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CP RMSCC 2133. 99. threshold for significance after correction for mult. testing. CP RMSCC 3700. CP RMSCC 1037. CP RMSCC 3488. CP CPA 0001. C. posadasii. 100. CP CPA 0020. 95. CP1. 100. CP RMSCC 1038. CPS2. 99. 99. CP CPA 0066. CI RMSCC 2394. C. immitis. 100. 73 kb cds

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threshold for significance after correction for mult. testing




CP CPA 0001

C. posadasii


CP CPA 0020








CP CPA 0066


C. immitis


73 kb cds






Natural SelectionMost genes exhibit purifying selection

Genome Sequencing

Heterogeneity in Ci vs Cp Divergence

Chromosome 1

Isolate Coverage Size (Mb)

C. immitis RS 14.41X 28.9

C. immitis H538.4 3.41X 27.7

C. immitis RMSCC_2394 8.22X 28.8

C. immitis RMSCC_3703 3.17X 27.6

C. posadasii Silveira 5.23X 27.5

C. posadasii RMSCC_3488 8.52X 28.1

C. posadasii RMSCC_2133 6.69X 27.8

C. posadasii RMSCC_3700 3.58X 25.5

C. posadasii CPA_0001 3.09X 28.6

C. posadasii CPA_0020 3.42X 27.3

C. posadasii CPA_0066 3.34X 27.7

C. posadasii RMSCC_1037 3.41X 26.6

C. posadasii RMSCC_1038 3.00X 26.1

C. posadasii C735 8X (JCVI) 26.7

Purifying Selection

Positive Selection

Neutrality Index (NI) measured for each gene using counts of divergent(D) vs. polymorphic(P) synonymous(S) & replacement(N) SNPs.

Divergence (as measured by Fst) is nearly complete along most of each chromosome (Fst=1), but there are regions of much lower differentiation.

Locally reduced genetic differentiation could be caused by introgression or incomplete lineage sorting.

Functional Enrichment in Positively Selected Genes

Reference Genome: C. immitis RS

Total Annotated Genes: 10,355

Total SNPs: 670,880

Desert Valley Fever Facts

  • Coccidioides On CDC list of select agents

  • Infection caused by inhalation of arthroconidia

  • >100,000 infections annually in US

    • 35% symptomatic, illness can last months

    • 5% require medical care

    • 30% of all pneumonia cases in Arizona

    • infections that spread past lungs (to bones, joints, skin, brain) can persist for life

C. immitis

C. posadasii

Coalescent Analysis: Introgression Occurring

Coalescent method to test H0(incomplete lineage sorting)

Wakeley & Hey 1997:

1. Use data from multiple loci to infer population parameters.

2. Analytically derive coalescent expectations for relative incidence of shared polymorphisms between species, fixed differences, and exclusive polymorphisms within species.

3. For individual loci, compare Obs vs. Exp mutation counts assuming no introgression.

(Chi sq. test results to left; significant results indicate evidence of introgression.)

Incomplete lineage sorting


CONCLUSION: Over 700 genes show evidence of recent introgresssion.

Analysis of 14 Coccidioides fungal genome sequences highlights incomplete speciation and natural selection

Evidence of Immune-Mediated Selection


We have fully sequenced the genomes of 4 C. immitis isolates and 9 C. posadasii isolates, allowing us to explore regional variation in patterns of intraspecific diversity and interspecific divergence. These genome sequences, in combination with the C. posadasii C735 genome previously sequenced by JCVI, offer an excellent resource for improving our understanding of these dimorphic fungal pathogens, which are the etiological agent of coccidioidomycosis (Valley Fever). Through analysis of all 14 genomes we find that although C. immitis and C. posadasii nominally diverged at least 5 million years ago, extensive regions of their genomes exhibit evidence of recent gene flow even while the majority of the genome exhibits perfect genetic isolation. We explore the signal of natural selection across all genes in both species, and identify signals of positive selection in membrane or cell wall associated proteins. These selection signals may indicate that immune-mediated selection pressure from mammalian hosts is an important driver of Coccidioides evolution, and help to clarify the relative importance of the saprophytic vs. parasitic phases of the Coccidioides life cycle.

  • Pathogens subject to immune selection typically exhibit enhanced genetic diversity in surface, secreted, or exported proteins due to immune-mediated balancing selection. If evolutionary fitness in Cocci is influenced by ability to evade the mammalian immune system, we would expect to find enhanced diversity in surface or excreted proteins, and we would expect immunogenic proteins to exhibit greater genetic diversity as a result of immune pressure.

  • We predicted ‘promiscuous’ HLAI and HLAII epitope sequences in the Cocci proteome using a position-specific scoring matrix approach similar to that implemented by the ProPred algorithm.

  • Findings:

  • SNP diversity (measured by p) is positively correlated with HLA II promiscuous epitope density (measured as the % of residues predicted to be part of promiscuous epitopes in a protein; Spearman’s rho = 0.085, P = 0.009)

  • HLAI and HLAII promiscuous epitope density is significantly enriched in secreted proteins (Mann-Whitney test, P = 3.13x10-11 and 7.01x10-6, respectively)

Daniel E. Neafsey1, Bridget Barker2, Garry T. Cole3, John Galgiani2, Matthew R. Henn1, ChiungYu Hung3, Theo Kirkland4, Scott Kroken2, Cody McMahan3, Marc Orbach2, Daniel Park1, Steve Rounsley2, Thomas J. Sharpton5, Jason E. Stajich5, John W. Taylor5, Emily Whiston5, Bruce W. Birren1

1Broad Institute of MIT and Harvard, Cambridge, MA, USA, ([email protected]). 2University of Arizona, Tucson, AZ, USA. 3University of Texas, San Antonio, TX, USA. 4University of California, San Diego, CA, USA. 5University of California at Berkeley, Berkeley, CA, USA.

  • Secreted proteins also exhibit a significantly higher degree of genetic diversity in the form of simple sequence repeats (SSRs; P = 0.01, see figure to right)


  • C. immitis and C. posadasii, the causative agents of Desert Valley Fever, are nominally distinct species that selectively exchange 7-10% of genes.

  • Cell surface and exported proteins exhibit signs of positive selection, suggesting immune pressure.

  • Knowledge of introgression and selection patterns will inform vaccine design.