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- van Rheenen, Wouter, et al.
(författare)
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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1043-1048
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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| 5. |
- Blauw, Hylke M, et al.
(författare)
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A large genome scan for rare CNVs in amyotrophic lateral sclerosis
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford Journals. - 0964-6906 .- 1460-2083. ; 19:20, s. 4091-4099
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
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- Lindblad-Toh, Kerstin, et al.
(författare)
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Genome sequence, comparative analysis and haplotype structure of the domestic dog.
- 2005
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 438:7069, s. 803-19
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Tidskriftsartikel (refereegranskat)abstract
- Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.
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- Carneiro, Ana P. B., et al.
(författare)
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A framework for mapping the distribution of seabirds by integrating tracking, demography and phenology
- 2020
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Ingår i: Journal of Applied Ecology. - : Wiley. - 0021-8901 .- 1365-2664. ; 57:3, s. 514-525
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Tidskriftsartikel (refereegranskat)abstract
- The identification of geographic areas where the densities of animals are highest across their annual cycles is a crucial step in conservation planning. In marine environments, however, it can be particularly difficult to map the distribution of species, and the methods used are usually biased towards adults, neglecting the distribution of other life-history stages even though they can represent a substantial proportion of the total population. Here we develop a methodological framework for estimating population-level density distributions of seabirds, integrating tracking data across the main life-history stages (adult breeders and non-breeders, juveniles and immatures). We incorporate demographic information (adult and juvenile/immature survival, breeding frequency and success, age at first breeding) and phenological data (average timing of breeding and migration) to weight distribution maps according to the proportion of the population represented by each life-history stage. We demonstrate the utility of this framework by applying it to 22 species of albatrosses and petrels that are of conservation concern due to interactions with fisheries. Because juveniles, immatures and non-breeding adults account for 47%-81% of all individuals of the populations analysed, ignoring the distributions of birds in these stages leads to biased estimates of overlap with threats, and may misdirect management and conservation efforts. Population-level distribution maps using only adult distributions underestimated exposure to longline fishing effort by 18%-42%, compared with overlap scores based on data from all life-history stages. Synthesis and applications. Our framework synthesizes and improves on previous approaches to estimate seabird densities at sea, is applicable for data-poor situations, and provides a standard and repeatable method that can be easily updated as new tracking and demographic data become available. We provide scripts in the R language and a Shiny app to facilitate future applications of our approach. We recommend that where sufficient tracking data are available, this framework be used to assess overlap of seabirds with at-sea threats such as overharvesting, fisheries bycatch, shipping, offshore industry and pollutants. Based on such an analysis, conservation interventions could be directed towards areas where they have the greatest impact on populations.
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| 8. |
- Evander, Mikael, et al.
(författare)
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Acoustic Differential Extraction - ultrasonic DNA-extraction from sexual assault evidence
- 2007
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Ingår i: International Congress on Ultrasonics. ; 1, s. 151-151
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Konferensbidrag (refereegranskat)abstract
- Isolation of the male and female DNA is one of the most important steps in obtaining the DNA profile of the perpetrator in sexual assault cases. The sample is obtained by taking a vaginal swab containing both epithelial cells from the female and sperm cells from the male from the victim. The purity of the extracted male fraction decides whether or not a single-source DNA profile of the suspect will be obtained or not. The existing techniques are have poor separation efficiency, time-consuming, labour-intensive and are neither easily automated nor integrated with further analysis steps. A novel method of DNA extraction based on ultrasonic trapping, Acoustic Differential Extraction, has been developed. A microfluidic device using laminar flow valving and miniature PZT transducers retains the sperm cells while mobilizing the female fraction into a separate outlet. The device was evaluated using a mock sexual assault sample and the separated fractions were analyzed using quantitative PCR and STR-profiling. A 16-fold enrichment of the male fraction, making an originally hard-to-detect-male DNA profile readily profiled, has been demonstrated. The STR-profiling of the male and female fractions showed a male fraction purity of up to 99 % making it possible to obtain a single-source DNA-profile of the suspect. The microfluidic format of the device makes it possible to downscale the sample time from 4-8 hours to 10 minutes. It is also possible to integrate this method with further downstream analysis steps necessarey for the full forensic DNA analysis.
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| 9. |
- Evander, Mikael, et al.
(författare)
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Using Acoustic Differential Extraction to enhance analysis of sexual assualt evidence on a valveless glass microdevice
- 2006
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Ingår i: Proceedings of µTAS 2006 Conference. ; 2, s. 1055-1057
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Konferensbidrag (refereegranskat)abstract
- The isolation of male and female DNA is an important step in the analysis of sexual assault evidence. A vaginal swab with female epithelial cells and male sperm cells is obtained from the female, and it is vital to separate the male and female fractions in order to obtain a single-source DNA profile of the suspect. In the case of a low abundance of sperm cells, it is very important that no cells are lost in the isolation step. The conventional isolation method used in the forensic DNA laboratories, differential extraction, is a time-consuming step, requiring up to 24 hours. It is neither highly amenable to automation, nor can it be easily integrated with other steps of the analysis. Therefore, a novel method of performing the isolation of male and female fractions of biological material from sexual assault evidence has been developed, termed acoustic differential extraction (ADE). After selectively lysing the female epithelial cells while keeping the sperm cells intact, the sample, now containing sperm cells and female cell lysate, is infused in a 900 μm wide and 70 μm deep microfabricated glass channel with miniature piezoelectric transducers mounted at the bottom of the channel, as shown in Figure 1. Upon activation of the ultrasound, the sperm cells will be trapped in a standing wave1 while free DNA will not be retained. The sperm cells, levitated in the 3D fluidic space above the transducer, can be washed with buffer and the unretained biological material directed to an output reservoir. Using laminar flow valving2, the sperm cells can be released and directed into a separate output reservoir in anticipation of DNA analysis, see Figure 2. With the purpose of evaluating the ADE microdevice for the collection of the two output fractions (male and female), preliminary work used a mock sexual assault sample created with polystyrene microparticles as sperm cells and Evan's Blue dye as female cell lysate. The particles were trapped over the transducer and the dye was directed to the female outlet reservoir as shown in Figure 3. After washing the particles, the ultrasound was deactivated and the flow redirected in order to collect the particles in the male outlet reservoir. A biological sample consisting of sperm cells and lysed female epithelial cells was subsequently tested by infusion into the device for five minutes while trapping the sperm cells over the transducer (Figure 4). The trapped sperm cells were washed with PBS for five minutes, then released and collected for analysis off-chip. DNA from the isolated cells was extracted with a commercial DNA extraction kit and analyzed with a duplex quantitative PCR assay3 to show the sample purity. An example of the qPCR data obtained is provided in Table 1. The results show that a highly-enriched sperm cell fraction can be obtained with the ADE technique. It is reasonable to expect that this technique can be integrated with on-chip downstream sample processing, e.g. DNA extraction and amplification. This would greatly diminish the analysis time from 24 hours to approximately 60 minutes. The time savings, in combination with the possibility to create a fully automated system, gives the ADE technique the potential to significantly alter the means by which sexual assault evidence is processed in crime laboratories today.
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| 10. |
- Kenna, Kevin P., et al.
(författare)
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NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1037-1042
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
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