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The promise and reality of personal genomics
Bryndis Yngvadottir, Daniel G MacArthur, Hanjun Jin, Chris Tyler-Smith
Genome Biology , 2009, DOI: 10.1186/gb-2009-10-9-237
Abstract: Which country has published the largest per-capita number of personal genomes? The United States, the United Kingdom? Actually, it is Korea. A recent article in Nature by Kim et al. [1] presents the genome sequence of a Korean male, AK1 - the seventh published sequence of an individual human genome and the second from Korea. The rapid progress in personal genome sequencing is possible because so-called 'next-generation' sequencing technology has decreased costs by orders of magnitude and increased throughput. But those advantages come at a price: short, error-prone reads derived from single molecules that have to be stitched back together to make a best-guess at the starting sequence. We are still at the stage of working out how to apply the available technologies to coax out biological information: the goal of a US$1,000 genome providing life-changing personal medical insights is still some way off.The first aim of a genome-sequencing project is to assemble around 6 billion As, Cs, Gs and Ts, comprising the diploid genome of the individual, in the right order. This is a challenge both of scale and because of sequence complexities such as repeated elements. By a series of frankly heroic measures, Kim et al. [1] have succeeded in generating a sequence that is likely to be substantially more complete and accurate than any other individual human genome derived so far using the new sequencing technology. Nonetheless, the effort invested in producing such a high-quality sequence, including the cloning and high-coverage sequencing of large segments of the genome from bacterial artificial chromosomes (BACs), is not routinely feasible and the final product is still far from complete. The clear message is that sequencing technology still has a long way to go before we enter the era of cheap, complete and reliable individual genome sequencing.The high depth of coverage for the AK1 sequence (most parts of the genome were sequenced around 28 times (28×)) meant that most variant
A Genome-Wide Survey of Genetic Variation in Gorillas Using Reduced Representation Sequencing
Aylwyn Scally, Bryndis Yngvadottir, Yali Xue, Qasim Ayub, Richard Durbin, Chris Tyler-Smith
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065066
Abstract: All non-human great apes are endangered in the wild, and it is therefore important to gain an understanding of their demography and genetic diversity. Whole genome assembly projects have provided an invaluable foundation for understanding genetics in all four genera, but to date genetic studies of multiple individuals within great ape species have largely been confined to mitochondrial DNA and a small number of other loci. Here, we present a genome-wide survey of genetic variation in gorillas using a reduced representation sequencing approach, focusing on the two lowland subspecies. We identify 3,006,670 polymorphic sites in 14 individuals: 12 western lowland gorillas (Gorilla gorilla gorilla) and 2 eastern lowland gorillas (Gorilla beringei graueri). We find that the two species are genetically distinct, based on levels of heterozygosity and patterns of allele sharing. Focusing on the western lowland population, we observe evidence for population substructure, and a deficit of rare genetic variants suggesting a recent episode of population contraction. In western lowland gorillas, there is an elevation of variation towards telomeres and centromeres on the chromosomal scale. On a finer scale, we find substantial variation in genetic diversity, including a marked reduction close to the major histocompatibility locus, perhaps indicative of recent strong selection there. These findings suggest that despite their maintaining an overall level of genetic diversity equal to or greater than that of humans, population decline, perhaps associated with disease, has been a significant factor in recent and long-term pressures on wild gorilla populations.
