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Moghadam, B. T., Etemadikhah, M., Rajkowska, G., Stocluneier, C., Grabherr, M., Komorowski, J., . . . Lindholm Carlström, E. (2019). Analyzing DNA methylation patterns in subjects diagnosed with schizophrenia using machine learning methods. Journal of Psychiatric Research, 114, 41-47
Öppna denna publikation i ny flik eller fönster >>Analyzing DNA methylation patterns in subjects diagnosed with schizophrenia using machine learning methods
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2019 (Engelska)Ingår i: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 114, s. 41-47Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Schizophrenia is a common mental disorder with high heritability. It is genetically complex and to date more than a hundred risk loci have been identified. Association of environmental factors and schizophrenia has also been reported, while epigenetic analyses have yielded ambiguous and sometimes conflicting results. Here, we analyzed fresh frozen post-mortem brain tissue from a cohort of 73 subjects diagnosed with schizophrenia and 52 control samples, using the Illumina Infinium HumanMethylation450 Bead Chip, to investigate genome-wide DNA methylation patterns in the two groups. Analysis of differential methylation was performed with the Bioconductor Minfi package and modern machine-learning and visualization techniques, which were shown previously to be successful in detecting and highlighting differentially methylated patterns in case-control studies. In this dataset, however, these methods did not uncover any significant signals discerning the patient group and healthy controls, suggesting that if there are methylation changes associated with schizophrenia, they are heterogeneous and complex with small effect.

Ort, förlag, år, upplaga, sidor
PERGAMON-ELSEVIER SCIENCE LTD, 2019
Nyckelord
DNA methylation, Schizophrenia, Machine learning, Classification, Clustering
Nationell ämneskategori
Psykiatri
Identifikatorer
urn:nbn:se:uu:diva-390083 (URN)10.1016/j.jpsychires.2019.04.001 (DOI)000472127300006 ()31022588 (PubMedID)
Forskningsfinansiär
Forskningsrådet FormaseSSENCE - An eScience CollaborationEU, Europeiska forskningsrådet, 282330
Tillgänglig från: 2019-08-06 Skapad: 2019-08-06 Senast uppdaterad: 2019-08-06Bibliografiskt granskad
Shebanits, K., Günther, T., Johansson, A. C. V., Maqbool, K., Feuk, L., Jakobsson, M. & Larhammar, D. (2019). Copy number determination of the gene for the human pancreatic polypeptide receptor NPY4R using read depth analysis and droplet digital PCR.. BMC Biotechnology, 19, Article ID 31.
Öppna denna publikation i ny flik eller fönster >>Copy number determination of the gene for the human pancreatic polypeptide receptor NPY4R using read depth analysis and droplet digital PCR.
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2019 (Engelska)Ingår i: BMC Biotechnology, ISSN 1472-6750, E-ISSN 1472-6750, Vol. 19, artikel-id 31Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Copy number variation (CNV) plays an important role in human genetic diversity and has been associated with multiple complex disorders. Here we investigate a CNV on chromosome 10q11.22 that spans NPY4R, the gene for the appetite-regulating pancreatic polypeptide receptor Y4. This genomic region has been challenging to map due to multiple repeated elements and its precise organization has not yet been resolved. Previous studies using microarrays were interpreted to show that the most common copy number was 2 per genome.

Results: We have investigated 18 individuals from the 1000 Genomes project using the well-established method of read depth analysis and the new droplet digital PCR (ddPCR) method. We find that the most common copy number for NPY4R is 4. The estimated number of copies ranged from three to seven based on read depth analyses with Control-FREEC and CNVnator, and from four to seven based on ddPCR. We suggest that the difference between our results and those published previously can be explained by methodological differences such as reference gene choice, data normalization and method reliability. Three high-quality archaic human genomes (two Neanderthal and one Denisova) display four copies of the NPY4R gene indicating that a duplication occurred prior to the human-Neanderthal/Denisova split.

Conclusions: We conclude that ddPCR is a sensitive and reliable method for CNV determination, that it can be used for read depth calibration in CNV studies based on already available whole-genome sequencing data, and that further investigation of NPY4R copy number variation and its consequences are necessary due to the role of Y4 receptor in food intake regulation.

