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Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain.

ABSTRACT: The human genome harbors numerous structural variants (SVs) which, due to their repetitive nature, are currently underexplored in short-read whole-genome sequencing approaches. Using single-molecule, real-time (SMRT) long-read sequencing technology in combination with FALCON-Unzip, we generated a de novo assembly of the diploid genome of a 115-year-old Dutch cognitively healthy woman. We combined this assembly with two previously published haploid assemblies (CHM1 and CHM13) and the GRCh38 reference genome to create a compendium of SVs that occur across five independent human haplotypes using the graph-based multi-genome aligner REVEAL. Across these five haplotypes, we detected 31,680 euchromatic SVs (>50?bp). Of these, ~62% were comprised of repetitive sequences with 'variable number tandem repeats' (VNTRs), ~10% were mobile elements (Alu, L1, and SVA), while the remaining variants were inversions and indels. We observed that VNTRs with GC-content >60% and repeat patterns longer than 15?bp were 21-fold enriched in the subtelomeric regions (within 5?Mb of the ends of chromosome arms). VNTR lengths can expand to exceed a critical length which is associated with impaired gene transcription. The genes that contained most VNTRs, of which PTPRN2 and DLGAP2 are the most prominent examples, were found to be predominantly expressed in the brain and associated with a wide variety of neurological disorders. Repeat-induced variation represents a sizeable fraction of the genetic variation in human genomes and should be included in investigations of genetic factors associated with phenotypic traits, specifically those associated with neurological disorders. We make available the long and short-read sequence data of the supercentenarian genome, and a compendium of SVs as identified across 5 human haplotypes.

SUBMITTER: Linthorst J

PROVIDER: S-EPMC7608644 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain.

Linthorst Jasper J Meert Wim W Hestand Matthew S MS Korlach Jonas J Vermeesch Joris Robert JR Reinders Marcel J T MJT Holstege Henne H

Translational psychiatry 20201102 1

The human genome harbors numerous structural variants (SVs) which, due to their repetitive nature, are currently underexplored in short-read whole-genome sequencing approaches. Using single-molecule, real-time (SMRT) long-read sequencing technology in combination with FALCON-Unzip, we generated a de novo assembly of the diploid genome of a 115-year-old Dutch cognitively healthy woman. We combined this assembly with two previously published haploid assemblies (CHM1 and CHM13) and the GRCh38 refer ...[more]

PMID: 33139705

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Project description:BackgroundIn fish, molecular mechanisms that control follicle-enclosed oocyte progression throughout oogenesis and oocyte developmental competence acquisition remain poorly understood. Existing data in mammals have indicated that the so called "oocyte-specific" genes play an important role in oogenesis, fertilization, and early embryo development. In teleost species, very little is known about "oocyte-specific" genes. The present study therefore aimed at identifying and characterizing oocyte-specific genes in fish.ResultsUsing digital differential display PCR, mouse ESTs exhibiting an oocyte-predominant expression were identified. Those murine ESTs were subsequently used to identify cognate rainbow trout (Oncorhynchus mykiss) ESTs using a reciprocal Blast search strategy. In the present study we report the identification of five previously uncharacterized rainbow trout cDNAs exhibiting a oocyte-specific, oocyte-predominant, or gonad-specific expression: zygote arrest 1 (zar1), v-mos Moloney murine sarcoma viral oncogene-like protein (mos), B-cell translocation gene (btg3), growth differentiation factor 9 (gdf9), and mutS homolog 4 (msh4). The orthology relationship of each of these genes with vertebrate counterparts was verified by phylogenetic analysis. Among those five genes, three had never been characterized in any fish species. In addition, we report the oocyte-predominant expression of btg3 for the first time in any vertebrate species. Finally, those five genes are present in unfertilized eggs as maternally-inherited mRNAs thus suggesting that they could participate in ovarian folliculogenesis as well as early embryonic development.ConclusionThe expression patterns of zar1, mos, btg3, gdf9 and msh4 in rainbow trout and the functions of their orthologs in higher vertebrates strongly suggest that they might play an important role in follicle-enclosed oocyte development, meiosis control and early embryonic development in fish. Future investigations are however required to unravel the participation of those strong candidates in the molecular processes that control folliculogenesis and/or oocyte developmental competence in fish.

Dataset Information

Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain.

Publications

Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain.

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