Faculty Collaboration Database

Chromosomal Substitution Strategies to Localize Genomic Regions Related to Complex Traits. Compr Physiol 2020 Mar 12;10(2):365-388

Date

03/13/2020

Pubmed ID

32163204

DOI

10.1002/cphy.c180029

Scopus ID

2-s2.0-85081890516 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

Chromosomal substitution strategies provide a powerful tool to anonymously reveal the relationship between DNA sequence variants and a normal or disease phenotype of interest. Even in this age of CRISPR-Cas9 genome engineering, the knockdown or overexpression of a gene provides relevant information to our understanding of complex disease only when a close association of an allelic variant with the phenotype has first been established. Limitations of genetic linkage approaches led to the development of more efficient breeding strategies to substitute chromosomal segments from one animal strain into the genetic background of a different strain, enabling a direct comparison of the phenotypes of the strains with variant(s) that differ only at a defined locus. This substitution can be a whole chromosome (consomic), a part of a chromosome (congenic), or as small as only a single or several alleles (subcongenics). In contrast to complete knockout of a specific candidate gene of interest, which simply studies the effects of complete elimination of the gene, the substitution of naturally occurring variants can provide special insights into the functional actions of wild-type alleles. Strategies for production of these inbred strains are reviewed, and a number of examples are used to illustrate the utility of these model systems. Consomic/congenic strains provide a number of experimental advantages in the study of functions of genes and their variants, which are emphasized in this article, such as replication of experimental studies; determination of temporal relationships throughout a life; rigorously controlled experiments in which relations between genotype and phenotype can be tested with the confounding effects of heterogeneous genetic backgrounds, both targeted and multilayered; and "omic" studies performed at many levels of functionality, from molecules to organelles, cells to organs, and organs to organismal behavior across the life span. The application of chromosomal substitution strategies and development of consomic/congenic rat and mouse strains have greatly expanded our knowledge of genomic variants and their phenotypic relationship to physiological functions and to complex diseases such as hypertension and cancer. © 2020 American Physiological Society. Compr Physiol 10:365-388, 2020.

Author List

Cowley AW Jr, Dwinell MR

Authors

Allen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin
Melinda R. Dwinell PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Congenic
Chromosomes
Genetic Linkage
Genomics
Humans
Hypertension
Mice
Multifactorial Inheritance
Phenotype
Quantitative Trait, Heritable
Rats