Nationell ämneskategori
Cellbiologi Genetik
Identifikatorer
urn:nbn:se:uu:diva-356569 (URN)10.1186/s12896-019-0523-9 (DOI)000470281900001 ()31164119 (PubMedID)
Forskningsfinansiär
VetenskapsrådetHjärnfonden
Tillgänglig från: 2018-08-01 Skapad: 2018-08-01 Senast uppdaterad: 2019-06-25Bibliografiskt granskad
Johansson, M., Pottmeier, P., Suciu, P., Ahmed, T., Zaghlool, A., Halvardson, J., . . . Jazin, E. (2019). Novel Y-Chromosome Long Non-Coding RNAs Expressed in Human Male CNS During Early Development. Frontiers in Genetics, 10, Article ID 891.
Öppna denna publikation i ny flik eller fönster >>Novel Y-Chromosome Long Non-Coding RNAs Expressed in Human Male CNS During Early Development
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2019 (Engelska)Ingår i: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 10, artikel-id 891Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Global microarray gene expression analyses previously demonstrated differences in female and male embryos during neurodevelopment. In particular, before sexual maturation of the gonads, the differences seem to concentrate on the expression of genes encoded on the X- and Y-chromosomes. To investigate genome-wide differences in expression during this early developmental window, we combined high-resolution RNA sequencing with qPCR to analyze brain samples from human embryos during the first trimester of development. Our analysis was tailored for maximum sensitivity to discover Y-chromosome gene expression, but at the same time, it was underpowered to detect X-inactivation escapees. Using this approach, we found that 5 out of 13 expressed game to log pairs showed unbalanced gene dosage, and as a consequence, a male-biased expression. In addition, we found six novel non-annotated long non-coding RNAs on the Y-chromosome with conserved expression patterns in newborn chimpanzee. The tissue specific and time-restricted expression of these long non-coding RNAs strongly suggests important functions during central nervous system development in human males.

Nyckelord
sex differences, gene expression, X-chromosome, Y-chromosome, long non-coding RNA, RNA sequencing, human brain development, Pan troglodytes
Nationell ämneskategori
Genetik Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-395797 (URN)10.3389/fgene.2019.00891 (DOI)000487628500001 ()
Forskningsfinansiär
Vetenskapsrådet, K2012-61X-22089-01-3EU, Europeiska forskningsrådet, 282330
Tillgänglig från: 2019-10-25 Skapad: 2019-10-25 Senast uppdaterad: 2019-10-25Bibliografiskt granskad
Thuresson, A.-C., Zander, C., Zhao, J. J., Halvardson, J., Maqbool, K., Månsson, E., . . . Feuk, L. (2019). Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability [Letter to the editor]. Clinical Genetics, 95(3), 436-439
Öppna denna publikation i ny flik eller fönster >>Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability
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2019 (Engelska)Ingår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 95, nr 3, s. 436-439Artikel i tidskrift, Letter (Refereegranskat) Published
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-326281 (URN)10.1111/cge.13470 (DOI)000458956100013 ()30525197 (PubMedID)
Forskningsfinansiär
EU, Europeiska forskningsrådet, 282330
Tillgänglig från: 2017-07-04 Skapad: 2017-07-04 Senast uppdaterad: 2019-03-14Bibliografiskt granskad
Shebanits, K., Andersson-Assarsson, J. C., Larsson, I., Carlsson, L. M. S., Feuk, L. & Larhammar, D. (2018). Copy number of pancreatic polypeptide receptor gene NPY4R correlates with body mass index and waist circumference. PLoS ONE, 13(4), Article ID e0194668.
Öppna denna publikation i ny flik eller fönster >>Copy number of pancreatic polypeptide receptor gene NPY4R correlates with body mass index and waist circumference
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2018 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 4, artikel-id e0194668Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Multiple genetic studies have linked copy number variation (CNV) in different genes to body mass index (BMI) and obesity. A CNV on chromosome 10q11.22 has been associated with body weight. This CNV region spans NPY4R, the gene encoding the pancreatic polypeptide receptor Y4, which has been described as a satiety-stimulating receptor. We have investigated CNV of the NPY4R gene and analysed its relationship to BMI, waist circumference and self-reported dietary intake from 558 individuals (216 men and 342 women) representing a wide BMI range. The copy number for NPY4R ranged from 2 to 8 copies (average 4.6 +/- 0.8). Rather than the expected negative correlation, we observed a positive correlation between NPY4R copy number and BMI as well as waist circumference (r = 0.267, p = 2.65x 10(-7) and r = 0.256, p = 8x10(-7), respectively). Each additional copy of NPY4R correlated with 2.6 kg/m(2) increase in BMI and 5.67 cm increase in waist circumference (p = 3.3x10(-7) and p = 1x10(-6), respectively) for women. For men, there was no statistically significant correlation between CNV and BMI. Our results suggest that NPY4R genetic variation influences body weight in women, but the exact role of this receptor appears to be more complex than previously proposed.

