ORCID Profile
0000-0002-8414-2190
Current Organisation
Uppsala University
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-04-2023
Abstract: Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.
Publisher: Cold Spring Harbor Laboratory
Date: 02-07-2020
DOI: 10.1101/2020.07.02.185108
Abstract: Here we present a new high-quality canine reference genome with gap number reduced 41-fold, from 23,836 to 585. Analysis of existing and novel data, RNA-seq, miRNA-seq and ATAC-seq, revealed a large proportion of these harboured previously hidden elements, including genes, promoters and miRNAs. Short-read dark regions were detected, and genomic regions completed, including the DLA, TCR and 366 cancer genes. 10x sequencing of 27 dogs uncovered a total of 22.1 million SNPs, Indels and larger structural variants (SVs). 1.4% overlap with protein coding genes and could provide a source of normal or aberrant phenotypic modifications.
Publisher: Cold Spring Harbor Laboratory
Date: 04-06-2019
DOI: 10.1101/660241
Abstract: There is a need to accurately call human leukocyte antigen (HLA) genes from existing short-read sequencing data, however there is no single solution that matches the gold standard of lab typing. Here we aimed to combine results from available software, minimising the biases of applied algorithm and HLA reference. The result is a robust HLA population resource for the published 1 000 Swedish genomes, and a framework for future HLA interrogation. HLA 2-field alleles were called using four imputation and inference methods for the classical eight genes (class I: HLA-A, -B, -C class II: HLA-DPA1, -DPB1, -DQA1, -DQB1, -DRB1 ). A high confidence population set (SweHLA) was determined using an n-1 concordance rule for class I (four software) and class II (three software) alleles. Results were compared across populations and in idual programs benchmarked to SweHLA. Per allele, 875 to 988 of the 1 000 s les were genotyped in SweHLA 920 s les had at least seven loci. While a small fraction of reference alleles were common to all software (class I=1.9% and class II=4.1%), this did not affect the overall call rate. Gene-level concordance was high compared to European populations ( .83%), with COX and PGF the dominant SweHLA haplotypes. We noted that 15/18 discordant alleles (delta allele frequency 2) were previously reported as disease-associated. These differences could in part explain across-study genetic replication failures, reinforcing the need to use multiple software. SweHLA demonstrates a way to use existing NGS data to generate a population resource agnostic to in idual HLA software biases.
Publisher: Wiley
Date: 02-11-2016
DOI: 10.1111/JOIM.12569
Abstract: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10 Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2021
DOI: 10.1038/S42003-021-01698-X
Abstract: We present GSD_1.0, a high-quality domestic dog reference genome with chromosome length scaffolds and contiguity increased 55-fold over CanFam3.1. Annotation with generated and existing long and short read RNA-seq, miRNA-seq and ATAC-seq, revealed that 32.1% of lifted over CanFam3.1 gaps harboured previously hidden functional elements, including promoters, genes and miRNAs in GSD_1.0. A catalogue of canine “dark” regions was made to facilitate mapping rescue. Alignment in these regions is difficult, but we demonstrate that they harbour trait-associated variation. Key genomic regions were completed, including the Dog Leucocyte Antigen (DLA), T Cell Receptor (TCR) and 366 COSMIC cancer genes. 10x linked-read sequencing of 27 dogs (19 breeds) uncovered 22.1 million SNPs, indels and larger structural variants. Subsequent intersection with protein coding genes showed that 1.4% of these could directly influence gene products, and so provide a source of normal or aberrant phenotypic modifications.
Publisher: Springer Science and Business Media LLC
Date: 09-11-2020
DOI: 10.1038/S41598-020-74580-1
Abstract: Breast cancer (BC) is a genetically heterogeneous disease with high prevalence in Northern Europe. However, there has been no detailed investigation into the Scandinavian somatic landscape. Here, in a homogeneous Swedish cohort, we describe the somatic events underlying BC, leveraging a targeted next-generation sequencing approach. We designed a 20.5 Mb array targeting coding and regulatory regions of genes with a known role in BC ( n = 765). The selected genes were either from human BC studies ( n = 294) or from within canine mammary tumor associated regions ( n = 471). A set of predominantly estrogen receptor positive tumors (ER + 85%) and their normal tissue counterparts (n = 61) were sequenced to ~ 140 × and 85 × mean target coverage, respectively. MuTect2 and VarScan2 were employed to detect single nucleotide variants (SNVs) and copy number aberrations (CNAs), while MutSigCV (SNVs) and GISTIC (CNAs) algorithms estimated the significance of recurrent somatic events. The significantly mutated genes ( q ≤ 0.01) were PIK3CA ( 28 % of patients), TP53 ( 21% ) and CDH1 ( 11% ). However, histone modifying genes contained the largest number of variants (KMT2C and ARID1A , together 28%) . Mutations in KMT2C were mutually exclusive with PI3KCA mutations ( p ≤ 0. 001 ) and half of these affect the formation of a functional PHD domain. The tumor suppressor CDK10 was deleted in 80% of the cohort while the oncogene MDM4 was lified. Mutational signature analyses pointed towards APOBEC deaminase activity ( COSMIC signature 2 ) and DNA mismatch repair ( COSMIC signature 6 ). We noticed two significantly distinct patterns related to patient age TP53 being more mutated in the younger group (29% vs 9% of patients) and CDH23 mutations were absent from the older group. The increased somatic mutation prevalence in the histone modifying genes KMT2C and ARID1A distinguishes the Swedish cohort from previous studies. KMT2C regulates enhancer activation and assists tumor proliferation in a hormone-rich environment, possibly pointing to a role in ER + BC, especially in older cases. Finally, age of onset appears to affect the mutational landscape suggesting that a larger age- erse population incorporating more molecular subtypes should be studied to elucidate the underlying mechanisms.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2019
DOI: 10.1038/S41431-019-0559-2
Abstract: There is a need to accurately call human leukocyte antigen (HLA) genes from existing short-read sequencing data, however there is no single solution that matches the gold standard of Sanger sequenced lab typing. Here we aimed to combine results from available software programs, minimizing the biases of applied algorithm and HLA reference. The result is a robust HLA population resource for the published 1000 Swedish genomes, and a framework for future HLA interrogation. HLA 2nd-field alleles were called using four imputation and inference methods for the classical eight genes (class I: HLA-A , HLA-B , HLA-C class II: HLA-DPA1 , HLA-DPB1 , HLA-DQA1 , HLA-DQB1 , HLA-DRB1 ). A high confidence population set (SweHLA) was determined using an n−1 concordance rule for class I (four software) and class II (three software) alleles. Results were compared across populations and in idual programs benchmarked to SweHLA. Per gene, 875 to 988 of the 1000 s les were genotyped in SweHLA 920 s les had at least seven loci called. While a small fraction of reference alleles were common to all software (class I = 1.9% and class II = 4.1%), this did not affect the overall call rate. Gene-level concordance was high compared to European populations ( .83%), with COX and PGF the dominant SweHLA haplotypes. We noted that 15/18 discordant alleles (delta allele frequency ) were previously reported as disease-associated. These differences could in part explain across-study genetic replication failures, reinforcing the need to use multiple software solutions. SweHLA demonstrates a way to use existing NGS data to generate a population resource agnostic to in idual HLA software biases.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2018
DOI: 10.1038/S41598-018-26842-2
Abstract: Autoimmune Addison’s disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator ( AIRE ) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.
No related grants have been discovered for Jessika Nordin.