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| 2. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 3. |
- Noguchi, S, et al.
(författare)
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FANTOM5 CAGE profiles of human and mouse samples
- 2017
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Ingår i: Scientific data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4, s. 170112-
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Tidskriftsartikel (refereegranskat)abstract
- In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
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| 4. |
- Kuriyama, T., et al.
(författare)
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Cellular basis of anti-predator adaptation in a lizard with autotomizable blue tail against specific predators with different colour vision
- 2016
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Ingår i: Journal of Zoology. - : Wiley. - 0952-8369 .- 1469-7998. ; 300:2, s. 89-98
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Tidskriftsartikel (refereegranskat)abstract
- Juveniles of numerous lizard species have a vividly blue-coloured tail that likely serves to deflect predator attacks toward the autotomizable tail rather than the lizard's body. The shades of blue colour in the tails of juvenile Plestiodon latiscutatus lizards vary across populations, most notably among those island populations with different predator assemblages. Here, we determine if this intraspecific variation is associated with the differences in colour vision capabilities of lizard predator species. If associated, it would be evidence for local adaptation of tail colour phenotype – natural selection is maximizing the conspicuousness of the tail to the dominant predator species to increase the chance of successfully deflecting attacks. We also use transmission electron microscopy (TEM) to determine the proximate cellular mechanisms that produce the shades of blue in different populations. We revealed that lizard tails with vivid blue reflectance evolved in communities with either weasel or snake predators, two groups of animals with the ability to detect blue wavelengths. However, lizard tail UV reflectance was much higher in populations with only snake predators; that snakes can detect UV, yet weasels cannot, suggests that high UV reflectance is an adaptation to increase tail conspicuousness specifically to snake predators. Finally, a cryptic brown tail evolved independently on the islands where birds are the primary lizard predator. We suggest that because birds have keen visual acuity; a brown, camouflaged phenotype is more advantageous. We also determined through TEM that the thickness of light reflecting platelets in iridophores, and densities of iridophores and xanthophores, predicted the wavelengths and intensity of light reflected by the lizard tail. For example, blue coloration was produced by selective reflection of short wavelengths of light by the thin light reflecting platelets of the iridophore. Greater iridophore density increased light reflectance, while greater xanthophore density decreased light reflectance.
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| 5. |
- Lue, L. F., et al.
(författare)
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Age-Dependent Relationship Between Plasma A beta 40 and A beta 42 and Total Tau Levels in cognitively Normal Subjects
- 2019
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Both amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with Alzheimer's disease (AD). However, the constituents of these hallmarks, amyloid beta (A beta) 40, A beta 42, and total Tau (t-Tau), have been detected in the blood of cognitively normal subjects by using an immunomagnetic reduction (IMR) assay. Whether these levels are age-dependent is not known, and their interrelation remains undefined. We determined the levels of these biomarkers in cognitively normal subjects of different age groups. A total of 391 cognitively normal subjects aged 23-91 were enrolled from hospitals in Asia, Europe, and North America. Healthy cognition was evaluated by NIA-AA guidelines to exclude subjects with mild cognitive impairment (MCI) and AD and by cognitive assessment using the Mini Mental State Examination and Clinical Dementia Rating (CDR). We examined the effect of age on plasma levels of A beta 40, A beta 42, and t-Tau and the relationship between these biomarkers during aging. Additionally, we explored age-related reference intervals for each biomarker. Plasma t-Tau and A beta 42 levels had modest but significant correlations with chronological age (r = 0.127, p = 0.0120 for t-Tau; r = -0.126, p = 0.0128 for A beta 42), ranging from ages 23 to 91. Significant positive correlations were detected between A beta 42 and t-Tau in the groups aged 50 years and older, with Rho values ranging from 0.249 to 0.474. Significant negative correlations were detected between A beta 40 and t-Tau from age 40 to 91 (r ranged from -0.293 to -0.582) and between A beta 40 and A beta 42 in the age groups of 30-39 (r = -0.562, p = 0.0235), 50-59 (r = -0.261, p = 0.0142), 60-69 (r = -0.303, p = 0.0004), and 80-91 (r = 0.459, p = 0.0083). We also provided age-related reference intervals for each biomarker. In this multicenter study, age had weak but significant effects on the levels of A beta 42 and t-Tau in plasma. However, the age group defined by decade revealed the emergence of a relationship between A beta 40, A beta 42, and t-Tau in the 6th and 7th decades. Validation of our findings in a large-scale and longitudinal study is warranted.
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| 8. |
- Wilson, R., et al.
(författare)
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Improved dendroclimatic calibration using blue intensity in the southern Yukon
- 2019
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 29:11, s. 1817-1830
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Tidskriftsartikel (refereegranskat)abstract
- In north-western North America, the so-called divergence problem (DP) is expressed in tree ring width (RW) as an unstable temperature signal in recent decades. Maximum latewood density (MXD), from the same region, shows minimal evidence of DP. While MXD is a superior proxy for summer temperatures, there are very few long MXD records from North America. Latewood blue intensity (LWB) measures similar wood properties as MXD, expresses a similar climate response, is much cheaper to generate and thereby could provide the means to profoundly expand the extant network of temperature sensitive tree-ring (TR) chronologies in North America. In this study, LWB is measured from 17 white spruce sites (Picea glauca) in south-western Yukon to test whether LWB is immune to the temporal calibration instabilities observed in RW. A number of detrending methodologies are examined. The strongest calibration results for both RW and LWB are consistently returned using age-dependent spline (ADS) detrending within the signal-free (SF) framework. RW data calibrate best with June-July maximum temperatures (Tmax), explaining up to 28% variance, but all models fail validation and residual analysis. In comparison, LWB calibrates strongly (explaining 43-51% of May-August Tmax) and validates well. The reconstruction extends to 1337 CE, but uncertainties increase substantially before the early 17th century because of low replication. RW-, MXD- and LWB-based summer temperature reconstructions from the Gulf of Alaska, the Wrangell Mountains and Northern Alaska display good agreement at multi-decadal and higher frequencies, but the Yukon LWB reconstruction appears potentially limited in its expression of centennial-scale variation. While LWB improves dendroclimatic calibration, future work must focus on suitably preserved sub-fossil material to increase replication prior to 1650 CE.
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