Diversity Outbred Mice at 21: Maintaining Allelic Variation in the Face of Selection.
Multi-parent populations (MPPs) capture and maintain the genetic diversity from multiple inbred founder strains to provide a resource for high-resolution genetic mapping through the accumulation of recombination events over many generations. Breeding designs that maintain a large effective population size with randomized assignment of breeders at each generation can minimize the impact of selection, inbreeding, and genetic drift on allele frequencies. Small deviations from expected allele frequencies will have little effect on the power and precision of genetic analysis, but a major distortion could result in reduced power and loss of important functional alleles. We detected strong transmission ratio distortion in the Diversity Outbred (DO) mouse population on chromosome 2, caused by meiotic drive favoring transmission of the WSB/EiJ allele at the R2d2 locus. The distorted region harbors thousands of polymorphisms derived from the seven non-WSB founder strains and many of these would be lost if the sweep was allowed to continue. To ensure the utility of the DO population to study genetic variation on chromosome 2, we performed an artificial selection against WSB/EiJ alleles at the R2d2 locus. Here, we report that we have purged the WSB/EiJ allele from the drive locus while preserving WSB/EiJ alleles in the flanking regions. We observed minimal disruption to allele frequencies across the rest of the autosomal genome. However, there was a shift in haplotype frequencies of the mitochondrial genome and an increase in the rate of an unusual sex chromosome aneuploidy. The DO population has been restored to genome-wide utility for genetic analysis, but our experience underscores that vigilant monitoring of similar genetic resource populations is needed to ensure their long-term utility.
The Jackson Laboratory, Bar Harbor, Maine 04609.
Elissa J
EJ
Chesler
The Jackson Laboratory, Bar Harbor, Maine 04609.
Daniel M
DM
Gatti
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599-7264.
Andrew P
AP
Morgan
The Jackson Laboratory, Bar Harbor, Maine 04609.
Marge
M
Strobel
The Jackson Laboratory, Bar Harbor, Maine 04609.
Laura
L
Trepanier
Department of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health & Science University, Oregon 97201.
Denesa
D
Oberbeck
Department of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health & Science University, Oregon 97201.
Shannon
S
McWeeney
Department of Behavioral Neuroscience and Portland Alcohol Research Center, Oregon Health & Science University, Oregon 97201.
Robert
R
Hitzemann
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599-7264.
Martin
M
Ferris
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599-7264.
Rachel
R
McMullan
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599-7264.
Amelia
A
Clayshultle
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599-7264.
Timothy A
TA
Bell
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599-7264.
Fernando Pardo
FP
Manuel de Villena
The Jackson Laboratory, Bar Harbor, Maine 04609 gary.churchill@jax.org.
Gary A
GA
Churchill
D000483:Alleles; D000818:Animals; D001947:Breeding; D019295:Computational Biology / Q000379:methods; D003433:Crosses, Genetic; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D014644:Genetic Variation; D005828:Genetics, Population; D016678:Genome; D023281:Genomics / Q000379:methods; D006239:Haplotypes; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000235:genetics; D058977:Molecular Sequence Annotation; D009154:Mutation; D010641:Phenotype; D012641:Selection, Genetic; D012729:Sex Chromosome Aberrations; D012744:Sex Ratio
Multiparent Advanced Generation Inter-Cross (MAGIC); aneuploidy; meiotic drive; multiparental populations MPP; transmission ratio distortion
G3 (Bethesda). 2014 Sep 18;4(9):1623-33
25237114
Genetics. 2016 Sep;204(1):267-85
27371833
Genetics. 2016 Feb;202(2):787-98
26614740
G3 (Bethesda). 2015 Dec 18;6(2):281-6
26684930
PLoS Genet. 2015 Feb 13;11(2):e1004850
25679959
Food Chem Toxicol. 2015 Feb;76:19-26
25446466
Nature. 2011 Sep 14;477(7364):289-94
21921910
Environ Health Perspect. 2015 Mar;123(3):237-45
25376053
Genetics. 2014 Sep;198(1):17-29
25236446
Genetics. 2012 Feb;190(2):437-47
22345611
Genetics. 2014 Dec;198(4):1751-8
25313128
Mamm Genome. 2008 Jun;19(6):382-9
18716833
Genetics. 2012 Feb;190(2):389-401
22345608
Mamm Genome. 2014 Jun;25(5-6):211-22
24700285
Genome Res. 2011 Aug;21(8):1213-22
21406540
BMC Genomics. 2010 Oct 19;11:585
20959017
Nature. 2016 Jun 15;534(7608):500-5
27309819
Mamm Genome. 2012 Aug;23(7-8):454-66
22763584
Genetics. 2008 Jun;179(2):1069-78
18505881
Mamm Genome. 2012 Oct;23(9-10):706-12
22847377
Mol Biol Evol. 2016 Jun;33(6):1381-95
26882987
Genetics. 2014 May;197(1):91-106
24578350
G3 (Bethesda). 2014 Oct 23;4(12 ):2353-63
25344410
Trends Endocrinol Metab. 2015 Dec;26(12 ):673-5
26555601
G3 (Bethesda). 2015 Dec 18;6(2):263-79
26684931
Nat Genet. 2011 May 29;43(7):648-55
21623374
Genome Biol. 2015 Sep 11;16:167
26357913
Genome Res. 2014 Jul;24(7):1193-208
24714809