Genome-Wide Analysis of Cold Adaptation in Indigenous Siberian Populations
Alexia Cardona, Luca Pagani, Tiago Antao, Daniel J. Lawson, Christina A. Eichstaedt, Bryndis Yngvadottir, Ma Than Than Shwe, Joseph Wee, Irene Gallego Romero, Srilakshmi Raj, Mait Metspalu, Richard Villems, Eske Willerslev, Chris Tyler-Smith, Boris A. Malyarchuk, Miroslava V. Derenko, Toomas Kivisild
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098076
Abstract: Following the dispersal out of Africa, where hominins evolved in warm environments for millions of years, our species has colonised different climate zones of the world, including high latitudes and cold environments. The extent to which human habitation in (sub-)Arctic regions has been enabled by cultural buffering, short-term acclimatization and genetic adaptations is not clearly understood. Present day indigenous populations of Siberia show a number of phenotypic features, such as increased basal metabolic rate, low serum lipid levels and increased blood pressure that have been attributed to adaptation to the extreme cold climate. In this study we introduce a dataset of 200 individuals from ten indigenous Siberian populations that were genotyped for 730,525 SNPs across the genome to identify genes and non-coding regions that have undergone unusually rapid allele frequency and long-range haplotype homozygosity change in the recent past. At least three distinct population clusters could be identified among the Siberians, each of which showed a number of unique signals of selection. A region on chromosome 11 (chr11:66–69 Mb) contained the largest amount of clustering of significant signals and also the strongest signals in all the different selection tests performed. We present a list of candidate cold adaption genes that showed significant signals of positive selection with our strongest signals associated with genes involved in energy regulation and metabolism (CPT1A, LRP5, THADA) and vascular smooth muscle contraction (PRKG1). By employing a new method that paints phased chromosome chunks by their ancestry we distinguish local Siberian-specific long-range haplotype signals from those introduced by admixture.
Selective Changes of GABAA Channel Subunit mRNAs in the Hippocampus and Orbitofrontal Cortex but not in Prefrontal Cortex of Human Alcoholics
Zhe Jin,Esa R. Korpi,Bryndis Birnir
Frontiers in Cellular Neuroscience , 2012, DOI: 10.3389/fncel.2011.00030
Abstract: Alcohol dependence is a common chronic relapsing disorder. The development of alcohol dependence has been associated with changes in brain GABAA channel-mediated neurotransmission and plasticity. We have examined mRNA expression of the GABAA channel subunit genes in three brain regions in individuals with or without alcohol dependence using quantitative real-time PCR assay. The levels of selective GABAA channel subunit mRNAs were altered in specific brain regions in alcoholic subjects. Significant increase in the α1, α4, α5, β1, and γ1 subunit mRNAs in the hippocampal dentate gyrus region, and decrease in the β2 and δ subunit mRNAs in the orbitofrontal cortex were identified whereas no changes in the dorsolateral prefrontal cortex were detected. The data increase our understanding of the role of GABAA channels in the development of alcohol dependence.
Different Subtypes of GABA-A Receptors Are Expressed in Human, Mouse and Rat T Lymphocytes
Suresh K. Mendu, Amol Bhandage, Zhe Jin, Bryndis Birnir
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042959
Abstract: γ-aminobutyric acid (GABA) is the most prominent neuroinhibitory transmitter in the brain, where it activates neuronal GABA-A receptors (GABA-A channels) located at synapses and outside of synapses. The GABA-A receptors are primary targets of many clinically useful drugs. In recent years, GABA has been shown to act as an immunomodulatory molecule. We have examined in human, mouse and rat CD4+ and CD8+ T cells which subunit isoforms of the GABA-A channels are expressed. The channel physiology and drug specificity is dictated by the GABA-A receptor subtype, which in turn is determined by the subunit isoforms that make the channel. There were 5, 8 and 13 different GABA-A subunit isoforms identified in human, mouse and rat CD4+ and CD8+ T cells, respectively. Importantly, the γ2 subunit that imposes benzodiazepine sensitivity on the GABA-A receptors, was only detected in the mouse T cells. Immunoblots and immunocytochemistry showed abundant GABA-A channel proteins in the T cells from all three species. GABA-activated whole-cell transient and tonic currents were recorded. The currents were inhibited by picrotoxin, SR95531 and bicuculline, antagonists of GABA-A channels. Clearly, in both humans and rodents T cells, functional GABA-A channels are expressed but the subtypes vary. It is important to bear in mind the interspecies difference when selecting the appropriate animal models to study the physiological role and pharmacological properties of GABA-A channels in CD4+ and CD8+ T cells and when selecting drugs aimed at modulating the human T cells function.
