In species with genetic sex-determination, the chromosomes carrying the sex-determining genes have often evolved non-recombining regions and subsequently evolved the full set of characteristics ...denoted by the term ‘sex chromosomes’. These include size differences, creating chromosomal heteromorphism, and loss of gene functions from one member of the chromosome pair. Such characteristics and changes have been widely reviewed, and underlie molecular genetic approaches that can detect sex chromosome regions. This review deals mainly with the evolution of new non-recombining regions, focusing on how certain evolutionary situations select for suppressed recombination (rather than the proximate mechanisms causing suppressed recombination between sex chromosomes). Particularly important is the likely involvement of sexually antagonistic polymorphisms in genome regions closely linked to sex-determining loci. These may be responsible for the evolutionary strata of sex chromosomes that have repeatedly formed by recombination suppression evolving across large genome regions. More studies of recently evolved non-recombining sex-determining regions should help to test this hypothesis empirically, and may provide evidence about whether other situations can sometimes lead to sex-linked regions evolving. Similarities with other non-recombining genome regions are discussed briefly, to illustrate common features of the different cases, though no general properties apply to all of them.
This article is part of the themed issue ‘Evolutionary causes and consequences of recombination rate variation in sexual organisms’.
We have developed an online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs). ...Reported TASs were common median risk allele frequency 36%, interquartile range (IQR) 21%-53% and were associated with modest effect sizes median odds ratio (OR) 1.33, IQR 1.20-1.61. Among 20 genomic annotation sets, reported TASs were significantly overrepresented only in nonsynonymous sites OR = 3.9 (2.2-7.0), p = 3.5 x 10⁻⁷ and 5kb-promoter regions OR = 2.3 (1.5-3.6), p = 3 x 10⁻⁴ compared to SNPs randomly selected from genotyping arrays. Although 88% of TASs were intronic (45%) or intergenic (43%), TASs were not overrepresented in introns and were significantly depleted in intergenic regions OR = 0.44 (0.34-0.58), p = 2.0 x 10⁻⁹. Only slightly more TASs than expected by chance were predicted to be in regions under positive selection OR = 1.3 (0.8-2.1), p = 0.2. This new online resource, together with bioinformatic predictions of the underlying functionality at trait/disease-associated loci, is well-suited to guide future investigations of the role of common variants in complex disease etiology.
Lung cancer in never smokers – A review Couraud, Sébastien; Zalcman, Gérard; Milleron, Bernard ...
European journal of cancer (1990),
06/2012, Letnik:
48, Številka:
9
Journal Article
Recenzirano
Abstract An estimated 10–25% of lung cancers worldwide occur in never smokers, i.e. individuals having smoked less than 100 cigarettes in their lifetime. Lung cancer in never smokers (LCINS) is more ...frequent in women, although large geographic variations are found. Histologically, adenocarcinomas predominate. The mere existence of LCINS suggests that risk factors other than smoking must be present. Exposure to environmental tobacco smoke (particularly in women) and exposure to workplace carcinogens (particularly in men) are the two most important alternative risk factors. However, a history of either is absent in more than a third of LCINS. The large proportion of women in LCINS suggest a hormonal element that may interact with other identified factors such as hereditary risks, a history of respiratory infections or disease, exposure to air pollution, cooking and heating fumes, or exposure to ionising radiation. The study of genomic polymorphisms finds constitutive DNA variations across subjects according to their smoking status, particularly in genes coding for enzymes that participate in the metabolism of certain carcinogens, in those coding for DNA repair enzymes, or in genes associated with tobacco addiction, or inflammatory processes. The type of molecular mutation in p53 or KRAS varies with smoking status. EGFR mutations are more frequent in never smokers, as are EML4-ALK fusions. The mutually exclusive nature of certain mutations is a strong argument in favour of separate genetic paths to cancer for ever smokers and never smokers. In the present paper we review current clinical and molecular aspects of LCINS.
Neurotoxicity is a burdensome side effect of platinum‐based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory ...neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA‐adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal‐regulated kinase 1/2, c‐Jun N‐terminal kinase/stress‐activated protein kinase, and p38 mitogen‐activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium‐sensitive voltage‐gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage‐gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance‐associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum‐induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum‐induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient‐oriented solution.
This review summarizes preclinical and clinical evidence of pathogenesis and pathophysiology of platinum‐induced peripheral neurotoxicity, as well as available evidence of neuroprotective and therapeutic strategies. These data may help to develop alternative options in the treatment of platinum‐induced neuropathy, studies on in vitro models, and appropriate trials planning to find the best patient‐oriented solution.
Despite broad agreement that Homo sapiens originated in Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent
. Progress is hampered by a ...shortage of fossil and genomic data, as well as variability in previous estimates of divergence times
. Here we seek to discriminate among such models by considering linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference
. We infer detailed demographic models for populations across Africa, including eastern and western representatives, and newly sequenced whole genomes from 44 Nama (Khoe-San) individuals from southern Africa. We infer a reticulated African population history in which present-day population structure dates back to Marine Isotope Stage 5. The earliest population divergence among contemporary populations occurred 120,000 to 135,000 years ago and was preceded by links between two or more weakly differentiated ancestral Homo populations connected by gene flow over hundreds of thousands of years. Such weakly structured stem models explain patterns of polymorphism that had previously been attributed to contributions from archaic hominins in Africa
. In contrast to models with archaic introgression, we predict that fossil remains from coexisting ancestral populations should be genetically and morphologically similar, and that only an inferred 1-4% of genetic differentiation among contemporary human populations can be attributed to genetic drift between stem populations. We show that model misspecification explains the variation in previous estimates of divergence times, and argue that studying a range of models is key to making robust inferences about deep history.
