Facilitating Complex Trait Analysis via Reduced Complexity Crosses

Camron D Bryant; Desmond J Smith; Kathleen M Kantak; Thaddeus S Nowak Jr; Robert W Williams; M Imad Damaj; Eva E Redei; Hao Chen; Megan K Mulligan

doi:10.1016/j.tig.2020.05.003

Facilitating Complex Trait Analysis via Reduced Complexity Crosses

Trends Genet. 2020 Aug;36(8):549-562. doi: 10.1016/j.tig.2020.05.003. Epub 2020 May 29.

Authors

Camron D Bryant¹, Desmond J Smith², Kathleen M Kantak³, Thaddeus S Nowak Jr⁴, Robert W Williams⁵, M Imad Damaj⁶, Eva E Redei⁷, Hao Chen⁸, Megan K Mulligan⁵

Affiliations

¹ Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, 72 E. Concord Street, L-606C, Boston, MA 02118, USA. Electronic address: camron@bu.edu.
² Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Box 951735, Los Angeles, CA 90095, USA.
³ Department of Psychological and Brain Sciences, Boston University, 64 Cummington Mall, Boston, MA 02215, USA.
⁴ Department of Neurology and Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, TN 38163, USA.
⁵ Department of Genetics, Genomics and Informatics, College of Medicine, The University of Tennessee Health Science Center, 71 S. Manassas, Memphis, TN 38163, USA.
⁶ Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁷ Department of Psychiatry and Behavioral Sciences and Physiology, Northwestern University, Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
⁸ Department of Pharmacology, Addiction Science, and Toxicology, College of Medicine, The University of Tennessee Health Science Center, 71 South Manassas, Memphis, TN 38163, USA.

Abstract

Genetically diverse inbred strains are frequently used in quantitative trait mapping to identify sequence variants underlying trait variation. Poor locus resolution and high genetic complexity impede variant discovery. As a solution, we explore reduced complexity crosses (RCCs) between phenotypically divergent, yet genetically similar, rodent substrains. RCCs accelerate functional variant discovery via decreasing the number of segregating variants by orders of magnitude. The simplified genetic architecture of RCCs often permit immediate identification of causal variants or rapid fine-mapping of broad loci to smaller intervals. Whole-genome sequences of substrains make RCCs possible by supporting the development of array- and targeted sequencing-based genotyping platforms, coupled with rapid genome editing for variant validation. In summary, RCCs enhance discovery-based genetics of complex traits.

Keywords: GWAS; functional variant; positional cloning; rat genetics; substrain, QTL.

Publication types

Research Support, N.I.H., Extramural
Review

MeSH terms

Animals
Chromosome Mapping
Chromosomes, Mammalian / genetics*
Crosses, Genetic*
Genotype
Multifactorial Inheritance*
Phenotype
Polymorphism, Single Nucleotide*
Quantitative Trait Loci*
Rodentia

Abstract

Publication types

MeSH terms

Grants and funding