecognised imbalance on chromosomes unrelated to the translocation; (C) four cases in which the translocation breakpoints appeared simple and balanced at the resolution used. Conclusions: This high level of unexpected rearrangement complexity, if generally confirmed in the study of further patients, will have an impact on current diagnostic investigations of this type and provides an argument for the more widespread adoption of microarray analysis or other high resolution genome-wide screens for chromosome imbalance and rearrangement.
GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic ...understanding is lacking
. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high
, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.
Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex bile acids in the intestinal lumen and decrease ...intestinal FXR activity. The BAS-BA complex also induces glucagon-like peptide-1 (GLP-1) production by L cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L cells and controls GLP-1 production is unknown. Here, we show that FXR activation in L cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycaemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes.
Objective: The authors describe a method, termed array painting, which allows the rapid, high resolution analysis of the content and breakpoints of aberrant chromosomes. Methods: Array painting is ...similar in concept to reverse chromosome painting and involves the hybridisation of probes generated by PCR of small numbers of flow sorted chromosomes on large insert genomic clone DNA microarrays. Results and Conclusions: By analysing patients with cytogenetically balanced chromosome rearrangements, the authors show the effectiveness of array painting as a method to map breakpoints prior to cloning and sequencing chromosome rearrangements.
CONTEXT The prevalence and distribution of gonococcal and chlamydial infections
in the general population are poorly understood. Development of nucleic acid
amplification tests, such as the ligase ...chain reaction assay, provides new
opportunities to estimate the prevalence of untreated infections in the population. OBJECTIVE To estimate the overall prevalence of untreated gonococcal and chlamydial
infections and to describe patterns of infection within specific demographic
subgroups of the young adult population in Baltimore, Md. DESIGN AND SETTING Cross-sectional behavioral survey based on a probability sample of Baltimore
households with collection of urine specimens between January 1997 and September
1998. PARTICIPANTS A total of 728 adults aged 18 to 35 years completed the interview portion
of the study, and 579 of these respondents also provided a urine specimen
adequate for testing. MAIN OUTCOME MEASURE Prevalence of untreated infection, as measured by the percentage of
specimens testing positive for gonococcal and chlamydial infection by ligase
chain reaction, weighted to reflect variations in probabilities of sample
selection from the population. Alternate estimates of the prevalence of recent
treated infection were derived from clinically diagnosed cases reported to
the Baltimore City Health Department and by diagnoses reported by participants
in the survey. RESULTS An estimated 5.3% (SE, 1.4%) of the population aged 18 to 35 years has
an untreated gonococcal infection, and 3.0% (SE, 0.8%) is estimated to have
an untreated chlamydial infection. While 7.9% (SE, 1.6%) of the population
is estimated to have either an untreated gonococcal or chlamydial infection,
estimated prevalence is substantially higher among black women (15.0%; SE,
3.7%). Few participants with untreated infections reported dysuria or discharge
during the 6 months preceding testing. The estimated number of untreated gonococcal
infections in the population (9241; SE, 2441) substantially exceeds both the
number of such infections diagnosed among Baltimore adults aged 18 to 35 years
and reported to the Baltimore City Health Department during 1998 (4566), and
the estimated number of diagnoses derived using participants' reports for
the 12 months prior to the survey (4708 SE, 1918 to 5231 SE, 2092). The
estimated number of untreated chlamydial infections (5231; SE, 1395) is also
greater than the number of cases reported to the health department in 1998
(3664) but is slightly less than the estimated number of diagnoses derived
using participants' reports of chlamydial infections diagnosed during the
12 months prior to the survey (5580 SE, 1918 to 6975 SE, 2441). CONCLUSION In 1997-1998, the estimated number of undiagnosed gonococcal and chlamydial
infections prevalent in the population of Baltimore adults aged 18 to 35 years
approached or exceeded the number of infections that were diagnosed and treated
annually.
Catches of sharks and bycatch in large-mesh nets and baited drumlines used by the Queensland Shark Control Program were examined to determine the efficacy of both gear types and assess fishing ...strategies that minimise their impacts. There were few significant differences in the size of both sharks and bycatch in the two gear types, apart from significantly smaller (p < 0.05) tiger sharks Galeocerdo cuvier being taken on drumlines and smaller green turtles Chelonia mydas in nets. Catch per unit effort showed orders of magnitude differences among species, even within the same family. Hammerhead sharks and rays were particularly vulnerable to net capture, whereas higher catch rates of tiger sharks were observed for drumlines. Nets caught more marine mammals, teleost fish and rays, whereas drumlines exhibited higher catch rates of the threatened loggerhead turtle Caretta caretta. Survival of most taxa (particularly obligate ram ventilators) was lower in nets than drumlines. Bycatch species (turtles and marine mammals) were able to swim to the surface to breathe when they were hooked on drumlines, enhancing their survival potential. Fishing strategies that recognise the different selectivity patterns of the gear can be developed to suit local biotic and abiotic conditions, although it is recognised that quantification of both ecological risk and risk to bathers is not a simple task.
Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in ...B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Studies of sexual and other sensitive behaviors are often fraught with a variety of reporting biases. When IAQs are used to collect data, respondents may underreport certain sensitive behaviors and ...overreport normative behaviors. SAQs can also pose problems: requiring that respondents be literate and be able to follow skip patterns. In recent years, the development of computerized technologies-audio-CASI and T-ACASI-have begun to overcome some of the limitations of IAQs and SAQs. By providing a more private mode for data collection and standardized delivery of all questions, as well as automated skip patterns and range checks, audio-CASI and T-ACASI have been tested in a number of studies and found to be an effective way of reducing response bias, and thus, contributing to a better understanding of the prevalence and patterns of sexual and other sensitive behaviors.
We report the analyses of breakpoints in 31 phenotypically normal and 14 abnormal carriers of balanced translocations. Our study assesses the differences between balanced translocations in normal ...carriers and those in abnormal carriers, focusing on the presence of genomic imbalances at the breakpoints or elsewhere in the genome, presence of cryptic chromosome rearrangements, and gene disruption. Our hypothesis is that all four features will be associated with phenotypic abnormalities and absent or much less frequent in a normal population. In the normal cohort, we identified neither genomic imbalances at the breakpoints or elsewhere in the genome nor cryptic chromosome rearrangements. In contrast, we identified candidate disease-causing imbalances in 4/14 abnormal patients. These were three breakpoint associated deletions and three deletions unrelated to the breakpoints. All six de novo deletions originated on the paternally inherited chromosome. Additional complexity was also present in one of these cases. Gene disruption by the breakpoints was present in 16/31 phenotypically normal individuals and in 5/14 phenotypically abnormal patients. Our results show that translocations in phenotypically abnormal patients are molecularly distinct from those in normal individuals: the former are more likely to be associated with genomic imbalances at the breakpoints or elsewhere and with chromosomal complexity, whereas the frequency of gene disruption is similar in both normal and abnormal translocation carriers.
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