1. Volume 168, Issue 5, Pages 830-842.e7 (February 2017)
An Organismal CNV Mutator Phenotype Restricted to Early Human Development 
Pengfei Liu, Bo Yuan, Claudia M.B. Carvalho, Arthur Wuster, Klaudia Walter, Ling Zhang, Tomasz Gambin, Zechen Chong, Ian M. Campbell, Zeynep Coban Akdemir, Violet Gelowani, Karin Writzl, Carlos A. Bacino, Sarah J. Lindsay, Marjorie Withers, Claudia Gonzaga-Jauregui, Joanna Wiszniewska, Jennifer Scull, Paweł Stankiewicz, Shalini N. Jhangiani, Donna M. Muzny, Feng Zhang, Ken Chen, Richard A. Gibbs, Bernd Rautenstrauss, Sau Wai Cheung, Janice Smith, Amy Breman, Chad A. Shaw, Ankita Patel, Matthew E. Hurles, James R. Lupski 
Cell 
Volume 168, Issue 5, Pages e7 (February 2017)
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3. Figure 1 The Landscape of dnCNVs in the Five Subjects
(A) The subject ID is shown at the top of each panel. The x axis indicates the genome view for chromosomes 1–22, X, and Y. The y axis indicates the proband versus control log2 ratio of the array CGH result, with duplications at 0.58, triplications at 1, and heterozygous deletions at −1. Each dot in the graph represents a dnCNV. The color of the dot indicates the parental origin of the dnCNV, with orange, blue, and black designating maternal, paternal, and unknown origin. The number above the dot denotes the CNV length in megabase. Numbers highlighted in red indicate that the corresponding CNV involves a complex rearrangement.
(B) A representative array CGH plot showing the de novo duplication on chromosome 17 in subject BAB3097.
See also Data S1 and S2 and Tables S1 and S2.
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4. Figure 2
Unique Features Are Shared by dnCNVs Identified from the Five Subjects
(A) Proportions of tandem duplication (TD), insertional double duplication (IDD), complex triplication (CT), deletion (DEL), and unresolved rearrangement structure (N/A) among MdnCNV events.
(B) A representative microhomeology from breakpoint BAB3097-chr5-1 (Data S1C and the first row in Table 2). The junction sequence is aligned with two reference sequences, with the red and blue colors indicating their origins from the colored rectangles above them. Microhomeology is highlighted in yellow. The junction sequence shares perfect identity to the blue reference, but not to the red reference, suggesting that MMBIR initiates from the blue end and invades into the red end.
(C) Density plots illustrating that dnCNVs identified in this study tend to be large in size.
See also Data S1 and Table S5.
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5. Figure 3
Model for the CNV Mutator Phenotype Restricted to Early Development
(A) A genetically normal oogonium synthesizing wild-type mRNA (black curved lines).
(B) A mutation (blue cross) on a gene that is critical for CNV formation occurs in the process of a primary oocyte development. Mutant mRNAs (red curved lines) are consequently synthesized, activating the CNV mutator phenotype, as is shown by the accumulation of dnCNVs (green bars) on chromosomes.
(C) After meiosis I, the chromosome harboring the mutation is lost to the first polar body, but the mutant mRNA is still present in the plasma of the oocyte at a high concentration. Meanwhile, a subset of the newly formed dnCNVs may also be segregated into the first polar body.
(D) As the sperm enters the oocyte, meiosis II is initiated. The second polar body is extruded.
(E) Maternal and paternal DNAs replicate separately, which is accompanied by generation of additional dnCNVs.
(F) A zygote is formed after the fusion of the two pronuclei.
(G) In the early cleavage stages, the cellular concentration of the mutant mRNA decreases as the cell divides. Meanwhile, dnCNVs keep accumulate. The inter-chromosomal dnCNVs involving both parental chromosomes observed in this study can be formed during this time interval.
(H) As the mutant mRNA is removed by maternal clearance (usually in 4- or 8-cell stage in humans) and the zygote transcription is activated, the number of dnCNV becomes stable.
(I) Schematic diagram showing the fluctuation of number of mutant DNA, mRNA, and dnCNV in the MdnCNV phenomenon. The x axis is in proportion to the timeline shown above in (A) to (H).
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6. Figure S1
The Number of dnCNVs in Each Patient Does Not Correlate with Parental Ages, Related to STAR Methods—Quantification and Statistical Analysis
The distribution of age of conception of fathers and mothers, when available, are plotted and compared with each other. The number of data points are as follows, father of patients with one dnCNV (n = 1368), two dnCNV (n = 38), MdnCNV (n = 4), mother of patients with one dnCNV (n = 1388), two dnCNV (n = 38), MdnCNV (n = 4). The distribution of parental ages is not significantly different between patients with two or more dnCNVs compared to those with one (Wilcoxon rank sum test, p > 0.05).
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7. Figure S2
Density Plot Showing that the MdnCNVs in the Five Subjects (Red Plot) and Single dnCNVs in Other Patients have Breakpoints Preferentially Distributed to Early-Replicating Areas, Related to STAR Methods—Characterization of Replication Timing and Rate for dnCNV Breakpoints
The x axis values indicate the standard deviation of replication timing deviating from the genome-wide mean (X = 0), with positive values indicating early and negative values late replication.
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