Insulin Reduces Neuronal Excitability by Turning on GABAA Channels that Generate Tonic Current
Zhe Jin,Yang Jin,Suresh Kumar-Mendu,Eva Degerman,Leif Groop,Bryndis Birnir
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016188
Abstract: Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-aminobutyric acid) decreases neuronal excitability by activating GABAA channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocamal slices that insulin (1 nM) “turns on” new extrasynaptic GABAA channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC50) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABAA antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease.
GABA Maintains the Proliferation of Progenitors in the Developing Chick Ciliary Marginal Zone and Non-Pigmented Ciliary Epithelium
Henrik Ring, Suresh Kumar Mendu, Shahrzad Shirazi-Fard, Bryndis Birnir, Finn Hallb??k
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036874
Abstract: GABA is more than the main inhibitory neurotransmitter found in the adult CNS. Several studies have shown that GABA regulates the proliferation of progenitor and stem cells. This work examined the effects of the GABAA receptor system on the proliferation of retinal progenitors and non-pigmented ciliary epithelial (NPE) cells. qRT-PCR and whole-cell patch-clamp electrophysiology were used to characterize the GABAA receptor system. To quantify the effects on proliferation by GABAA receptor agonists and antagonists, incorporation of thymidine analogues was used. The results showed that the NPE cells express functional extrasynaptic GABAA receptors with tonic properties and that low concentration of GABA is required for a baseline level of proliferation. Antagonists of the GABAA receptors decreased the proliferation of dissociated E12 NPE cells. Bicuculline also had effects on progenitor cell proliferation in intact E8 and E12 developing retina. The NPE cells had low levels of the Cl–transporter KCC2 compared to the mature retina, suggesting a depolarising role for the GABAA receptors. Treatment with KCl, which is known to depolarise membranes, prevented some of the decreased proliferation caused by inhibition of the GABAA receptors. This supported the depolarising role for the GABAA receptors. Inhibition of L-type voltage-gated Ca2+ channels (VGCCs) reduced the proliferation in the same way as inhibition of the GABAA receptors. Inhibition of the channels increased the expression of the cyclin-dependent kinase inhibitor p27KIP1, along with the reduced proliferation. These results are consistent with that when the membrane potential indirectly regulates cell proliferation with hyperpolarisation of the membrane potential resulting in decreased cell division. The increased expression of p27KIP1 after inhibition of either the GABAA receptors or the L-type VGCCs suggests a link between the GABAA receptors, membrane potential, and intracellular Ca2+ in regulating the cell cycle.
Persistent Chlamydia Pneumoniae serology is related to decline in lung function in women but not in men. Effect of persistent Chlamydia pneumoniae infection on lung function
Thorarinn Gislason, Vilmundur Guenason, Bryndis Benediktsdottir, Isleifur Olafsson, Thor Aspelund, Bjarni Thjodleifsson, Christer Janson
BMC Pulmonary Medicine , 2010, DOI: 10.1186/1471-2466-10-44
Abstract: The study comprised of 1109 subjects (500 men and 609 women, mean age 28 ± 6 years) that participated in the Reykjavik Heart Study of the Young. Spirometry and blood samples for measurements of IgG antibodies for C pn were done at inclusion and at the end of the follow-up period (mean follow-up time 27 ± 4 years).Having IgG against C pn at both examinations was significantly associated to a larger decrease in FEV1 (6 mL/year) and FVC (7 mL/year) in women but not in men. In women the association between C pn and larger FEV1 decline was only found in women that smoked at baseline where having C pn IgG was associated with 10 mL/year decline compared to smokers without C pn IgG. These results were still significant after adjustment for age, smoking and change in body weight.Our results indicate that persistent C pn serology is related to increased decline in lung function in women but not in men. This effect was, however, primarily found in smoking women. This study is a further indication that the pathophysiological process leading to lung impairment may differ between men and women.Chlamydia pneumoniae (C pn) is an intracellular gram-negative pathogen that is detected in 5 to 10% of community-acquired pneumonia and other lower respiratory tract infections [1] Most adults are infected at least once during their lifetime, as indicated by seroprevalence of 70 to 80% [2]. C pn respiratory diseases may manifest as an acute disease or persistent and recurring infection that causes intense chronic inflammation. Growing evidence indicates that inflammation results from cellular responses by non immune cells, including mucosal epithelial and vascular endothelial cells [3]. Studies have suggested that C pn may be related to the pathogenesis of wheeze in children [4], asthma in adults [5] and to chronic obstructive pulmonary disease (COPD) [6]. Systemic aspects of COPD include oxidative stress and altered circulating levels of inflammatory mediators and acute-phase proteins. C-r
