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Modifier genes in mice and humans

Key Points

  • 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.

  • Genetic modification is apparent in humans and mice when environmental factors and alleles of a disease gene cannot explain the modification of a phenotype.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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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Figure 1: Types of modification.
Figure 2: A model of modification.

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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.

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASE LINKS

disorganization

undulated

short-ear

Pax1

Bmp5

mdfw

T mutation

brachyury

splotch

Pax3

Fidget

Fign

dilute suppressor mutation

Myo5a

dsu

ashen

Rab27a

leaden

ln

ruby-eye

ru

ruby-eye 2

ru2

tubby

Patch

Pdgfrα

undulated

Curly-tail

DFNB26

mitochondrial 12S ribosomal gene

PRP1

retinitis pigmentosa

ROM1

familial hypercholesterolaemia

familial Meditteranean fever

pyrin/marenostrin

serum amyloid A

cystic fibrosis

CFTR

Cftr

familial adenomatous polyposis

APC

Min

Apc

Pla2g2a

Cox2 activity in the prostaglandin pathway

Cox2

cytosolic phospholipase A2

FURTHER INFORMATION

Mouse genome sequencing at Celera

ENCYCLOPEDIA OF LIFE SCIENCES

Genotype–phenotype relationships

Glossary

INBRED STRAINS

Mouse strains generated through systematic inbreeding, which results in virtual genetic homozygosity.

CONGENIC STRAINS

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

Fused digits.

POLYDACTYLY

Supernumerary digits.

FORAMINA TRANSVERSARIA IMPERFECTA

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

Failure of vertebral fusion but when skin covers the open arches and without the protrusion of a hernia.

KYPHOSIS

The abnormal curvature of the thoracic spine.

RACHISCHISIS

A form of spina bifida in which the spinal cord is split.

ANENCEPHALY

Absence of the greater part of the brain, often with skull deformity.

RENAL AMYLOIDOSIS

A metabolic disorder associated with the deposition of amyloid (a protein–polysaccharide complex) in the kidney.

SEROSAL INFLAMMATION

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

The inadequate functioning of the pancreas that results from the blockage of the pancreatic duct, which prevents the secretion of pancreatic fluids.

MECONIUM ILEUS

Obstruction of the intestine by mucus.

BILIARY CIRRHOSIS

Cirrhosis of the liver that results from the obstruction and inflammation of the bile ducts and from the chronic retention of bile.

ADENOMATOUS POLYPS

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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