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The Role of Microhomology in Genomic Structural Variation
Diego Ottaviani*, Magdalena LeCain* & Denise Sheer
SUPPLEMENTARY INFORMATION
Figure. S1. Microhomology at breakpoint junctions of microdeletions of the FOXL2 gene or its regulatory domain.
(A) Junctionalmicrohomology (red) of 66 bp (adapted from[1], Supplementary Data Deletion 8).
(B) Junctionalmicrohomology (red) of 26 bp (adapted from[1], Supplementary Data Deletion 14).
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Table S1: Mechanisms that give rise to genomic structural variation
Mechanism / Description / Proposed involvement in genomic structural variation / Characteristics / ReferencesNHEJ / Homology independent rejoining of DNA ends following a DNA double-strand break (DSB) / V(D)J recombination, class switch recombination (CSR), non-recurrent CNVs / Insertion or deletion of nucleotides, short sequence homology may be present at breakpoint junctions / [2, 3]
MMEJ / Rejoining of DNA ends following a DSB through the annealing of a microhomologous sequence / LINE-1 retrotransposition, rescue mechanism for CSR, chromosomal translocations, non-recurrent CNVs / Microhomology overlying or flanking breakpoints, deletions / [4-6]
NAHR / Homologous recombination between nonallelic homologous loci / Recurrent CNVs, younger Alu events and segmental duplications / Proximity of breakpoints to repetitive sequences: low copy repeats (LCRs), Alu repeats, L1, pseudogenes / [7]
MEI / Insertion of mobile elements / Actively mobilizingretrotransposons LINE-1, Alu element and SVA element (SINE-R, VNTR and Alu); repetitive sequences may offer substrate for NAHR or predispose to rearrangements through complex architecture leading to fork stalling or DSBs / Repetitive transposable DNA sequences / [8]
FoSTeS / Invasion of distant loci by the lagging strand, following replication fork stalling / Complex rearrangements, non-recurrent CNVs, large scale DNA rearrangements / Template switching, multiple rearrangements / [9]
MMBIR / Invasion of distant loci following the breakdown of a replication fork with a resultant single-ended DNA double strand / Complex rearrangements, non-recurrent CNVs, large scale DNA rearrangements / Template switching, multiple rearrangements / [10]
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Table S2. Examples of microhomology at rearrangement junctions
Genomic region analysed / Associated genomic disorders and complex traits / Type of rearrangements / Rearrangements withmicrohomology junctions / Length of microhomology / Genomic features near rearrangement junction / ReferencesPLP1 / Pelizaeus-Merzbacher disease (PMD) / Non-recurrent duplications / 100% (3/3) / 2-5bp / LCRs / [9]
FOXL2 gene and regulatory domain / Blepharophimosis syndrome (BPES) / Non-recurrent microdeletions / 91.7% (22/24) / 1-66bp / Alu elements / [1]
MECP2 / Neurodevelopmental delay in males / Non-recurrent duplications / 75% (3/4) / 2-4bp / LCRs / [11]
NRXN1 / Susceptibility locus for neurodevelopmental and neurobehavioral abnormalities / Non-recurrent deletions / 68.8% (22/32) / 2-19bp / LTRs, unique non-B-DNA structures, MEME-defined sequence motifs† / [12]
NIPL / Cornelia de Lange syndrome / Non-recurrent deletions / 80% (4/5) / 1-5bp / [13]
SPAST / Autosomal dominant spastic paraplegia, type 4 (SPG4) / Deletions / 100% (3/3) / 1-26bp / Alu elements / [14]
(F)VIII gene (F8) / Haemophilia A / Duplications / 30% (3/10) / 2-3bp / LINEs, Alu elements / [15]
X chromosome / Turner syndrome / Isochromosome of the long arm of chromosome X i(Xq) / 17.6% (6/34) / 2-5bp / SVA repeat, LINEs, Alu elements, LTRs / [16]
-/cont.
Table S2 (cont.)
Genomic region analysed / Associated genomic disorders and complex traits / Type of rearrangements / Rearrangements withmicrohomology junctions / Length of microhomology / Genomic features near rearrangement junction / ReferencesCDKL5 / Early-onset seizure disorder in females / Deletions / 66.7% (2/3) / 7-15bp / Alu elements / [17]
Various pathogenic CNVs on different chromosomes / Multiple congenital anomalies (MCA), mental retardation with or without MCA, epilepsy, autism / Deletions and tandem duplications / 78.9% (30/38)
80% (24/30) deletions 75% (6/8) tandem duplications / 2 to over 75 bp / Alu elements, LINEs, DNA repeats, LTRs, MEME-defined sequence motifs / [18]
Whole Genome Sequencing / N.A. / Deletions, insertions and inversions / 28.2% (297/1054)
1054 rearrangements from 17 human genomes (589 deletions, 384 insertions, 81 inversions) / 2-20bp / [19]
Whole Genome Sequencing / N.A / Deletions, tandem duplications, mobile element insertions, non-reference insertions / 70.8% (15593/22025) deletions
89.6% insertions (5376/6000)
28025 CNVs from 185 human genomes / 2–376* bp
(distribution modes of 2 bp for deletions and 15 bp for insertions) / [20]
Whole Genome Sequencing / N.A. / CNVs / 69.5% (219/315) deletions / 1−30 bp / [21]
- microhomology/ homology
†Multiple Em for Motif Elicitation (MEME): a sequence search tool
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References
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