Biology subjects

Norddahl, G.

Publications and source records attributed to Norddahl, G..

3 recordsLinked to original sources

bioRxiv2026

Endometriosis lesions are oligoclonal structures derived from the normal endometrium

Endometriosis is characterized by the presence of endometrium-like tissue outside the uterus. The origin of this ectopic tissue is debated, with leading theories including retrograde menstruation and embryonic remnants. Using somatic mutations as markers, we show that endometriosis lesions consist of unrelated clones of epithelial cells, with stromal cells being distinct, and that lesions at different body sites have different sets of clones. We observed that mutation burdens, signatures and driver landscapes are similar in cells from lesions and normal endometrium and the distribution of somatic mutations along the length of chromosomes is consistent with uterine origin. Furthermore a large-scale screen of the normal endometrium of endometriosis patients identified clones that are ancestral to endometriosis, indicating that the ectopic tissue in endometriosis originates from the normal endometrium.

genetics↗

bioRxiv2021

Genome-wide association study on 13,167 individuals identifies regulators of hematopoietic stem and progenitor cell levels in human blood

Understanding how hematopoietic stem and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and stem cell transplantation. To date, HSPC regulation has been extensively studied in vitro and in animal models, but less is known about the mechanisms in vivo in humans. Here, in a genome-wide association study on 13,167 individuals, we identify 9 significant and 2 suggestive DNA sequence variants that influence HSPC (CD34+) levels in human blood. The identified loci associate with blood disorders, harbor known and novel HSPC genes, and affect gene expression in HSPCs. Interestingly, our strongest association maps to the PPM1H gene, encoding an evolutionarily conserved serine/threonine phosphatase never previously implicated in stem cell biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. By functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates a MYB transcription factor binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, rs772557-A selectively increases HSPC subpopulations in which the MYB site is active, and PPM1H shRNA- knockdown increased CD34+ and CD34+90+ cell proportions in umbilical cord blood cultures. Our findings represent the first large-scale association study on a stem cell trait, illuminating HSPC regulation in vivo in humans, and identifying PPM1H as a novel inhibition target that can potentially be utilized clinically to facilitate stem cell harvesting for transplantation.

genomics↗

bioRxiv2017

Mutations in RPL3L and MYZAP increase risk of atrial fibrillation

We performed a meta-analysis of genome-wide association studies on atrial fibrillation (AF) among 14,710 cases and 373,897 controls from Iceland and 14,792 cases and 393,863 controls from the UK Biobank, focusing on low frequency coding and splice mutations, with follow-up in samples from Norway and the US. We observed associations with two missense (OR=1.19 for both) and one splice-donor mutation (OR=1.52) in RPL3L, encoding a ribosomal protein primarily expressed in skeletal muscle and heart. Analysis of 167 RNA samples from the right atrium revealed that the splice donor mutation in RPL3L results in exon skipping. AF is the first disease associated with RPL3L and RPL3L is the first ribosomal gene implicated in AF. This finding is consistent with tissue specialization of ribosomal function. We also found an association with a missense variant in MYZAP (OR=1.37), encoding a component of the intercalated discs of cardiomyocytes, the organelle harbouring most of the mutated proteins involved in arrhythmogenic right ventricular cardiomyopathy. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.

genetics↗