Ort, förlag, år, upplaga, sidor
PUBLIC LIBRARY SCIENCE, 2018
Nationell ämneskategori
Genetik
Identifikatorer
urn:nbn:se:uu:diva-352692 (URN)10.1371/journal.pone.0194668 (DOI)000429206800023 ()29621259 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, K2013-54X-11285-19Vetenskapsrådet, K2013-55X-22189-01-2Hjärnfonden, F02016-0217
Tillgänglig från: 2018-06-08 Skapad: 2018-06-08 Senast uppdaterad: 2019-01-03Bibliografiskt granskad
Ameur, A., Che, H., Martin, M., Bunikis, I., Dahlberg, J., Höijer, I., . . . Gyllensten, U. B. (2018). De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data. Genes, 9(10), Article ID 486.
Öppna denna publikation i ny flik eller fönster >>De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data
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2018 (Engelska)Ingår i: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 9, nr 10, artikel-id 486Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The current human reference sequence (GRCh38) is a foundation for large-scale sequencing projects. However, recent studies have suggested that GRCh38 may be incomplete and give a suboptimal representation of specific population groups. Here, we performed a de novo assembly of two Swedish genomes that revealed over 10 Mb of sequences absent from the human GRCh38 reference in each individual. Around 6 Mb of these novel sequences (NS) are shared with a Chinese personal genome. The NS are highly repetitive, have an elevated GC-content, and are primarily located in centromeric or telomeric regions. Up to 1 Mb of NS can be assigned to chromosome Y, and large segments are also missing from GRCh38 at chromosomes 14, 17, and 21. Inclusion of NS into the GRCh38 reference radically improves the alignment and variant calling from short-read whole-genome sequencing data at several genomic loci. A re-analysis of a Swedish population-scale sequencing project yields > 75,000 putative novel single nucleotide variants (SNVs) and removes > 10,000 false positive SNV calls per individual, some of which are located in protein coding regions. Our results highlight that the GRCh38 reference is not yet complete and demonstrate that personal genome assemblies from local populations can improve the analysis of short-read whole-genome sequencing data.

Nyckelord
de novo assembly, SMRT sequencing, GRCh38, human reference genome, human whole-genome sequencing, population sequencing, Swedish population
Nationell ämneskategori
Genetik
Identifikatorer
urn:nbn:se:uu:diva-369762 (URN)10.3390/genes9100486 (DOI)000448656700024 ()30304863 (PubMedID)
Forskningsfinansiär
Knut och Alice Wallenbergs Stiftelse, 2014.0272Vetenskapsrådet
Tillgänglig från: 2018-12-17 Skapad: 2018-12-17 Senast uppdaterad: 2019-10-23Bibliografiskt granskad
Höijer, I., Tsai, Y.-C., Clark, T. A., Kotturi, P., Dahl, N., Stattin, E., . . . Ameur, A. (2018). Detailed analysis of HTT repeat elements in human blood using targeted amplification-free long-read sequencing. Human Mutation, 39(9), 1262-1272
Öppna denna publikation i ny flik eller fönster >>Detailed analysis of HTT repeat elements in human blood using targeted amplification-free long-read sequencing
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2018 (Engelska)Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, nr 9, s. 1262-1272Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Amplification of DNA is required as a mandatory step during library preparation in most targeted sequencing protocols. This can be a critical limitation when targeting regions that are highly repetitive or with extreme guanine-cytosine (GC) content, including repeat expansions associated with human disease. Here, we used an amplification-free protocol for targeted enrichment utilizing the CRISPR/Cas9 system (No-Amp Targeted sequencing) in combination with single molecule, real-time (SMRT) sequencing for studying repeat elements in the huntingtin (HTT) gene, where an expanded CAG repeat is causative for Huntington disease. We also developed a robust data analysis pipeline for repeat element analysis that is independent of alignment of reads to a reference genome. The method was applied to 11 diagnostic blood samples, and for all 22 alleles the resulting CAG repeat count agreed with previous results based on fragment analysis. The amplification-free protocol also allowed for studying somatic variability of repeat elements in our samples, without the interference of PCR stutter. In summary, with No-Amp Targeted sequencing in combination with our analysis pipeline, we could accurately study repeat elements that are difficult to investigate using PCR-based methods.

