| 1. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 2. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 3. |
- Talavera, David, et al.
(författare)
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Covariation Is a Poor Measure of Molecular Coevolution
- 2015
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 32:9, s. 2456-2468
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Tidskriftsartikel (refereegranskat)abstract
- Recent developments in the analysis of amino acid covariation are leading to breakthroughs in protein structure prediction, protein design, and prediction of the interactome. It is assumed that observed patterns of covariation are caused by molecular coevolution, where substitutions at one site affect the evolutionary forces acting at neighboring sites. Our theoretical and empirical results cast doubt on this assumption. We demonstrate that the strongest coevolutionary signal is a decrease in evolutionary rate and that unfeasibly long times are required to produce coordinated substitutions. We find that covarying substitutions are mostly found on different branches of the phylogenetic tree, indicating that they are independent events that may or may not be attributable to coevolution. These observations undermine the hypothesis that molecular coevolution is the primary cause of the covariation signal. In contrast, we find that the pairs of residues with the strongest covariation signal tend to have low evolutionary rates, and that it is this low rate that gives rise to the covariation signal. Slowly evolving residue pairs are disproportionately located in the protein's core, which explains covariation methods' ability to detect pairs of residues that are close in three dimensions. These observations lead us to propose the "coevolution paradox": The strength of coevolution required to cause coordinated changes means the evolutionary rate is so low that such changes are highly unlikely to occur. As modern covariation methods may lead to breakthroughs in structural genomics, it is critical to recognize their biases and limitations.
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| 4. |
- Abolfathi, Bela, et al.
(författare)
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The Fourteenth Data Release of the Sloan Digital Sky Survey : First Spectroscopic Data from the Extended Baryon Oscillation Spectroscopic Survey and from the Second Phase of the Apache Point Observatory Galactic Evolution Experiment
- 2018
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Ingår i: Astrophysical Journal Supplement Series. - : IOP Publishing Ltd. - 0067-0049 .- 1538-4365. ; 235:2
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Tidskriftsartikel (refereegranskat)abstract
- The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
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| 5. |
- Ali, Raja Hashim, et al.
(författare)
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Identifying Clusters of High Confidence Homologies in Multiple Sequence Alignments
- 2019
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Ingår i: Molecular biology and evolution. - : OXFORD UNIV PRESS. - 0737-4038 .- 1537-1719. ; 36:10, s. 2340-2351
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sequence alignment (MSA) is ubiquitous in evolution and bioinformatics. MSAs are usually taken to be a known and fixed quantity on which to perform downstream analysis despite extensive evidence that MSA accuracy and uncertainty affect results. These errors are known to cause a wide range of problems for downstream evolutionary inference, ranging from false inference of positive selection to long branch attraction artifacts. The most popular approach to dealing with this problem is to remove (filter) specific columns in the MSA that are thought to be prone to error. Although popular, this approach has had mixed success and several studies have even suggested that filtering might be detrimental to phylogenetic studies. We present a graph-based clustering method to address MSA uncertainty and error in the software Divvier (available at https://github.com/simonwhelan/Divvier), which uses a probabilistic model to identify clusters of characters that have strong statistical evidence of shared homology. These clusters can then be used to either filter characters from the MSA (partial filtering) or represent each of the clusters in a new column (divvying). We validate Divvier through its performance on real and simulated benchmarks, finding Divvier substantially outperforms existing filtering software by retaining more true pairwise homologies calls and removing more false positive pairwise homologies. We also find that Divvier, in contrast to other filtering tools, can alleviate long branch attraction artifacts induced by MSA and reduces the variation in tree estimates caused by MSA uncertainty.
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| 6. |
- Blanton, Michael R., et al.
(författare)
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Sloan Digital Sky Survey IV : Mapping the Milky Way, Nearby Galaxies, and the Distant Universe
- 2017
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Ingår i: Astronomical Journal. - : IOP Publishing Ltd. - 0004-6256 .- 1538-3881. ; 154:1
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Tidskriftsartikel (refereegranskat)abstract
- We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and. high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median z similar to 0.03). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between z similar to 0.6 and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs. and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the. Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July.
