Diversity outbred mice at 21: Maintaining allelic variation in the face of selection

Elissa J. Chesler, Daniel M. Gatti, Andrew P. Morgan, Marge Strobel, Laura Trepanier, Denesa Oberbeck, Shannon McWeeney, Robert Hitzemann, Martin Ferris, Rachel McMullan, Amelia Clayshultle, Timothy A. Bell, Fernando Pardo Manuel de Villena, Gary A. Churchill

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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 theWSB/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.

Original languageEnglish (US)
Pages (from-to)3893-3902
Number of pages10
JournalG3: Genes, Genomes, Genetics
Volume6
Issue number12
DOIs
StatePublished - 2016

Fingerprint

Alleles
Gene Frequency
Chromosomes, Human, Pair 2
Population
Genome
Genetic Drift
Sex Chromosomes
Mitochondrial Genome
Inbreeding
Population Genetics
Aneuploidy
Population Density
Haplotypes
Genetic Recombination
Breeding

Keywords

  • Aneuploidy
  • Meiotic drive
  • Multiparent Advanced Generation Inter-Cross (MAGIC)
  • Multiparental populations MPP
  • Transmission ratio distortion

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Chesler, E. J., Gatti, D. M., Morgan, A. P., Strobel, M., Trepanier, L., Oberbeck, D., ... Churchill, G. A. (2016). Diversity outbred mice at 21: Maintaining allelic variation in the face of selection. G3: Genes, Genomes, Genetics, 6(12), 3893-3902. https://doi.org/10.1534/g3.116.035527

Diversity outbred mice at 21 : Maintaining allelic variation in the face of selection. / Chesler, Elissa J.; Gatti, Daniel M.; Morgan, Andrew P.; Strobel, Marge; Trepanier, Laura; Oberbeck, Denesa; McWeeney, Shannon; Hitzemann, Robert; Ferris, Martin; McMullan, Rachel; Clayshultle, Amelia; Bell, Timothy A.; de Villena, Fernando Pardo Manuel; Churchill, Gary A.

In: G3: Genes, Genomes, Genetics, Vol. 6, No. 12, 2016, p. 3893-3902.

Research output: Contribution to journalArticle

Chesler, EJ, Gatti, DM, Morgan, AP, Strobel, M, Trepanier, L, Oberbeck, D, McWeeney, S, Hitzemann, R, Ferris, M, McMullan, R, Clayshultle, A, Bell, TA, de Villena, FPM & Churchill, GA 2016, 'Diversity outbred mice at 21: Maintaining allelic variation in the face of selection', G3: Genes, Genomes, Genetics, vol. 6, no. 12, pp. 3893-3902. https://doi.org/10.1534/g3.116.035527
Chesler EJ, Gatti DM, Morgan AP, Strobel M, Trepanier L, Oberbeck D et al. Diversity outbred mice at 21: Maintaining allelic variation in the face of selection. G3: Genes, Genomes, Genetics. 2016;6(12):3893-3902. https://doi.org/10.1534/g3.116.035527
Chesler, Elissa J. ; Gatti, Daniel M. ; Morgan, Andrew P. ; Strobel, Marge ; Trepanier, Laura ; Oberbeck, Denesa ; McWeeney, Shannon ; Hitzemann, Robert ; Ferris, Martin ; McMullan, Rachel ; Clayshultle, Amelia ; Bell, Timothy A. ; de Villena, Fernando Pardo Manuel ; Churchill, Gary A. / Diversity outbred mice at 21 : Maintaining allelic variation in the face of selection. In: G3: Genes, Genomes, Genetics. 2016 ; Vol. 6, No. 12. pp. 3893-3902.
@article{275cd1dd90ca4a90b8a9f38e3a5f7f04,
title = "Diversity outbred mice at 21: Maintaining allelic variation in the face of selection",
abstract = "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 theWSB/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.",
keywords = "Aneuploidy, Meiotic drive, Multiparent Advanced Generation Inter-Cross (MAGIC), Multiparental populations MPP, Transmission ratio distortion",
author = "Chesler, {Elissa J.} and Gatti, {Daniel M.} and Morgan, {Andrew P.} and Marge Strobel and Laura Trepanier and Denesa Oberbeck and Shannon McWeeney and Robert Hitzemann and Martin Ferris and Rachel McMullan and Amelia Clayshultle and Bell, {Timothy A.} and {de Villena}, {Fernando Pardo Manuel} and Churchill, {Gary A.}",
year = "2016",
doi = "10.1534/g3.116.035527",
language = "English (US)",
volume = "6",
pages = "3893--3902",
journal = "G3: Genes, Genomes, Genetics",
issn = "2160-1836",
publisher = "Genetics Society of America",
number = "12",

}

TY - JOUR

T1 - Diversity outbred mice at 21

T2 - Maintaining allelic variation in the face of selection

AU - Chesler, Elissa J.

AU - Gatti, Daniel M.

AU - Morgan, Andrew P.

AU - Strobel, Marge

AU - Trepanier, Laura

AU - Oberbeck, Denesa

AU - McWeeney, Shannon

AU - Hitzemann, Robert

AU - Ferris, Martin

AU - McMullan, Rachel

AU - Clayshultle, Amelia

AU - Bell, Timothy A.

AU - de Villena, Fernando Pardo Manuel

AU - Churchill, Gary A.

PY - 2016

Y1 - 2016

N2 - 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 theWSB/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.

AB - 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 theWSB/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.

KW - Aneuploidy

KW - Meiotic drive

KW - Multiparent Advanced Generation Inter-Cross (MAGIC)

KW - Multiparental populations MPP

KW - Transmission ratio distortion

UR - http://www.scopus.com/inward/record.url?scp=85008506997&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85008506997&partnerID=8YFLogxK

U2 - 10.1534/g3.116.035527

DO - 10.1534/g3.116.035527

M3 - Article

C2 - 27694113

AN - SCOPUS:85008506997

VL - 6

SP - 3893

EP - 3902

JO - G3: Genes, Genomes, Genetics

JF - G3: Genes, Genomes, Genetics

SN - 2160-1836

IS - 12

ER -