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Population Genetics in the Human Microbiome.
Garud, NR, Pollard, KS
Trends in genetics : TIG. 2020;(1):53-67
Abstract
While the human microbiome's structure and function have been extensively studied, its within-species genetic diversity is less well understood. However, genetic mutations in the microbiome can confer biomedically relevant traits, such as the ability to extract nutrients from food, metabolize drugs, evade antibiotics, and communicate with the host immune system. The population genetic processes by which these traits evolve are complex, in part due to interacting ecological and evolutionary forces in the microbiome. Advances in metagenomic sequencing, coupled with bioinformatics tools and population genetic models, facilitate quantification of microbiome genetic variation and inferences about how this diversity arises, evolves, and correlates with traits of both microbes and hosts. In this review, we explore the population genetic forces (mutation, recombination, drift, and selection) that shape microbiome genetic diversity within and between hosts, as well as efforts towards predictive models that leverage microbiome genetics.
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Determining the scale at which variation in a single gene changes population yields.
McGale, E, Valim, H, Mittal, D, Morales Jimenez, J, Halitschke, R, Schuman, MC, Baldwin, IT
eLife. 2020
Abstract
Plant trait diversity is known to influence population yield, but the scale at which this happens remains unknown: divergent individuals might change yields of immediate neighbors (neighbor scale) or of plants across a population (population scale). We use Nicotiana attenuata plants silenced in mitogen-activated protein kinase 4 (irMPK4) - with low water-use efficiency (WUE) - to study the scale at which water-use traits alter intraspecific population yields. In the field and glasshouse, we observed overyielding in populations with low percentages of irMPK4 plants, unrelated to water-use phenotypes. Paired-plant experiments excluded the occurrence of overyielding effects at the neighbor scale. Experimentally altering field arbuscular mycorrhizal fungal associations by silencing the Sym-pathway gene NaCCaMK did not affect reproductive overyielding, implicating an effect independent of belowground AMF interactions. Additionally, micro-grafting experiments revealed dependence on shoot-expressed MPK4 for N. attenuata to vary its yield per neighbor presence. We find that variation in a single gene, MPK4, is responsible for population overyielding through a mechanism, independent of irMPK4's WUE phenotype, at the aboveground, population scale.
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3.
Lessons learned from 40 novel PIGA patients and a review of the literature.
Bayat, A, Knaus, A, Pendziwiat, M, Afenjar, A, Barakat, TS, Bosch, F, Callewaert, B, Calvas, P, Ceulemans, B, Chassaing, N, et al
Epilepsia. 2020;(6):1142-1155
Abstract
OBJECTIVE To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. METHODS Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. RESULTS Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. SIGNIFICANCE Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
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Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human TNNT2 Variants.
Pettinato, AM, Ladha, FA, Mellert, DJ, Legere, N, Cohn, R, Romano, R, Thakar, K, Chen, YS, Hinson, JT
Circulation. 2020;(23):2262-2275
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Abstract
BACKGROUND Pathogenic TNNT2 variants are a cause of hypertrophic and dilated cardiomyopathies, which promote heart failure by incompletely understood mechanisms. The precise functional significance for 87% of TNNT2 variants remains undetermined, in part, because of a lack of functional genomics studies. The knowledge of which and how TNNT2 variants cause hypertrophic and dilated cardiomyopathies could improve heart failure risk determination, treatment efficacy, and therapeutic discovery, and provide new insights into cardiomyopathy pathogenesis, as well. METHODS We created a toolkit of human induced pluripotent stem cell models and functional assays using CRISPR/Cas9 to study TNNT2 variant pathogenicity and pathophysiology. Using human induced pluripotent stem cell-derived cardiomyocytes in cardiac microtissue and single-cell assays, we functionally interrogated 51 TNNT2 variants, including 30 pathogenic/likely pathogenic variants and 21 variants of uncertain significance. We used RNA sequencing to determine the transcriptomic consequences of pathogenic TNNT2 variants and adapted CRISPR/Cas9 to engineer a transcriptional reporter assay to assist prediction of TNNT2 variant pathogenicity. We also studied variant-specific pathophysiology using a thin filament-directed calcium reporter to monitor changes in myofilament calcium affinity. RESULTS Hypertrophic cardiomyopathy-associated TNNT2 variants caused increased cardiac microtissue contraction, whereas dilated cardiomyopathy-associated variants decreased contraction. TNNT2 variant-dependent changes in sarcomere contractile function induced graded regulation of 101 gene transcripts, including MAPK (mitogen-activated protein kinase) signaling targets, HOPX, and NPPB. We distinguished pathogenic TNNT2 variants from wildtype controls using a sarcomere functional reporter engineered by inserting tdTomato into the endogenous NPPB locus. On the basis of a combination of NPPB reporter activity and cardiac microtissue contraction, our study provides experimental support for the reclassification of 2 pathogenic/likely pathogenic variants and 2 variants of uncertain significance. CONCLUSIONS Our study found that hypertrophic cardiomyopathy-associated TNNT2 variants increased cardiac microtissue contraction, whereas dilated cardiomyopathy-associated variants decreased contraction, both of which paralleled changes in myofilament calcium affinity. Transcriptomic changes, including NPPB levels, directly correlated with sarcomere function and can be used to predict TNNT2 variant pathogenicity.
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Meta-analytic method reveal a significant association of theBDNF Val66Met variant with smoking persistence based on a large samples.
