2. What is the “cost of
domestication?”
• Relaxation of selection and changing selective regimens
will increase the proportion of deleterious variants in
cultigens
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
12.
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
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