Key Points
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The consistent expression of Mendelian traits in both mice and humans is the exception rather than the rule. Many biological aspects of a trait can vary and for different reasons. However, one common cause of phenotypic variation is when the expression of one gene alters the expression of another gene. This is called genetic modification.
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Genetic modification is apparent in humans and mice when environmental factors and alleles of a disease gene cannot explain the modification of a phenotype.
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The effects of modifier genes include reduced penetrance, dominance modification, expressivity and phenotypic pleiotropy. These effects are commonly seen when mice (with single gene mutations) are crossed onto different genetic backgrounds.
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Modifier genes also alter the onset, the range of symptoms and the severity of disease in humans. Studies in animal models can guide the search for modifier loci in humans and their identification.
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The discovery of a mouse gene that modifies cystic fibrosis in Cftr-knockout mice led to the successful prediction of a corresponding gene in humans.
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Not all mouse modifier loci lead to the identification of corresponding loci in humans. But they can lead to the identification of therapeutically relevant pathways, as did the identification of a gene, Mom1, that modifies polyp number in a mouse model of adenomatous polyposis coli.
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New disease therapeutic opportunities could come from mimicking the effects of trait-suppressing modifiers. And studies into modifier genes and their targets should lead to new insights into biological processes and pathways. Future advances in this field are likely to stem from the availability of the human and mouse genomes.
Abstract
An emerging theme of studies with spontaneous, engineered and induced mutant mice is that phenotypes often depend on genetic background, implying that genetic modifiers have a role in guiding the functional consequences of genetic variation. Understanding the molecular and cellular basis by which modifier genes exert their influence will provide insights into developmental and physiological pathways that are critical to fundamental biological processes, as well as into novel targets for therapeutic interventions in human diseases.
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Acknowledgements
I thank A. Matin for insightful discussions about modifier genes, N. Robin for sharing examples of modifier genes, and M. Drumm and M. Taketo for comments on portions of this manuscript. This work was supported by grants from the NIH, by a grant from the Keck Foundation to the Department of Genetics, and by a grant from the Howard Hughes Medical Institute to the Case Western Reserve University School of Medicine.
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DATABASE LINKS
mitochondrial 12S ribosomal gene
familial hypercholesterolaemia
familial adenomatous polyposis
Cox2 activity in the prostaglandin pathway
FURTHER INFORMATION
Mouse genome sequencing at Celera
ENCYCLOPEDIA OF LIFE SCIENCES
Glossary
- INBRED STRAINS
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Mouse strains generated through systematic inbreeding, which results in virtual genetic homozygosity.
- CONGENIC STRAINS
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Mouse strains in which a chromosome segment from one inbred strain background has been transferred to another inbred strain background by repeated backcrossing and selection, either for the phenotype of interest or for genotypes of marker loci that flank the mutant gene of interest.
- SYNDACTYLY
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Fused digits.
- POLYDACTYLY
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Supernumerary digits.
- FORAMINA TRANSVERSARIA IMPERFECTA
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An opening for nerves and blood vessels in the transverse process of the cervical vertebrae. The presence and size of this aperture (called a foramen) is variable.
- SPINA BIFIDA OCCULTA
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Failure of vertebral fusion but when skin covers the open arches and without the protrusion of a hernia.
- KYPHOSIS
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The abnormal curvature of the thoracic spine.
- RACHISCHISIS
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A form of spina bifida in which the spinal cord is split.
- ANENCEPHALY
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Absence of the greater part of the brain, often with skull deformity.
- RENAL AMYLOIDOSIS
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A metabolic disorder associated with the deposition of amyloid (a protein–polysaccharide complex) in the kidney.
- SEROSAL INFLAMMATION
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Inflammation of the membranes that line the chest and peritoneal cavities and that enclose the lungs, the heart, the main blood vessels and the gut.
- PANCREATIC INSUFFICIENCY
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The inadequate functioning of the pancreas that results from the blockage of the pancreatic duct, which prevents the secretion of pancreatic fluids.
- MECONIUM ILEUS
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Obstruction of the intestine by mucus.
- BILIARY CIRRHOSIS
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Cirrhosis of the liver that results from the obstruction and inflammation of the bile ducts and from the chronic retention of bile.
- ADENOMATOUS POLYPS
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Benign growths that arise from the lining of the colon or rectum, which can protrude into the intestinal lumen.
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Nadeau, J. Modifier genes in mice and humans. Nat Rev Genet 2, 165–174 (2001). https://doi.org/10.1038/35056009
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DOI: https://doi.org/10.1038/35056009
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