Zhao, H, Xiong, S, Li, Z, Wu, X, Li, L
The pharmacogenomics journal. 2020;(3):398-407
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Abstract
Although numerous genetic studies have reported the link between Val66Met in BDNF gene with smoking, the findings remain controversial, mainly due to small-to-moderate sample sizes. The main aim of current investigation is to explore whether the variant of Val66Met has any genetic functions in the progress of smoking persistence. The Val-based dominant genetic model considering Val/* (namely, Val/Val + Val/Met) and Met/Met as two genotypes with comparison of the frequency of each genotype in current smokers and never smokers. There were seven genetic association articles including eight independent datasets with 10,160 participants were chosen in current meta-analytic investigation. In light of the potent effects of ethnicity on homogeneity across studies, we carried out separated meta-analyses according to the ancestry origin by using the wide-used tool of Comprehensive Meta-analysis software (V 2.0). Our meta-analyses results indicated that the Val66Met polymorphism was significantly linked with smoking persistence based on either all the chosen samples (N = 10,160; Random and fixed models: pooled OR = 1.23; 95% CI = 1.03-1.46; P value = 0.012) or Asian samples (N = 2,095; Fixed model: pooled OR = 1.25; 95% CI = 1.01-1.54; P value = 0.044; Random model: pooled OR = 1.25; 95% CI = 1.001-1.56; P value = 0.049). No significant clue of bias in publications or heterogeneity across studies was detected. Thus, we conclude that the Val66Met (rs6265) variant conveys genetic susceptibility to maintaining smoking, and smokers who carry Val/* genotypes have a higher possibility of maintaining smoking than those having Met/Met genotype.
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Impact of Serum Calcium Levels on Alzheimer's Disease: A Mendelian Randomization Study.
He, Y, Zhang, H, Wang, T, Han, Z, Ni, QB, Wang, K, Wang, L, Zhang, Y, Hu, Y, Jin, S, et al
Journal of Alzheimer's disease : JAD. 2020;(2):713-724
Abstract
BACKGROUND Altered calcium homeostasis is hypothesized to underlie Alzheimer's disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. OBJECTIVE To develop effective therapies, we should establish the causal link between serum calcium levels and AD. METHODS Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. RESULTS IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35-0.95, p = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. CONCLUSION In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.
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Colletotrichum: species complexes, lifestyle, and peculiarities of some sources of genetic variability.
da Silva, LL, Moreno, HLA, Correia, HLN, Santana, MF, de Queiroz, MV
Applied microbiology and biotechnology. 2020;(5):1891-1904
Abstract
The genus Colletotrichum comprises species with different lifestyles but is mainly known for phytopathogenic species that infect crops of agronomic relevance causing considerable losses. The fungi of the genus Colletotrichum are distributed in species complexes and within each complex some species have particularities regarding their lifestyle. The most commonly found and described lifestyles in Colletotrichum are endophytic and hemibiotrophic phytopathogenic. Several of these phytopathogenic species show wide genetic variability, which makes long-term maintenance of resistance in plants difficult. Different mechanisms may play an important role in the emergence of genetic variants but are not yet fully understood in this genus. These mechanisms include heterokaryosis, a parasexual cycle, sexual cycle, transposable element activity, and repeat-induced point mutations. This review provides an overview of the genus Colletotrichum, the species complexes described so far and the most common lifestyles in the genus, with a special emphasis on the mechanisms that may be responsible, at least in part, for the emergence of new genotypes under field conditions.
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The influence of rare variants in circulating metabolic biomarkers.
Riveros-Mckay, F, Oliver-Williams, C, Karthikeyan, S, Walter, K, Kundu, K, Ouwehand, WH, Roberts, D, Di Angelantonio, E, Soranzo, N, Danesh, J, et al
PLoS genetics. 2020;(3):e1008605
Abstract
Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT<2.41x10-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.
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Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study.
Smit, RAJ, Trompet, S, Leong, A, Goodarzi, MO, Postmus, I, Warren, H, Theusch, E, Barnes, MR, Arsenault, BJ, Li, X, et al
The pharmacogenomics journal. 2020;(3):462-470
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Abstract
It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, nmax = 40,914) and DIAGRAM (nmax = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (rgenetic = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.
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Genetic variation in Charcot-Marie-Tooth genes contributes to sensitivity to paclitaxel-induced peripheral neuropathy.
Chen, Y, Fang, F, Kidwell, KM, Vangipuram, K, Marcath, LA, Gersch, CL, Rae, JM, Hayes, DF, Lavoie Smith, EM, Henry, NL, et al
Pharmacogenomics. 2020;(12):841-851
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Abstract
Aim: This study explored whether inherited variants in genes causing the hereditary neuropathy condition Charcot-Marie-Tooth disease are associated with sensitivity to paclitaxel-induced peripheral neuropathy (PN). Patients & methods: Hereditary neuropathy genes previously associated with risk of paclitaxel-induced PN were sequenced in paclitaxel-treated patients. Eight putative genetic predictors in five hereditary neuropathy genes (ARHGEF10, SBF2, FGD4, FZD3 and NXN) were tested for association with PN sensitivity after accounting for systemic exposure and clinical variables. Results:FZD3 rs7833751, a proxy for rs7001034, decreased PN sensitivity (additive model, β = -0.41; 95% CI: -0.66 to -0.17; p = 0.0011). None of the other genetic predictors were associated with PN sensitivity. Conclusion: Our results support prior evidence that FZD3 rs7001034 is protective of PN and may be useful for individualizing paclitaxel treatment to prevent PN.