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Cost of domestication - Plant & Animal Genome Conference 2018
- 1. Deleterious Variants and the Genetic Cost of Domestication Plant & Animal Genome 2018
- 2. What is the “cost of domestication?” • Relaxation of selection and changing selective regimens will increase the proportion of deleterious variants in cultigens
- 3. Distribution of Fitness Effects Frequency Relative Fitness 0 1 Strongly Deleterious Approximately Neutral Weakly Deleterious Eyre-Walker et al. 2006 Eyre-Walker and Keightley, 2007
- 4. • The proportion of deleterious variants will increase owing to genetic bottlenecks • Deleterious variants will be enriched near targets of selection • Selection for yield in elite cultivars could purge deleterious variants Justin Fay
- 5. Genetic Effects of Human Demography • Human populations migrated from Africa, many expanded • Altered the number, dominance, and distribution of fitness effects of deleterious variants Henn et al. 2015
- 6. Genetic and Mutational Load • The number of derived variants at phylogenetically conserved sites is directly measurable • These are a large component of “mutational load” • Counts of derived variants are sometimes referred to colloquially as “genetic load”
- 7. How are deleterious variants identified? A•••••••T••A••T ... Banana ••T••••A•••A••A ... Switchgrass ••••••••••••••C ... Purple False Brome ••T•••••••••••A ... Foxtail Millet •••••••••••A••A ... Maize •••••C•••••T••C ... Wild Red Einkorn ••••••••••••••T ... Cutgrass •••••C••••••••C ... Goatgrass ••••••••••••••T ... Asian Rice •••••••••••A••A ... Milo Barley GTCCCTTTCCCGCTM ... Consensus •••••••C••••••C ... N D DDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDDD H Y CCCCYY--YYYCCCCCCCCCCCCCCCCCCCCCCCCCCC C F FFFFFFF-FFFFFFFFFFFFFFFFFFFFFFFFFFFFFF R T TTTMTTTTTTTTTTTTTTTDTTTTTTTTTTTTTTTTTT A T VVAAVVVAVAAAVSVVVTVVVVIVAAAALATTTVVVVV A V VVVVVIVVVIIIIIVVVV-VVV-VVVVVVVVVVVVVVV D E EDDEEEEEEEE-EEEEEEEEEEEEEEEVVEEEEEEEEE Q L LLLLLLL-LMLLLLLLLLLLLL-LLLLLLLLLLLLLLL D N NDDDNNNNNDDDDNDNNNNDDDDDDDDDDNNNNNNDNN V I VVLVVVMMVVVVVVVSVIIIIVMVVVVVIVVVVVIVVV A V AAAAAAAAAAAAAAAAAA-AVT-TA-SAAATTTTTAAT D E DDDDDDDN-DDDDDDDDDNEDD-EEEEEEEDDDDDDDD A P EKSKEEEKEENAENEEEEDAAPAAAEKKEEGGEEEEEE E D RNKKKRK-KKKKKNSSKDPESSPS-KS-SN---KKHHN E D EEEEEEQDDEEEEEEEDEEEDEEDDDDEEEEEEEEEED E A TATTMTTSTTTTATSSCA-SPPMASREECGSSSMTAAT Deleterious Tolerated Kono et al. 2016 https://github.com/MorrellLAB/BAD_Mutations Predict! All Variants SNPs Coding SNPs Nonsynonymous SNPs Length Polymorphisms Noncoding SNPs Synonymous SNPs
- 8. Measuring the Cost of Domestication Measure Individuals Populations Absolute number of derived variants at conserved sites Ratio of deleterious to synonymous variants Average frequency of deleterious variants
- 9. Flavors of Ascertainment Bias • Reference bias - discovery of variants as differences from references versus pairwise differences between samples • Annotation bias - what is identified as a coding difference depends on source of gene model annotations • Ancestral bias - can’t determine ancestral state of all variants, often outside exons • Segregation bias - harder to detect deleterious variants fixed in a cultigen
- 10. Reference Bias and Ancestral State Reference has derived 1""2""3""4 Ancestral 0""0""0""0 0""1""0""1 0""1""0""1 Reference Sample 1 Sample 2 0""1""1""0 0 0 0 0 1 10 0 1 Cultivated Species Outgroup Species
- 11. Assumptions • Gene (codon) function is conserved across the phylogeny • Includes no selection for new function along branches of phylogeny • Epistasis (and compensatory mutations) are ignored • Degree of deleteriousness more readily inferred from frequency than phylogenetic conservation
- 13. A cost of domestication in rice? Measure Individuals Populations Absolute number of derived variants at conserved sites Ratio of deleterious to synonymous variants Average frequency of deleterious variants Measure Individuals Populations Absolute number of derived variants at conserved sites Ratio of deleterious to synonymous variants Average frequency of deleterious variants Liu et al. 2017
- 14. Deleterious Mutations - Change Phenotypes? • 2,910 phenotype-changing amino acid variants in Arabidopsis thaliana • Variants that are phenotype changing are more likely to annotated as deleterious • Adjusted for frequency • BAD_Mutations annotations use alignments across published plant genomes & LRT Kono et al. 2017 - bioRvix
- 15. How many deleterious variants are segregating? • At nonsynonymous sites • 1,250/cultivar in barley • 800/cultivar in soybean
- 17. Where do we go from here? chr1H chr2H chr3H chr4H chr5H chr6H chr7H NA 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 Physical Position (Mb) 7 UMN 8 ND 6 BA F3 50 Selected 50 Random F3 50 Selected 50 Random F3 50 Selected 50 Random 21 Parents (Cycle 0) 1080 F3 Progeny 45 Families (Cycle 1) 1296 F3 Progeny 54 Families (Cycle 2) 960 F3 Progeny 40 Families (Cycle 3) 45 Crosses 54 Crosses 40 Crosses Yield Trials Yield Trials Yield Trials Kevin Smith chr1H chr2H chr3H chr4H chr5H chr6H chr7H NA 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 0 5 10 Physical Position (Mb) A B 5000 6000 7000 Check Parents C1 C2 C3 Cycle YieldBLUE(kg/ha) ● ● ● ● ● ● ● ●● 5 10 15 20 25 Check Parents C1 C2 C3 Cycle DONConcentrationBLUE(ppm)
- 18. Conclusions • Deleterious variants are abundant in the genomes of cultivated plants (and domesticated animals) • More abundant in regions of reduced recombination and near targets of selection (will vary by species) • In very deep resequencing panels, conservation can be inferred based on constrained sites • SNPs annotated as deleterious could be selected against using genomic prediction
- 19. Read More About It!
- 20. Acknowledgements • NSF Plant Genome Research • USDA Biotech Risk Assessment • MN Ag Experiment Station • USDA National Needs • MnDrive • UMN Doctoral Dissertation Fellowships
- 21. Acknowledgements Li Lei Chaochih Liu Thomas Kono Emily Vonderharr
- 22. Code and Data Sharing • https://github.com/MorrellLab/ BAD_Mutations • https://github.com/MorrellLab/ sequence_handling • Sequences - NCBI Sequence Read Archive
- 23. Types of Deleterious Variants Fixed differences Segregating variants 0 1 CultigenOutgroup Ancestral Derived Wild Progenitor 0 1 10 00 11 0 0 0 0 1 1 0 1 CultigenOutgroup Ancestral Derived Wild Progenitor 0 0 0 0 1110