|KREMLING, KARL - Cornell University|
|CHEN, SHU-YUN - Cornell University|
|SU, MEI-HSIU - Cornell University|
|ROMAY, MARIA CINTA - Cornell University|
|SWARTS, KELLY - Cornell University|
|LU, FEI - Cornell University|
|LORANT, ANNE - University Of California, Davis|
|Buckler, Edward - Ed|
Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/1/2018
Publication Date: 3/14/2018
Citation: Kremling, K., Chen, S., Su, M., Jannink, J., Romay, M., Swarts, K., Lu, F., Lorant, A., Bradbury, P., Buckler IV, E.S. 2018. Dysregulation of expression correlates with rare allele burden and fitness loss in maize. Nature. 555:520-523. https://doi.org/10.1038/nature25966.
Interpretive Summary: Whether phenotype is affected by many common variants or a few large effect rare variants is of interest across species, but it has not been investigated in a tightly selected and systematically inbred species like maize. The answer to this question has implications for how artificial selection leads to genetic improvement. To explore these questions we created the largest gene expression resource in plants. This resource consists of 1,960 samples from 7 tissues across an average of 255 diverse inbreds, which is of great interest to the plant genetics community. We arrive at our conclusions by exploiting maize's extreme diversity, rapid LD decay, unique population structure, and the capacity to destructively collect RNA from live tissues in replicated individuals. Furthermore, unlike humans, maize affords the opportunity to measure fitness in the form of yield, which we explicitly tie to dysregulation of expression. This suggests a regulatory constraint on fitness by rare alleles which is relevant across species, even those that have undergone systematic selection and inbreeding. We conclude that, despite strong artificial selection and systematic inbreeding to purge deleterious variants, genetic load affecting expression remains ubiquitous in the maize genome and was shaped by adaptation.
Technical Abstract: Replicating a 2.5 billion base-pair genome over generations leads to the accumulation of new mutations. Mutations resulting from this process can be deleterious and impact phenotype by contributing to disease and inbreeding depression. Although selection acts to keep deleterious variants rare, their complete removal is impaired by genetic linkage to favorable loci and finite population size. Modern maize breeders have systematically reduced the effects of this constant mutational pressure through artificial selection and self-fertilization to expose rare recessive variants in elite inbred lines. However, the ongoing effect of these rare alleles on modern inbred maize is unknown. We created the largest existing multi-tissue gene expression resource in maize by performing RNAseq on an average of 255 lines in seven tissues. By analyzing this resource and exploiting the extreme diversity and rapid linkage disequilibrium (LD) decay of maize, we show the outsize impact of rare alleles and evolutionary history on the regulation of expression. We consistently see that rare alleles drive dysregulation of expression. We explicitly tie this dysregulation to fitness and show that historic bottlenecks dramatically shaped regulation as is evident from the enrichment of ancestral rare variants among eQTL mapped in modern inbred lines. Our results reveal that regulatory genetic load remains abundant in intensively selected agricultural species. This suggests that an important path to further genetic gain in agricultural species lies in purging of rare deleterious variants at the base-pair level.