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| 7. |
- Bogusz, Marcin
(författare)
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Evolutionary Approaches to Sequence Alignment
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Molecular evolutionary biology allows us to look into the past by analyzing sequences of amino acids or nucleotides. These analyses can be very complex, often involving advanced statistical models of sequence evolution to construct phylogenetic trees, study the patterns of natural selection and perform a number of other evolutionary studies. In many cases, these evolutionary studies require a prerequisite of multiple sequence alignment (MSA) - a technique, which aims at grouping the characters that share a common ancestor, or homology, into columns. This information regarding shared homology is needed by statistical models to describe the process of substitutions in order to perform evolutionary inference. Sequence alignment, however, is difficult and MSAs often contain whole regions of wrongly aligned characters, which impact downstream analyses.In this thesis I use two broad groups of approaches to avoid errors in the alignment. The first group addresses the analysis methods without sequence alignment by explicitly modelling the processes of substitutions, and insertions and deletions (indels) between pairs of sequences using pair hidden Markov models. I describe an accurate tree inference method that uses a neighbor joining clustering approach to construct a tree from a matrix of model-based evolutionary distances.Next, I develop a pairwise method of modelling how natural selection acts on substitutions and indels. I further show the relationship between the constraints acting on these two evolutionary forces to show that natural selection affects them in a similar way.The second group of approaches deals with errors in existing alignments. I use a statistical model-based approach to evaluate the quality of multiple sequence alignments.First, I provide a graph-based tool for removing wrongly aligned pairs of residues by splitting them apart. This approach tends to produce better results when compared to standard column-based filtering.Second, I provide a way to compare MSAs using a probabilistic framework. I propose new ways of scoring of sequence alignments and show that popular methods produce similar results.The overall purpose of this work is to facilitate more accurate evolutionary analyses by addressing the problem of sequence alignment in a statistically rigorous manner.
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| 8. |
- Bogusz, Marcin, et al.
(författare)
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Phylogenetic Tree Estimation With and Without Alignment : New Distance Methods and Benchmarking
- 2017
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Ingår i: Systematic Biology. - : Oxford University Press (OUP). - 1063-5157 .- 1076-836X. ; 66:2, s. 218-231
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Tidskriftsartikel (refereegranskat)abstract
- Phylogenetic tree inference is a critical component of many systematic and evolutionary studies. The majority of these studies are based on the two-step process of multiple sequence alignment followed by tree inference, despite persistent evidence that the alignment step can lead to biased results. Here we present a two-part study that first presents PaHMM-Tree, a novel neighbor joining-based method that estimates pairwise distances without assuming a single alignment. We then use simulations to benchmark its performance against a wide-range of other phylogenetic tree inference methods, including the first comparison of alignment-free distance-based methods against more conventional tree estimation methods. Our new method for calculating pairwise distances based on statistical alignment provides distance estimates that are as accurate as those obtained using standard methods based on the true alignment. Pairwise distance estimates based on the two-step process tend to be substantially less accurate. This improved performance carries through to tree inference, where PaHMM-Tree provides more accurate tree estimates than all of the pairwise distance methods assessed. For close to moderately divergent sequence data we find that the two-step methods using statistical inference, where information from all sequences is included in the estimation procedure, tend to perform better than PaHMM-Tree, particularly full statistical alignment, which simultaneously estimates both the tree and the alignment. For deep divergences we find the alignment step becomes so prone to error that our distance-based PaHMM-Tree outperforms all other methods of tree inference. Finally, we find that the accuracy of alignment-free methods tends to decline faster than standard two-step methods in the presence of alignment uncertainty, and identify no conditions where alignment-free methods are equal to or more accurate than standard phylogenetic methods even in the presence of substantial alignment error.
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| 9. |
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| 10. |
- Chrobok, Daria, et al.
(författare)
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Dissecting the Metabolic Role of Mitochondria during Developmental Leaf Senescence
- 2016
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Ingår i: Plant Physiology. - : Oxford University Press (OUP). - 0032-0889 .- 1532-2548. ; 172:4, s. 2132-2153
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Tidskriftsartikel (refereegranskat)abstract
- The functions of mitochondria during leaf senescence, a type of programmed cell death aimed at the massive retrieval of nutrients from the senescing organ to the rest of the plant, remain elusive. Here, combining experimental and analytical approaches, we showed that mitochondrial integrity in Arabidopsis (Arabidopsis thaliana) is conserved until the latest stages of leaf senescence, while their number drops by 30%. Adenylate phosphorylation state assays and mitochondrial respiratory measurements indicated that the leaf energy status also is maintained during this time period. Furthermore, after establishing a curated list of genes coding for products targeted to mitochondria, we analyzed in isolation their transcript profiles, focusing on several key mitochondrial functions, such as the tricarboxylic acid cycle, mitochondrial electron transfer chain, iron-sulfur cluster biosynthesis, transporters, as well as catabolic pathways. In tandem with a metabolomic approach, our data indicated that mitochondrial metabolism was reorganized to support the selective catabolism of both amino acids and fatty acids. Such adjustments would ensure the replenishment of alpha-ketoglutarate and glutamate, which provide the carbon backbones for nitrogen remobilization. Glutamate, being the substrate of the strongly up-regulated cytosolic glutamine synthase, is likely to become a metabolically limiting factor in the latest stages of developmental leaf senescence. Finally, an evolutionary age analysis revealed that, while branched-chain amino acid and proline catabolism are very old mitochondrial functions particularly enriched at the latest stages of leaf senescence, auxin metabolism appears to be rather newly acquired. In summation, our work shows that, during developmental leaf senescence, mitochondria orchestrate catabolic processes by becoming increasingly central energy and metabolic hubs.
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