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Experimental assay of a fitness landscape on a macroevolutionary scale

ABSTRACT: Characterization of the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here, we reconstruct the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. We find that the His3 fitness landscape is dominated by synergistic epistasis, such that the cumulative effect of amino acid substitutions causes a dramatic decline in fitness. Furthermore, in 63% of sites substitutions were strongly positive in one genetic background and strongly negative in another, with 41% of sites showing reciprocal sign epistasis. This sign epistasis, present in proportionally few genotypes, was caused by simultaneous interaction of multiple sites with demonstrating a complex multidimensional nature of the His3 fitness landscape.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE99990 | GEO | 2017/07/02

SECONDARY ACCESSION(S): PRJNA390287

REPOSITORIES: GEO

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Project description:Mutant KRAS (mut-KRAS) is present in 30% of all human cancers and plays a critical role in cancer cell growth and resistance to therapy. There is evidence from colon cancer that mut-KRAS is a poor prognostic factor and negative predictor of patient response to molecularly targeted therapy. However, evidence for such a relationship in non small cell lung cancer (NSCLC) is conflicting. KRAS mutations are primarily found at codons 12 and 13, where different base changes lead to alternate amino acid substitutions that lock the protein in an active state. The patterns of mut-KRas amino acid substitutions in colon cancer and NSCLC are quite different, with aspartate (D) predominating in colon cancer (50%) and cysteine (C) in NSCLC (47%). Through an analysis of a recently completed biopsy biomarker-driven, molecularly targeted multi-arm trial of 215 evaluable patients with refractory NSCLC we show that mut-KRas-G12C/V but not total mut-KRAS predicts progression free survival for the overall group, and for the sorafenib and vandetanib treatment arms. Transcriptome microarray data shows differential expression of cell cycle genes between mut-KRas-G12C/V and G12D patient tumors. A panel of NSCLC cell lines with known mut-KRas amino acid substitutions was used to identify pathways activated by the different mut-KRas, showing that mut-KRas-G12D activates both PI-3-K and MEK signaling, while mut-KRas G12C does not, and alternatively activates RAL signaling. This finding was confirmed using immortalized human bronchial epithelial cells stably transfected with wt-KRAS and different forms of mut-KRAS. Molecular modeling studies show that the different conformation imposed by mut-KRas-G12C could lead to altered association with downstream signaling transducers compared to wild type and mut-KRas-G12D. The significance of the findings for developing mut-KRAS therapies is profound, since it suggests that not all mut-KRas amino acid substitutions signal to effectors in a similar way, and may require different therapeutic interventions. Gene expression profiles were measured in 22 core biopsies from patients with refractory non-small cell lung cancer included in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE). All tumors were KRAS mutants, but with different patterns of amino acid substitutions. Supervised analysis of transcriptome profiling was performed to compare cysteine or valine KRAS mutants with other KRAS mutants.

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Experimental assay of a fitness landscape on a macroevolutionary scale

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