Nyckelord
amplification-free sequencing, HTT, Huntington disease, No-Amp Targeted sequencing, repeat expansion, SMRT sequencing, somatic mosaicism, targeted enrichment, targeted sequencing
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-364189 (URN)10.1002/humu.23580 (DOI)000443229000010 ()29932473 (PubMedID)
Tillgänglig från: 2018-11-07 Skapad: 2018-11-07 Senast uppdaterad: 2018-11-16Bibliografiskt granskad
Zhao, J. J., Halvardson, J., Zander, C., Zaghlool, A., Georgii-Hemming, P., Månsson, E., . . . Feuk, L. (2018). Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 177(1), 10-20
Öppna denna publikation i ny flik eller fönster >>Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
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2018 (Engelska)Ingår i: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 177, nr 1, s. 10-20Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2-3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient-parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-326280 (URN)10.1002/ajmg.b.32574 (DOI)000417876700002 ()28990276 (PubMedID)
Forskningsfinansiär
EU, Europeiska forskningsrådet
Tillgänglig från: 2017-07-04 Skapad: 2017-07-04 Senast uppdaterad: 2018-01-17Bibliografiskt granskad
Zaghlool, A., Ameur, A., Wu, C., Westholm, J. O., Niazi, A., Manivannan, M., . . . Feuk, L. (2018). Expression profiling and in situ screening of circular RNAs in human tissues. Scientific Reports, 8, Article ID 16953.
Öppna denna publikation i ny flik eller fönster >>Expression profiling and in situ screening of circular RNAs in human tissues
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2018 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 16953Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Circular RNAs (circRNAs) were recently discovered as a class of widely expressed noncoding RNA and have been implicated in regulation of gene expression. However, the function of the majority of circRNAs remains unknown. Studies of circRNAs have been hampered by a lack of essential approaches for detection, quantification and visualization. We therefore developed a target-enrichment sequencing method suitable for screening of circRNAs and their linear counterparts in large number of samples. We also applied padlock probes and in situ sequencing to visualize and determine circRNA localization in human brain tissue at subcellular levels. We measured circRNA abundance across different human samples and tissues. Our results highlight the potential of this RNA class to act as a specific diagnostic marker in blood and serum, by detection of circRNAs from genes exclusively expressed in the brain. The powerful and scalable tools we present will enable studies of circRNA function and facilitate screening of circRNA as diagnostic biomarkers.

Ort, förlag, år, upplaga, sidor
NATURE PUBLISHING GROUP, 2018
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-371872 (URN)10.1038/s41598-018-35001-6 (DOI)000450280500013 ()30446675 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2012-4530Vetenskapsrådet, 2017-01861EU, Europeiska forskningsrådet, 282330Knut och Alice Wallenbergs Stiftelse
Tillgänglig från: 2019-01-07 Skapad: 2019-01-07 Senast uppdaterad: 2019-01-07Bibliografiskt granskad
Kuderna, L. F. K., Tomlinson, C., Hillier, L. W., Tran, A., Fiddes, I. T., Armstrong, J., . . . Marques-Bonet, T. (2017). A 3-way hybrid approach to generate a new high-quality chimpanzee reference genome (Pan_tro_3.0). GigaScience, 6(11), 1-6
Öppna denna publikation i ny flik eller fönster >>A 3-way hybrid approach to generate a new high-quality chimpanzee reference genome (Pan_tro_3.0)
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2017 (Engelska)Ingår i: GigaScience, ISSN 2047-217X, E-ISSN 2047-217X, Vol. 6, nr 11, s. 1-6Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The chimpanzee is arguably the most important species for the study of human origins. A key resource for these studies is a high-quality reference genome assembly; however, as with most mammalian genomes, the current iteration of the chimpanzee reference genome assembly is highly fragmented. In the current iteration of the chimpanzee reference genome assembly (Pan tro 2.1.4), the sequence is scattered across more then 183 000 contigs, incorporating more than 159 000 gaps, with a genome-wide contig N50 of 51 Kbp. In this work, we produce an extensive and diverse array of sequencing datasets to rapidly assemble a new chimpanzee reference that surpasses previous iterations in bases represented and organized in large scaffolds. To this end, we show substantial improvements over the current release of the chimpanzee genome (Pan tro 2.1.4) by several metrics, such as increased contiguity by > 750% and 300% on contigs and scaffolds, respectively, and closure of 77% of gaps in the Pan tro 2.1.4 assembly gaps spanning > 850 Kbp of the novel coding sequence based on RNASeq data. We further report more than 2700 genes that had putatively erroneous frame-shift predictions to human in Pan tro 2.1.4 and show a substantial increase in the annotation of repetitive elements. We apply a simple 3-way hybrid approach to considerably improve the reference genome assembly for the chimpanzee, providing a valuable resource for the study of human origins. Furthermore, we produce extensive sequencing datasets that are all derived from the same cell line, generating a broad non-human benchmark dataset.

Nyckelord
chimpanzee reference genome, assembly, genomics
Nationell ämneskategori
Genetik
Identifikatorer
urn:nbn:se:uu:diva-340340 (URN)10.1093/gigascience/gix098 (DOI)000419634200001 ()
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Tillgänglig från: 2018-01-30 Skapad: 2018-01-30 Senast uppdaterad: 2018-01-30Bibliografiskt granskad
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