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Genetic Drift: What It Is and Its Impact on Your Research

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Genetic Drift: What It Is and Its Impact on Your Research Genetic Drift: What It Is and Its Impact on Your Research Name: Jens Fritsche, Ph.D. Date: Homburg, 24.10.2019 Presented by Charles River, exclusive distributor of JAX ™ Mice in Europe and parts of Asia Mission of The Jackson Laboratory™ “To discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.” Biomedical Research Genetics, genomics and biology of human disease Resources & Services PRECLINICAL: Mouse models & research services CLINICAL: Clinical genomics services and JAX Clinical Knowledgebase (JAX-CKB) Education & Training Courses, conferences, internships, pre-doctoral and post-doctoral training, live webinars, on-demand videos, on-site seminars and other programs 2 JAX™ MiceJAX™ Mice TheThe Gold Gold StandardStandard forfor BiomedicalBiomedical Research Research NIH-funded resource >11,000 strains and growing o >3 million mice shipped annually Unsurpassed genetic quality and animal health Best characterized and referenced (~100 new pubs/week) Common inbred strains (e.g., C57BL/6J, BALB/cJ) support development/collection of specialty strains and other valuable community research resources JAX™ Mice | 3 Online Resources to Expedite Research JAX™ Mice Database www.jax.org/mouse-search Mouse Genome Informatics www.informatics.jax.org Mouse Phenome Database www.jax.org/phenome Others, including: JAX-Clinical Knowledgebase Mouse Tumor Biology Database JAX™ Technical Support | 4 Today’s Learning Goals Recognize genetic background of your mouse strain o Use proper nomenclature o Select appropriate controls Implement strategies to reduce genetic drift and increase experimental reproducibility JAX.org | 5 What is Genetic Drift? “The constant tendency of genes to evolve even in the absence of selective forces. Genetic drift is fueled by spontaneous neutral mutations that disappear or become fixed in a population at random” o Lee Silver, “Mouse Genetics” Oxford University Press, 1995 www.informatics.jax.org/silverbook/ Genetic changes resulting from mistakes in meiosis or DNA repair o Single base changes o Deletions o Duplications o Inversions JAX.org | 6 Genetic Drift Promotes Diversity muscular dystrophy Lama2dy-2J Phenotypic Diversity Species Diversity Data Diversity JAX.org | 7 Visible Genetic Drift Coat Color Mutations C57BL/6J-Aw-J/J B6(Cg)-Tyrc-2J/J (000051) (000058) C57BL/6J (000664) C57BL/6J-Lystbg-J/J C57BL/6J-KitW-v/J (000629) (000049) JAX™ Mice | 8 How Rapidly Do Colonies Drift? “Visible” mutation example Using spontaneous mutation rates in coat color genes, -5 o Measured ~1.1 x 10 mutations/locus/gamete/gen. Assuming ~25,000 genes in mice, -5 o (1.1 x 10 mutations/locus/gamete/gen.)*(25,000 loci) o 0.275 mutations/gamete/gen. o 1 mutations/3.64 gametes/gen. 1 phenotypic mutation arises every 1.8 generations o Likely underrepresents overall mutation rate due to visibility of mutation Russell LB and Russell WL., 1996. PNAS PMID 8917546 Drake JW et al., 1998, Genetics PMID 9560386 JAX.org | 9 How Rapidly Do Colonies Drift? Mice have a high rate of spontaneous mutation Approx. 25% chance that new mutations will become fixed New mutations in coding sequence become fixed every 6-9 generations o (Assumptions: inbreeding; small breeding population) JAX.org | 10 How Rapidly Do Colonies Drift? “Invisible” mutation example Using whole genome sequencing of C57BL/6J, o Measured 2 samples separated by 69 filial gens. Differences found o 669 SNPs (~ 10/gen.) o 272/669 SNPs were in genetic coding & non-coding regions o 7/272 SNPs altered DNA coding sequence or RNA splicing ~1 “impactful” mutation every 10 generations o Likely underrepresents overall mutation rate because the analysis did not include non-SNP mutations (deletions, inversions, CNV changes). JAX.org | 11 “Invisible” Genetic Drift in C57BL/6 Published example: Loss of presynaptic protein α-synuclein (Snca) C57BL/6J Genomic DNA from The Jackson Laboratory Wild-type Snca C57BL/6NCrl Mice from Charles River, Margate, UK Wild-type Snca C57BL/6JOlaHsd Mice from Harlan, Bicester, UK Deletion of Snca – No visible phenotype but… SNCA protein: implicated in a range of neurodegenerative diseases; primary structural component of Lewy bodies found in Parkinson’s disease brains Specht CG and Schoepfer R. 2001. BMC Neurosci 2:11. PMID:11591219 JAX® Mice | 12 Genetic Drift and Colony Size Small colonies are more vulnerable to fix a mutation For any given mutation, = heterozygous mutation JAX.org | 13 Genetic Drift and Colony Size Small colonies are more vulnerable to fix a mutation WT Het Hom JAX.org | 14 C57BL/6 Substrain Divergence Substrains: Branch of an inbred strain known or suspected to be genetically different from the parent colony. JAX™ Mice | 15 Substrain Development 20 generations apart JAX® Mice | 16 Know Your Substrain Use Proper Nomenclature C57BL/6J Parent strain Substrain designation C57BL/6NJ NIH (N) By (Dr. Bailey) C57BL/6NCrl Laboratory maintaining the strain Jackson (J) Crl (Charles River Laboratories) C57BL/6ByJ Institute for Laboratory Animal Research (ILAR) Lab Codes http://dels.nas.edu/global/ilar/Lab-Codes JAX™ Mice | 17 C57BL/6 Publications Complete nomenclature benefits everyone! Based on October, 2018 PubMed citations search (without limits) Nomenclature for Mouse Strains | 18 But Aren’t All B6 Mice the Same? C57BL/6 substrains are not the same! They differ genetically o Single Nucleotide Polymorphisms (SNPs) o Insertions & deletions (Indels) o Copy number variations (CNVs) o Spontaneous mutations JAX™ Mice | 20 Genetic Differences Translate into Phenotypic Differences Neurobiology o Retinal degeneration, Case #1 Metabolism o Response to high-fat diet, Case #2 Immunology o Sensitivity to infection, Case #3 o Immune phenotypes, Case #4 And more… JAX™ Mice | 21 “Invisible” Genetic Drift in C57BL/6 Case Study #1: Retinal degeneration in C57BL/6N substrains Crb1 (crumbs-like 1) Localized to Muller cells and photoreceptor (PC) inner segments Mutations in CRB1 associated with retinal diseases in humans Retinitis pigmentosa o http://crfb.univ-mrs.fr/Crumbs/section/en/CRB1_function/105 o Leber congenital amaurosis Crb1rd8 Single base deletion Shorter PC inner & outer segments as early as two weeks Progressive, spotty retinal degeneration Mehallow AK et al. 2003. Hum Mol Gen 12(17):2179-2189. PMID:12915475 JAX™ Mice | 22 “Invisible” Genetic Drift in C57BL/6 Case Study #1: Retinal degeneration in C57BL/6N substrains C57BL/6J: Crb1 wild-type C57BL/6N: Crb1rd8/Crb1rd8 C57BL/6N – For C57BL/6N – Rev C57BL/6J – For C57BL/6J – Rev ALL C57BL/6N substrains are Crb1rd8/Crb1rd8 HSD (Harlan) CRL (Charles River) rd8 DCT (Frederick Nat’l Lab) wild-type TAC (Taconic) Mattapallil, MJ et al. 2012. Invest Ophthalmol Vis Sci PMID 22447858 JAX™ Mice | 23 Metabolic Differences (DIO) Case Study #2: Response to high-fat diet in C57BL/6 C57BL/6J (000664) vs C57BL/6NJ (005304) Mice fed a 60 kcal% high fat diet Nicholson, A et al. 2010. Obesity 18(10): 1902-1905. PMID: 20057372 JAX™ Mice | 24 Metabolic Differences (DIO) Case Study #2: Response to high-fat diet in C57BL/6 C57BL/6J (000664) vs C57BL/6NJ (005304) 2 wks on HFD 14 wks on HFD Glucose Tolerance Test Measures ability of mice to clear glucose from blood Both B6J and B6NJ mice have severely impaired glucose tolerance Nicholson, A et al. 2010. Obesity 18(10): 1902-1905. PMID: 20057372 JAX™ Mice | 25 Immunological Differences Case Study #3: Sensitivity to infection 1952 C3H/HeJ C3H/HeOuJ (000659) (000635) +LPS +LPS Endotoxin resistant Endotoxin sensitive Tlr4Lps-d (1958-1965) Tlr4 wild-type Sultzer BM. 1968. Nature PMID 4877918 Watson J et al. 1978. J Immunol PMID 202651 Poltarak A et al. 1998. Blood Cells Mol Dis PMID 10087992 Poltarak A et al. 1998. Science PMID 9851930 JAX™ Mice | 26 Immunological Differences Case Study #4: Dock2 CNV in C57BL6/NHsd affects immune phenotypes CD8+ MP MZB Live, Live, CD3+, CD8+ CD19+, IgDlo IgMhi C57BL/6J C57BL/6NJ C57BL/6NHsd Increased CD8+ memory T cells Loss of marginal zone B cells Mahajan, V et al. 2016. Cell Reports PMID: 27210752 JAX™ Mice | 27 More Published Examples JAX™ Mice | 28 Considerations for Control Selection Congenic Strains* o Littermates (het x het, het x wt, or hemi x wt mating scheme) Wild type or heterozygous for mutant gene or allele Non-carriers of transgene Can also use non-littermate controls from the colony o Inbred (hom x hom mating) Match background mutant is on (including substrain) ? Mixed Background (B6J and B6N) o Littermates Wild type or heterozygous for mutant gene or allele Non-carriers of transgene Can also use non-littermate controls from the colony * Congenic strains have been crossed more than 10 generations to inbred strain. Acceptable to use inbred as control after N5 JAX™ Mice | 29 Selecting Proper Controls Case Study # 5: C57BL/6 control selection Influence of Mapk9 (Jnk2) on acetaminophen-induced liver injury (AILI) Bourdi M et al. 2011. Chem Res Toxicol PMID 21557537 JAX™ Mice | 30 Selecting Proper Controls Experimental conclusions may be in opposition Effects of Mapk9 (Jnk2) on acetaminophen-induced liver injury (AILI) Bourdi M et al. 2011. Chem Res Toxicol PMID 21557537 JAX™ Mice | 31 Selecting Proper Controls Experimental conclusions may be in opposition Effects of Mapk9 (Jnk2) on acetaminophen-induced liver injury (AILI) Bourdi M et al. 2011. Chem Res Toxicol PMID 21557537 JAX™ Mice | 32 Genetic Drift and Substrains Spontaneous mutations can be overt or hidden o only apparent by physiological assay Substrains can vary significantly genetically and phenotypically Know what
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