Evidence map›Paper›PMID 39520989›Full record

ArticleAmerican journal of human genetics2024

Resolution of ring chromosomes, Robertsonian translocations, and complex structural variants from long-read sequencing and telomere-to-telomere assembly.

Yulia Mostovoy, Philip M Boone, Yongqing Huang, Kiran V Garimella, Kar-Tong Tan, Bianca E Russell, Monica Salani, Celine E F de Esch, John Lemanski, Benjamin Curall and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed.

  1. Ring chromosomes uncovered by optical genome mapping: impact of telomeric-associated regions and reference genome selection on structural variant interpretation.Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2026
    Article
  2. Review
  3. Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Article
  9. Article
  10. Article
  11. Chromothripsis.Methods in molecular biology (Clifton, N.J.) · 2025
    Review
  12. Chromoanagenesis and Beyond: Catastrophic Events Shaping the Genome.Methods in molecular biology (Clifton, N.J.) · 2025
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors.

Yulia MostovoyCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.
Philip M BooneCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
Yongqing HuangData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Kiran V GarimellaData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Kar-Tong TanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Bianca E RussellDivision of Genetics, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Monica SalaniCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Celine E F de EschCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.
John LemanskiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Benjamin CurallCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.
Jen HauensteinBionano Genomics, Inc, San Diego, CA 92121, USA.
Diane LucenteCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Tera BowersGenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Tim DeSmetGenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Stacey GabrielGenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cynthia C MortonProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Departments of Obstetrics and Gynecology and of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Manchester Center for Audiology and Deafness, School of Health Sciences, University of Manchester, Manchester M13 9PL, UK.
Matthew MeyersonDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Alex R HastieBionano Genomics, Inc, San Diego, CA 92121, USA.
James GusellaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Fabiola Quintero-RiveraDepartments of Pathology, Laboratory Medicine, and Pediatrics, Division of Genetic and Genomic Medicine, University of California, Irvine, Irvine, CA 92697, USA.
Harrison BrandCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA; Pediatric Surgery Research Laboratory, Department of Pediatrics, Boston, MA 02114, USA.
Michael E TalkowskiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: mtalkowski@mgh.harvard.edu.

Funding

RAPID GENE DISCOVERYP01GM061354 · NIGMS · BRIGHAM AND WOMEN'S HOSPITAL · PI MORTON, CYNTHIA CASSON · 2001 to 2019
$24.3M
Broad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6M
The Massachusetts General Hospital Harvard Center for Reproductive MedicineP50HD104224 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI SEMINARA, STEPHANIE BETH · 2021 to 2025
$7.8M
Clinical Diagnostic Sequencing of Structural VariationR01HD081256 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2015 to 2025
$7.2M
Scalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR01MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2019 to 2025
$5.4M
Molecular mechanisms and genetic drivers of reciprocal genomic disordersR01HD096326 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2018 to 2022
$3.5M
Evaluating the Impact of Mutations in Distant-Acting Enhancers in Structural Birth DefectsR01HD114353 · NICHD · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI Len Alexander Pennacchio, Axel Visel · 2023 to 2026
$3.3M
The Genomic Architecture of Pregnancy LossR01HD105266 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E, WAPNER, RONALD · 2021 to 2024
$3.1M
Defining the Disorders of Genome OrganizationK08NS117891 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI BOONE, PHILIP MICHAEL · 2020 to 2024
$988k
Scalable tools and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR56MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2018 to 2018
$870k
Exploring the genetic architecture of structural birth defectsR03HD099547 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2019 to 2020
$336k
NHGRI NIH HHS U01 HG011755NICHD NIH HHS P50 HD104224NICHD NIH HHS R01 HD081256NICHD NIH HHS R01 HD096326NICHD NIH HHS R01 HD105266NICHD NIH HHS R01 HD114353NICHD NIH HHS R03 HD099547NIGMS NIH HHS P01 GM061354NIMH NIH HHS R01 MH115957NIMH NIH HHS R56 MH115957NINDS NIH HHS K08 NS117891
6 · The paper itself

Abstract

Delineation of structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. The sequence properties, origins, and functional effects of classes of genomic rearrangements such as ring chromosomes and Robertsonian translocations thus remain unknown. To resolve these complex structures, we leveraged several recent milestones in the field, including (1) the emergence of long-read sequencing, (2) the gapless telomere-to-telomere (T2T) assembly, and (3) a tool (BigClipper) to discover chromosomal rearrangements from long reads. We applied these technologies across 13 cases with ring chromosomes, Robertsonian translocations, and complex SVs that were unresolved by short reads, followed by validation using optical genome mapping (OGM). Our analyses resolved 10 of 13 cases, including a Robertsonian translocation and all ring chromosomes. Multiple breakpoints were localized to genomic regions previously recalcitrant to sequencing such as acrocentric p-arms, ribosomal DNA arrays, and telomeric repeats, and involved complex structures such as a deletion-inversion and interchromosomal dispersed duplications. We further performed methylation profiling from long-read data to discover phased differential methylation in a gene promoter proximal to a ring fusion, suggesting a long-range position effect (LRPE) with heterochromatin spreading. Breakpoint sequences suggested mechanisms of SV formation such as microhomology-mediated and non-homologous end-joining, as well as non-allelic homologous recombination. These methods provide some of the first glimpses into the sequence resolution of Robertsonian translocations and illuminate the structural diversity of ring chromosomes and complex chromosomal rearrangements with implications for genome biology, prediction of LRPEs from integrated multi-omics technologies, and molecular diagnostics in rare disease cases.

Indexed as

Ring ChromosomesTelomereTranslocation, GeneticChromosome MappingGenomic Structural VariationHigh-Throughput Nucleotide SequencingHumansSequence Analysis, DNAacrocentric p-arminversionlong-read sequencingoptical genome mappingring chromosomeRobertsonian translocationtelomere-to-telomere

Identifiers

PMID39520989
PMCPMC11639088

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.