Phenytoin is metabolized through CYP2C9 and CYP2C19
Polymorphisms of
and
may increase plasma concentration and side effects.
Systematic review and meta-analysis were performed to evaluate the effects ...of
and
polymorphism on pharmacokinetic parameters. PubMed, Science Direct, Cochrane library, and Thai databases were systematically searched.
Eight observational studies, comprising a total of 633 patients were included. Michaelis-Menten constant was significantly higher in the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups as compared with the control groups (CYP2C9EM/CYP2C19EM) at 2.16 and 1.55 mg/l (p < 0.00001, p < 0.0001). The maximum rate of action was significantly lower in the control groups as compared with the polymorphism of CYP2C9IM/CYP2C19EM and CYP2C9IM/CYP2C19IM groups at 3.10 and 3.53 mg/kg/day (p = 0.00001, <0.0001).
The dosage regimen for patients in the CYP2C9IM group to achieve phenytoin therapeutic levels was 2.1-3.4 mg/kg/day.
Viral pathogens causing global disease burdens are often characterized by high rates of evolutionary changes. The extensive viral diversity at baseline can shorten the time to escape from therapeutic ...or immune selective pressure and alter mutational pathways. The impact of genotypic background on the barrier to resistance can be difficult to capture, particularly for agents in experimental stages or that are recently approved or expanded into new patient populations. We developed an evolutionary model-based counting method to quickly quantify the population genetic potential to resistance and assess population differences. We demonstrate its applicability to HIV-1 integrase inhibitors, as their increasing use globally contrasts with limited availability of non-B subtype resistant sequence data and corresponding knowledge gap. A large sequence data set encompassing most prevailing HIV-1 subtypes and resistance-associated mutations of currently approved integrase inhibitors was investigated. A complex interplay between codon predominance, polymorphisms, and associated evolutionary costs resulted in a subtype-dependent varied genetic potential for 15 resistance mutations against integrase inhibitors. While we confirm the lower genetic barrier of subtype B for G140S, we convincingly discard a similar effect previously suggested for G140C. A supplementary analysis for HIV-1 reverse transcriptase inhibitors identified a lower genetic barrier for K65R in subtype C through differential codon usage not reported before. To aid evolutionary interpretations of genomic differences for antiviral strategies, we advanced existing counting methods with increased sensitivity to identify subtype dependencies of resistance emergence. Future applications include novel HIV-1 drug classes or vaccines, as well as other viral pathogens.
More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of ...triggering obesity in a non-Mendelian, “on/off” manner. Trim28+/D9 mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-“on” state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.
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•Trim28 haploinsufficiency triggers stochastic bi-stable obesity or polyphenism•Non-classical imprinted gene dysregulation specifies “on” versus “off” obese states•Peg3 and Nnat perturbation trigger stochastic bi-stable obesity•Human BMI distributions and transcriptomes suggest Trim28-associated subpopulations
TRIM28 insufficiency in both mouse and human leads to polyphenism, wherein lean and obese phenotypes can arise from the identical genotypes through dysregulation of an imprinted gene network.
Aim: The etiology of schizophrenia has been linked to complex interactions of genetic and environmental factors, and among them are genes that regulate BDNF (Brain-derived Neurotrophic Factor) ...expression. The BDNF has been linked to the pathophysiology of schizophrenia, particularly the Val66Met polymorphism. This study aims to assess BDNF Val66Met polymorphism and its role in positive and negative symptoms in patients with schizophrenia in East Java. Subjects and Methods: A total of 52 subjects with schizophrenia living in East Java were assessed for BDNF Val66Met polymorphism. The analysis was performed using Statistical the Social Sciences (SPSS) software version 22. Clinical assessment was conducted using the positive and negative syndrome scale (PANSS). Data were analyzed using linear regression multivariate analysis. Results: Our study found that Val/Met polymorphism is associated negatively with the total PANSS scores (beta coefficient = -12.299, p = 0.017). The Val/Val polymorphism is associated with negative symptoms (beta coefficient = 22.607, p = 0.043). The present study’s findings considered age, gender, education level, number of antipsychotics consumed, medication adherence, and duration of untreated psychosis. Conclusion: Val/Val polymorphism is associated with a higher PANSS total score. Val/Met genotype is associated with more severe positive symptoms, while the Val/Val genotype is associated with more negative symptoms. Further study with a larger and multicenter sample is needed to clarify further the relationship of BDNF polymorphism to clinical outcomes of schizophrenia.
Supergenes often have multiple phenotypic effects, including unexpected detrimental ones, because recombination suppression maintains associations among co-adapted alleles but also allows the ...accumulation of recessive deleterious mutations and selfish genetic elements. Yet, supergenes often persist over long evolutionary periods. How are such polymorphisms maintained in the face of selection, drive and drift? We present a population genetic model that investigates the conditions necessary for a stable polymorphic equilibrium when one of the supergene haplotypes is a selfish genetic element. The model fits the characteristics of the Alpine silver ant,
, in which a large supergene underlies colony social organization, and one haplotype distorts Mendelian transmission by killing progeny that did not inherit it. The model shows that such maternal-effect killing strongly limits the maintenance of social polymorphism. Under random mating, transmission ratio distortion prevents rare single-queen colonies from invading populations of multiple-queen colonies, regardless of the fitness of each genotype. A stable polymorphic equilibrium can, however, be reached when high rates of assortative mating are combined with large fitness differences among supergene genotypes. The model reveals that the persistence of the social polymorphism is non-trivial and expected to occur only under restrictive conditions that deserve further empirical investigation. This article is part of the theme issue 'Genomic architecture of supergenes: causes and evolutionary consequences'.
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