Volume 15, Issue 9, Pages (May 2016)

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Volume 15, Issue 9, Pages 1901-1909 (May 2016) Striking Immune Phenotypes in Gene-Targeted Mice Are Driven by a Copy-Number Variant Originating from a Commercially Available C57BL/6 Strain Vinay S. Mahajan, Ezana Demissie, Hamid Mattoo, Vinay Viswanadham, Ajit Varki, Robert Morris, Shiv Pillai Cell Reports Volume 15, Issue 9, Pages 1901-1909 (May 2016) DOI: 10.1016/j.celrep.2016.04.080 Copyright © 2016 The Author(s) Terms and Conditions

Cell Reports 2016 15, 1901-1909DOI: (10.1016/j.celrep.2016.04.080) Copyright © 2016 The Author(s) Terms and Conditions

Figure 1 Siae-Deficient Mice Exhibit a Background-Dependent Increase in CD8+ MP Cells and a Loss of MZ B Cells (A) The proportion of CD8+ MP cells in the spleens of 1- to 3-month-old N10-Siae mice with age-matched C57BL/6J controls. (B) CD8+ MP and MZ B cells in N10-Siae, N23-Siae, Siaetm1a/tm1a, and C57BL/6J mice. The data shown are representative of five mice. See also Figure S1. Cell Reports 2016 15, 1901-1909DOI: (10.1016/j.celrep.2016.04.080) Copyright © 2016 The Author(s) Terms and Conditions

Figure 2 Hematopoietic Phenotypes Observed in N10-Siae Mice Are Mendelian, Recessive, and Unlinked to Siae (A) (N10-Siae × C57BL/6J) F1 animals have a normal CD8+ MP cell compartment. Upon subsequent backcrossing to the N10-Siae background, Siae does not segregate with the altered CD8+ MP cells (n = 13). An approximately equal number of mice with (n = 79) and without (n = 77) the phenotype (<40% and >40% CD8 MP cells, respectively) are observed. (B) A strong correlation between loss of MZ B cells and increase in CD8 MP is observed. (C) About 25% of Siae+/+ (wild-type) mice obtained from an intercross between heterozygous N10-Siae mice exhibit normal CD8+ MP cells. Cell Reports 2016 15, 1901-1909DOI: (10.1016/j.celrep.2016.04.080) Copyright © 2016 The Author(s) Terms and Conditions

Figure 3 A SNP on Chr11 Segregates with Increase in CD8 MP T Cells (A) Whole-genome SNP array revealed 399 SNPs that differ between N10-Siae and C57BL/6J. On chr9, 276 SNPs (blue triangles) in the Siae locus are shared by 129 strains; 123 SNPs (red triangles) appear to be of C57BL/6N origin. (B) Linkage between candidate SNPs and CD8+ MP expansion in the progeny of test crosses (n = 18) described in Figure 2A. A SNP on chr11 (rs29391827) was found to segregate with the CD8 MP (n = 18). (C) The observation in (B) was validated in a larger cohort (n = 156). See also Figure S2 and Table S1. Cell Reports 2016 15, 1901-1909DOI: (10.1016/j.celrep.2016.04.080) Copyright © 2016 The Author(s) Terms and Conditions

Figure 4 A Genomic Segment Encoding Exons 28 and 29 of Dock2 Is Duplicated in N10-Siae and Cmah−/− Mice (A) An abrupt increase in coverage depth within the putative pathogenic locus on chr11 mapped by SNPs encompasses exons 28 and 29 of Dock2 in the N10-Siae genome. (B) PCR detection of Dock2 duplication in N10-Siae, Cmah−/−, N23-Siae, and C57BL/6J mice. See also Figures S3–S5. Cell Reports 2016 15, 1901-1909DOI: (10.1016/j.celrep.2016.04.080) Copyright © 2016 The Author(s) Terms and Conditions

Figure 5 The Dock2 Duplication Is Present in the C57BL/6NHsd Strain, which Exhibits Multiple Characteristics of Dock2 Deficiency (A) PCR detection of Dock2 duplication in C57BL/6NHsd mice and other C57BL6/N sublines (C57BL/6NTac and C57BL6/NJ). (B) Sequences of the Dock2 duplication breakpoint (arrow) from C57BL/6NHsd, N10-Siae, and IRF5−/− mice. A low-complexity sequence at the site of the breakpoint is shown in lowercase. (C) Proportion of CD8+ MP cells, MZ B cells, invariant NK T cells, and plasmacytoid dendritic cells in C57BL/6NHsd, C57BL/6NTac, and C57BL/6J mice. The data shown are representative of five mice each. See also Figure S5. Cell Reports 2016 15, 1901-1909DOI: (10.1016/j.celrep.2016.04.080) Copyright © 2016 The Author(s) Terms and Conditions