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Remarkably ancient balanced polymorphisms in a multi-locus gene network

Abstract

Local adaptations within species are often governed by several interacting genes scattered throughout the genome. Single-locus models of selection cannot explain the maintenance of such complex variation because recombination separates co-adapted alleles. Here we report a previously unrecognized type of intraspecific multi-locus genetic variation that has been maintained over a vast period. The galactose (GAL) utilization gene network of Saccharomyces kudriavzevii, a relative of brewer’s yeast, exists in two distinct states: a functional gene network in Portuguese strains and, in Japanese strains, a non-functional gene network of allelic pseudogenes. Genome sequencing of all available S. kudriavzevii strains revealed that none of the functional GAL genes were acquired from other species. Rather, these polymorphisms have been maintained for nearly the entire history of the species, despite more recent gene flow genome-wide. Experimental evidence suggests that inactivation of the GAL3 and GAL80 regulatory genes facilitated the origin and long-term maintenance of the two gene network states. This striking example of a balanced unlinked gene network polymorphism introduces a remarkable type of intraspecific variation that may be widespread.

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Figure 1: The functional and non-functional GAL gene networks share a common ancestor within the S. kudriavzevii lineage.
Figure 2: The divergence of the GAL loci contrasts sharply with the rest of the genome.
Figure 3: Key roles of the Gal3 co-inducer and Gal80 co-repressor.
Figure 4: Regulatory upheaval and the origin and maintenance of the GAL polymorphisms.

Accession codes

Data deposits

All short sequencing reads are deposited with Sequence Read Archive at the National Center for Biotechnology Information under accession number SRP001457 of SRA010159; the IFO1803 and ZP591 GAL sequences are deposited in GenBank under accession numbers GU299171–GU299178.

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Acknowledgements

We thank E. Barrio; B. L. Williams; the Centraalbureau voor Schimmelcultures, Netherlands and the National Institute of Technology and Evaluation Biological Resource Center, Japan for providing strains; J. Fay for critical reading of the manuscript; and the Howard Hughes Medical Institute (HHMI) and S. B. Carroll for supporting preliminary experiments when C.T.H. was a HHMI Predoctoral Fellow. This work was also supported by the James S. McDonnell Foundation (C.T.H., M.J.); the National Institutes of Health (C.T.H., 2T32HG00045; M.J., 5R01GM032540); the Fundação para a Ciência e a Tecnologia, Portugal (P.G. and J.P.S., PTDC/BIA-BDE/71734/2006); the Searle Scholars Program (A.R.); the National Science Foundation (A.R., DEB-0844968) and Vanderbilt University (A.R.). C.T.H. is the Maclyn McCarty Fellow of the Helen Hay Whitney Foundation.

Author Contributions C.T.H., P.G., J.P.S., M.J. and A.R. conceived and designed experiments; C.T.H., P.G. and J.D. performed experiments; C.T.H. sequenced and assembled genomes; C.T.H. and A.R. analysed data; C.T.H., M.J. and A.R. wrote the paper with advice and consent from all authors.

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Correspondence to Mark Johnston.

Supplementary information

Supplementary Information

This file contains Supplementary Tables S1- S4, Supplementary Figures S1- S5 with Legends and Supplementary References. (PDF 1682 kb)

Supplementary Database S1

This file contains the complete supporting data for Supplementary Figure S2: summary of hits to annotated all annotated ORFs from each Saccharomyces genome for each sequenced strain of S. kudriavzevii. Despite examining 2,805 ORFs for each species, no conclusive evidence of introgression was found. (XLS 22335 kb)

Supplementary Database S2

This file shows the divergence of all genes between Japanese and Portuguese reference strain. It reveals additional genes that may be under balancing selection and establishes the genome-wide average divergence. (XLS 1836 kb)

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Hittinger, C., Gonçalves, P., Sampaio, J. et al. Remarkably ancient balanced polymorphisms in a multi-locus gene network. Nature 464, 54–58 (2010). https://doi.org/10.1038/nature08791

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