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Articles by M Guttman
Total Records ( 4 ) for M Guttman
  M Garber , M Guttman , M Clamp , M. C Zody , N Friedman and X. Xie
 

Motivation: Comparing the genomes from closely related species provides a powerful tool to identify functional elements in a reference genome. Many methods have been developed to identify conserved sequences across species; however, existing methods only model conservation as a decrease in the rate of mutation and have ignored selection acting on the pattern of mutations.

Results: We present a new approach that takes advantage of deeply sequenced clades to identify evolutionary selection by uncovering not only signatures of rate-based conservation but also substitution patterns characteristic of sequence undergoing natural selection. We describe a new statistical method for modeling biased nucleotide substitutions, a learning algorithm for inferring site-specific substitution biases directly from sequence alignments and a hidden Markov model for detecting constrained elements characterized by biased substitutions. We show that the new approach can identify significantly more degenerate constrained sequences than rate-based methods. Applying it to the ENCODE regions, we identify as much as 10.2% of these regions are under selection.

Availability: The algorithms are implemented in a Java software package, called SiPhy, freely available at http://www.broadinstitute.org/science/software/.

Contact: [email protected]

Supplementary information: Supplementary data are available at Bioinformatics online.

  J Tong , H Wong , M Guttman , L. C Ang , L. S Forno , M Shimadzu , A. H Rajput , M. D Muenter , S. J Kish , O Hornykiewicz and Y. Furukawa
 

-Synuclein is a major component of Lewy bodies and glial cytoplasmic inclusions, pathological hallmarks of idiopathic Parkinson's disease and multiple system atrophy, and it is assumed to be aetiologically involved in these conditions. However, the quantitative status of brain -synuclein in different Parkinsonian disorders is still unresolved and it is uncertain whether -synuclein accumulation is restricted to regions of pathology. We compared membrane-associated, sodium dodecyl sulfate-soluble -synuclein, both the full-length 17 kDa and high molecular weight species, by western blotting in autopsied brain of patients with Parkinson's disease (brainstem-predominant Lewy body disease: n = 9), multiple system atrophy (n = 11), progressive supranuclear palsy (n = 16), and of normal controls (n = 13). Brain of a patient with familial Parkinsonism-dementia due to -synuclein locus triplication (as positive control) showed increased membrane-associated, sodium dodecyl sulfate-soluble -synuclein levels with abundant high molecular weight immunoreactivity. In multiple system atrophy, a massive increase in 17 kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein was observed in highly pathologically affected regions, including putamen (+1760%, range +625–2900%), substantia nigra [+1000% (+356–1850%)], and white matter of internal capsule [+2210% (+430–6830%)] together with numerous high molecular weight species. Levels of 17 kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein were only modestly increased in less affected areas (cerebellar cortex, +95%; caudate, +30%; with both also showing numerous high molecular weight species) and were generally normal in cerebral cortices. In both Parkinson's disease and progressive supranuclear palsy, membrane-associated, sodium dodecyl sulfate-soluble -synuclein levels were normal in putamen and frontal cortex whereas a trend was observed for variably increased 17 kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein concentrations [+184% (–60% to +618%)] with additional high molecular weight species in Parkinson's disease substantia nigra. No obvious correlation was observed between nigral membrane-associated, sodium dodecyl sulfate-soluble -synuclein accumulation and Lewy body density in Parkinson's disease. Two progressive supranuclear palsy cases had membrane-associated, sodium dodecyl sulfate-soluble -synuclein accumulation in substantia nigra similar to multiple system atrophy. Several Parkinson's disease patients had very modest high molecular weight membrane-associated, sodium dodecyl sulfate-soluble -synuclein accumulation in putamen. Levels of 17-kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein were generally positively correlated with those of high molecular weight membrane-associated, sodium dodecyl sulfate-soluble -synuclein and there was a trend for a positive correlation between striatal dopamine loss and 17-kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein concentrations in multiple system atrophy. Brain membrane-associated, sodium dodecyl sulfate-soluble -synuclein accumulations in Parkinson's disease and multiple system atrophy are regionally specific, suggesting that these sporadic -synucleinopathies, unlike familial Parkinsonism-dementia, are not associated with a simple global over-expression of the protein. Despite a similar extent of dopamine depletion, the magnitude of brain membrane-associated, sodium dodecyl sulfate-soluble -synuclein changes is disease specific, with multiple system atrophy clearly having the most severe accumulation. Literature discrepancies on -synuclein status in ‘Parkinson's disease’ might be explained by inclusion of cases not having classic brainstem-predominant Lewy body disease and by variable -synuclein accumulation within this diagnostic classification.

  F Ozsolak , A Goren , M Gymrek , M Guttman , A Regev , B. E Bernstein and P. M. Milos
 

Accurate profiling of minute quantities of RNA in a global manner can enable key advances in many scientific and clinical disciplines. Here, we present low-quantity RNA sequencing (LQ-RNAseq), a high-throughput sequencing-based technique allowing whole transcriptome surveys from subnanogram RNA quantities in an amplification/ligation-free manner. LQ-RNAseq involves first-strand cDNA synthesis from RNA templates, followed by 3' polyA tailing of the single-stranded cDNA products and direct single molecule sequencing. We applied LQ-RNAseq to profile S. cerevisiae polyA+ transcripts, demonstrate the reproducibility of the approach across different sample preparations and independent instrument runs, and establish the absolute quantitative power of this method through comparisons with other reported transcript profiling techniques and through utilization of RNA spike-in experiments. We demonstrate the practical application of this approach to define the transcriptional landscape of mouse embryonic and induced pluripotent stem cells, observing transcriptional differences, including over 100 genes exhibiting differential expression between these otherwise very similar stem cell populations. This amplification-independent technology, which utilizes small quantities of nucleic acid and provides quantitative measurements of cellular transcripts, enables global gene expression measurements from minute amounts of materials and offers broad utility in both basic research and translational biology for characterization of rare cells.

 
 
 
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