Genome-wide analysis of macrosatellite repeat copy number variation in worldwide populations: Evidence for differences and commonalities in size distributions and size restrictions

Background: Macrosatellite repeats (MSRs), usually spanning hundreds of kilobases of genomic DNA, comprise a significant proportion of the human genome. Because of their highly polymorphic nature, MSRs represent an extreme example of copy number variation, but their structure and function is largely understudied. Here, we describe a detailed study of six autosomal and two X chromosomal MSRs among 270 HapMap individuals from Central Europe, Asia and Africa. Copy number variation, stability and genetic heterogeneity of the autosomal macrosatellite repeats RS447 (chromosome 4p), MSR5p (5p), FLJ40296 (13q), RNU2 (17q) and D4Z4 (4q and 10q) and X chromosomal DXZ4 and CT47 were investigated. Results: Repeat array size distribution analysis shows that all of these MSRs are highly polymorphic with the most genetic variation among Africans and the least among Asians. A mitotic mutation rate of 0.4-2.2% was observed, exceeding meiotic mutation rates and possibly explaining the large size variability found for these MSRs. By means of a novel Bayesian approach, statistical support for a distinct multimodal rather than a uniform allele size distribution was detected in seven out of eight MSRs, with evidence for equidistant intervals between the modes. Conclusions: The multimodal distributions with evidence for equidistant intervals, in combination with the observation of MSR-specific constraints on minimum array size, suggest that MSRs are limited in their configurations and that deviations thereof may cause disease, as is the case for facioscapulohumeral muscular dystrophy. However, at present we cannot exclude that there are mechanistic constraints for MSRs that are not directly disease-related. This study represents the first comprehensive study of MSRs in different human populations by applying novel statistical methods and identifies commonalities and differences in their organization and function in the human genome

Decolonizar la investigación sobre migraciones : apuntes desde una etnografía colaborativa

En este artículo analizamos los significados asumidos por la idea de "(in)migración(es)" y la categoría de "(in)migrante(s)" en los contextos sociales, políticos y académicos contemporáneos. Resaltando su estrecha relación con el pensamiento de Estado y la colonialidad del poder/saber, nos preguntamos por otros posibles acercamientos a la movilidad humana. Discutimos la etnografía colaborativa, entendida como una metodología decolonial que rechaza las representaciones pasivizantes hegemónicas y aspira a visibilizar los procesos de subjetivación política de las personas junto a las que se investiga. Aportando ejemplos de nuestra propia investigación colaborativa junto a Stop Desahucios-Granada 15M, ilustramos cómo la idea de (in)migración(es) y la categoría "(in)migrante(s)" se han materializado en nuestro contexto, que se encuentra definido por el activismo político y no había sido previamente alterizado como "migratorio". Concluimos resaltando la ambivalencia implícita en estas dos expresiones y reflexionamos sobre los pros y los contras implícitos en su uso.In this paper we analyze the meaning of "immigration" and "immigrant" within contemporary social, political and academic contexts. We emphasize their narrow relation with State thought and the coloniality of power/knowledge and search for alternative approaches to human mobility. With this aim, we discuss collaborative ethnography as a decolonial methodology addressed to visibilize the political subjectivation processes of the people we research with. Drawing on examples from our own collaborative research with Stop Evictions-Granada 15M, we show how the idea of "immigration" and the category "immigrants" have come into being within our field, a space of political activism which had not been previously constructed as a "migratory context". We conclude underlining the ambivalence implicit in the two aforementioned concepts and discuss the pros and cons of using them

Deep characterization of a common D4Z4 variant identifies biallelic DUX4 expression as a modifier for disease penetrance in FSHD2

Development and application of statistical models for medical scientific researc

Optical genome mapping for the molecular diagnosis of facioscapulohumeral muscular dystrophy: advancement and challenges

Facioscapulohumeral muscular dystrophy (FSHD) is the second most common muscular dystrophy in adults, and it is associated with local D4Z4 chromatin relaxation, mostly via the contraction of the D4Z4 macrosatellite repeat array on chromosome 4q35. In this study, we aimed to investigate the use of Optical Genome Mapping (OGM) as a diagnostic tool for testing FSHD cases from the UK and India and to compare OGM performance with that of traditional techniques such as linear gel (LGE) and Pulsed-field gel electrophoresis (PFGE) Southern blotting (SB). A total of 6 confirmed and 19 suspected FSHD samples were processed with LGE and PFGE, respectively. The same samples were run using a Saphyr Genome-Imaging Instrument (1-color), and the data were analysed using custom EnFocus FSHD analysis. OGM was able to confirm the diagnosis of FSHD1 in all FSHD1 cases positive for SB (n = 17), and D4Z4 sizing highly correlated with PFGE-SB (p < 0.001). OGM correctly identified cases with mosaicism for the repeat array contraction (n = 2) and with a duplication of the D4Z4 repeat array. OGM is a promising new technology able to unravel structural variants in the genome and seems to be a valid tool for diagnosing FSHD1.Functional Genomics of Muscle, Nerve and Brain Disorder

Generation of genetically matched hiPSC lines from two mosaic facioscapulohumeral dystrophy type 1 patients

Facioscapulohumeral dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4q resulting in sporadic misexpression of the transcription factor DUX4 in skeletal muscle tissue. In ~4% of families, de novo D4Z4 contractions occur after fertilization resulting in somatic mosaicism with control and FSHD1 cell populations present within the same patient. Reprogramming of mosaic fibroblasts from two FSHD1 patients into human induced pluripotent stem cells (hiPSCs) generated genetically matched control and FSHD1 hiPSC lines. All hiPSC lines contained a normal karyotype, expressed pluripotency genes and differentiated into cells from the three germ layers

Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation

Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem prate inopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, TOP-43, hnRNPA1, hnRNPA2B1, and TIA1, underlie ALS, IBM, and other neurodegenerative diseases. Here, we characterize 4 potentially novel HNRNPA1 mutations (yielding 3 protein variants: *321Eext*6, *321Qext*6, and G304Nfs*3) and 2 known HNRNPA1 mutations (P288A and D262V), previously connected to ALS and MSP, in a broad spectrum of patients with hereditary motor neuropathy, ALS, and myopathy. We establish that the mutations can have different effects on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics. P288A accelerated fibrillization and decelerated SG disassembly, whereas *321Eext*6 had no effect on fibrillization but decelerated SG disassembly. By contrast, G3D4Nfs*3 decelerated fibrillization and impaired liquid phase separation. Our findings suggest different underlying pathomechanisms for HNRNPA1 mutations with a possible link to clinical phenotypes.Functional Genomics of Muscle, Nerve and Brain Disorder

Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26 : implications for genetic counselling and etiology of FSHD1

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Milder phenotype in facioscapulohumeral dystrophy with 7-10 residual D4Z4 repeats

Functional Genomics of Muscle, Nerve and Brain Disorder

Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35

Contains fulltext : 24067___.PDF (publisher's version ) (Open Access

Interchromosomal repeat array interactions between chromosomes 4 and 10: a model for subtelomeric plasticity.

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