Genetic background effects in Neuroligin-3 mutant mice: Minimal behavioral abnormalities on C57 background

BackgroundDeletions removing 100s–1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individual’s clinical phenotype is challenging.MethodsHere, as an example of this common phenomenon, we analysed 41 patients with simple deletions of ~177 to ~2000 kb affecting one allele of the well-characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised deletion extents and screened for genetic background effects, telomere position effect and compensatory upregulation of hemizygous genes.ResultsWe find the risk of developmental and neurological abnormalities arises from much smaller distal chromosome 16 deletions (~400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes; however, genetic background effects substantially modify phenotypic abnormalities.ConclusionsUsing ATR-16 as a general model of disorders caused by CNVs, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling.

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Deletion of Ku70, Ku80, or Both Causes Early Aging without Substantially Increased Cancer

Molecular and Cellular Biology ◽

10.1128/mcb.00785-07 ◽

2007 ◽

Vol 27 (23) ◽

pp. 8205-8214 ◽

Cited By ~ 85

Author(s):

Han Li ◽

Hannes Vogel ◽

Valerie B. Holcomb ◽

Yansong Gu ◽

Paul Hasty

Keyword(s):

Genetic Background ◽

Double Mutant ◽

Severe Combined Immunodeficiency ◽

Nonhomologous End Joining ◽

Mutant Mice ◽

Combined Immunodeficiency ◽

End Joining ◽

High Incidence ◽

Early Aging ◽

Increased Sensitivity

ABSTRACT Ku70 forms a heterodimer with Ku80, called Ku, that is critical for repairing DNA double-stand breaks by nonhomologous end joining and for maintaining telomeres. Mice with either gene mutated exhibit similar phenotypes that include increased sensitivity to ionizing radiation and severe combined immunodeficiency. However, there are also differences in the reported phenotypes. For example, only Ku70 mutants are reported to exhibit a high incidence of thymic lymphomas while only Ku80 mutants are reported to exhibit early aging with very low cancer levels. There are two explanations for these differences. First, either Ku70 or Ku80 functions outside the Ku heterodimer such that deletion of one is not identical to deletion of the other. Second, divergent genetic backgrounds or environments influence the phenotype. To distinguish between these possibilities, the Ku70 and Ku80 mutations were crossed together to generate Ku70, Ku80, and double-mutant mice in the same genetic background raised in the same environment. We show that these three cohorts have similar phenotypes that most resemble the previous report for Ku80 mutant mice, i.e., early aging without substantially increased cancer levels. Thus, our observations suggest that the Ku heterodimer is important for longevity assurance in mice since divergent genetic backgrounds and/or environments likely account for these previously reported differences.

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Influence of genetic background and gender on hypertension and renal failure in COX-2-deficient mice

AJP Renal Physiology ◽

10.1152/ajprenal.00219.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. F1125-F1132 ◽

Cited By ~ 59

Author(s):

Tianxin Yang ◽

Yuning G. Huang ◽

Wenling Ye ◽

Pernille Hansen ◽

Jurgen B. Schnermann ◽

...

Keyword(s):

Renal Failure ◽

Knockout Mice ◽

Genetic Background ◽

Inflammatory Cells ◽

Inbred Strains ◽

Cox 2 ◽

And Gender ◽

Genetic Background Effects ◽

Deficient Mice ◽

Nephrogenic Zone

The present study was undertaken to determine whether the severity of renal failure or hypertension in homozygous cyclooxygenase (COX)-2-deficient (COX-2−/−) mice affected by genetic background or gender. COX-2 deletion was introduced into three congenic genetic backgrounds, 129/Sv (129/COX-2−/−), C57/BL6 (C57/COX-2−/−), and BALB/c (BALB/COX-2−/−), by backcrossing the original mixed-background knockout mice with the respective inbred strains for 9 or 10 generations. Evaluation of the severity of hypertension and renal failure was performed in knockout and wild-type mice at the age of 2.5–3.5 mo. Blood pressure measured by tail-cuff plethysmography was significantly elevated in the male 129/COX-2−/− mice (165.8 ± 9.2 vs. 116 ± 5.1 mmHg, P < 0.05), and to a much lesser extent in the female 129/COX-2−/− mice (127.4 ± 3.3 vs. 102.4 ± 3.3), whereas it was unchanged in the C57- or BALB/COX-2−/− mice regardless of gender. Urinary excretion of albumin, determined by EIA, was remarkably increased in the 129/COX-2−/− (16.4 ± 4.1 vs. 0.16 ± 0.043 mg albumin/mg creatinine, P < 0.001), and to a lesser extent in the male C57/COX-2−/− mice (0.595 ± 0.416 vs. 0.068 ± 0.019). Albumin excretion was not elevated in the male BALB/COX-2−/− or in female COX-2−/− mice on any of the three genetic backgrounds. Histological analysis showed abundant protein casts, dilated tubules, and infiltration of inflammatory cells in the male 129/COX-2−/− mice, but not in COX-2−/− mice in other strains or gender. However, the presence of small glomeruli in the nephrogenic zone was observed in all strains of COX-2 knockout mice, regardless of genetic background and gender. Therefore, we conclude that the severity of hypertension and renal failure in COX-2-deficient mice is influenced by genetic background and gender, whereas the incomplete maturation of outer cortical nephrons appears to be independent of genetic background effects.

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Genetic background effects on dental and other craniofacial abnormalities in homozygous small eye ( Pax6 Sey /Pax6 Sey ) mice

Anatomy and Embryology ◽

10.1007/s004290050100 ◽

1997 ◽

Vol 196 (4) ◽

pp. 311-321 ◽

Cited By ~ 23

Author(s):

Jane C. Quinn ◽

John D. West ◽

M. H. Kaufman

Keyword(s):

Genetic Background ◽

Craniofacial Abnormalities ◽

Genetic Background Effects

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ATR16 Syndrome: Mechanisms Linking Monosomy to Phenotype

10.1101/768895 ◽

2019 ◽

Author(s):

Christian Babbs ◽

Jill Brown ◽

Sharon W. Horsley ◽

Joanne Slater ◽

Evie Maifoshie ◽

...

Keyword(s):

Genetic Background ◽

Position Effect ◽

Distal Region ◽

Copy Number Variations ◽

Chromosome 16 ◽

Developmental Abnormalities ◽

Telomere Position Effect ◽

Wide Range ◽

Genetic Background Effects ◽

Critical Regions

AbstractBackgroundSporadic deletions removing 100s-1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individual’s clinical phenotype is challenging.MethodsHere, as an example of this common phenomenon, we analysed 34 patients with simple deletions of ∼177 to ∼2000 kb affecting one allele of the well characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised precise deletion extent and screened for genetic background effects, telomere position effect and compensatory up regulation of hemizygous genes.ResultsWe find the risk of developmental and neurological abnormalities arises from much smaller terminal chromosome 16 deletions (∼400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes, however, genetic background effects substantially modify phenotypic abnormalities.ConclusionsUsing ATR-16 as a general model of disorders caused by sporadic copy number variations, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but also depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling.

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