Dietary fiber and the glycemic index: a background paper for the Nordic Nutrition Recommendations 2012
Nina Cecilie ?verby,Emily Sonestedt,David E. Laaksonen,Bryndis Eva Birgisdottir
Food & Nutrition Research , 2013, DOI: 10.3402/fnr.v57i0.20709
Abstract: The aim of this study is to review recent data on dietary fiber (DF) and the glycemic index (GI), with special focus on studies from the Nordic countries regarding cardiometabolic risk factors, type 2 diabetes, cardiovascular disease, cancer, and total mortality. In this study, recent guidelines and scientific background papers or updates on older reports on DF and GI published between 2000 and 2011 from the US, EU, WHO, and the World Cancer Research Fund were reviewed, as well as prospective cohort and intervention studies carried out in the Nordic countries. All of the reports support the role for fiber-rich foods and DF as an important part of a healthy diet. All of the five identified Nordic papers found protective associations between high intake of DF and health outcomes; lower risk of cardiovascular disease, type 2 diabetes, colorectal and breast cancer. None of the reports and few of the Nordic papers found clear evidence for the GI in prevention of risk factors or diseases in healthy populations, although association was found in sub-groups, e.g. overweight and obese individuals and suggestive for prevention of type 2 diabetes. It was concluded that DF is associated with decreased risk of different chronic diseases and metabolic conditions. There is not enough evidence that choosing foods with low GI will decrease the risk of chronic diseases in the population overall. However, there is suggestive evidence that ranking food based on their GI might be of use for overweight and obese individuals. Issues regarding methodology, validity and practicality of the GI remain to be clarified.
Does high sugar consumption exacerbate cardiometabolic risk factors and increase the risk of type 2 diabetes and cardiovascular disease?
Emily Sonestedt,Nina Cecilie ?verby,David E. Laaksonen,Bryndis Eva Birgisdottir
Food & Nutrition Research , 2012, DOI: 10.3402/fnr.v56i0.19104
Abstract: Consumption of sugar has been relatively high in the Nordic countries; the impact of sugar intake on metabolic risk factors and related diseases has been debated. The objectives were to assess the effect of sugar intake (sugar-sweetened beverages, sucrose and fructose) on association with type 2 diabetes, cardiovascular disease and related metabolic risk factors (impaired glucose tolerance, insulin sensitivity, dyslipidemia, blood pressure, uric acid, inflammation markers), and on all-cause mortality, through a systematic review of prospective cohort studies and randomised controlled intervention studies published between January 2000 and search dates. The methods adopted were as follows: the first search was run in PubMed in October 2010. A second search with uric acid as risk marker was run in April 2011. The total search strategy was rerun in April 2011 in SveMed+. An update was run in PubMed in January 2012. Two authors independently selected studies for inclusion from the 2,743 abstracts according to predefined eligibility criteria. The outcome was that out of the 17 studies extracted, 15 were prospective cohort studies and two were randomised controlled crossover trials. All of the studies included only adults. With respect to incident type 2 diabetes (nine studies), four of six prospective cohort studies found a significant positive association for sugar-sweetened beverage intake. In general, larger cohort studies with longer follow-up more often reported positive associations, and BMI seemed to mediate part of the increased risk. For other metabolic or cardiovascular risk factors or outcomes, too few studies have been published to draw conclusions. In conclusion, data from prospective cohort studies published in the years 2000–2011 suggest that sugar-sweetened beverages probably increase the risk of type 2 diabetes. For related metabolic risk factors, cardiovascular disease or all-cause mortality and other types of sugars, too few studies were available to draw conclusions.
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