Environmental change drives accelerated adaptation (e.g. resistance of yeast to copper) through stimulated copy number variations (CNVs)

This is a great example of gene-environment interactions.

Copy number variations (CNVs) represent a category of duplication or deletion event that affects a considerable number of base-pairs (i.e. a segment of the DNA). CNVs are common in all kingdoms –– animals, plants, fungi, bacteria. It is now clear that approximately two-thirds of the entire human genome comprises nucleotide repeats, and 5-10% of the human genome can be classified as “CNVs”. In mammals, CNVs appear to play an important role in generating variation in the population, as well as contributing to multifactorial traits including complex diseases. CNVs are classified into two main groups: short repeats and long repeats –– with no clear boundary between the two groups (it’s a continuous gradient). Long repeats include duplicationss of entire genes. For example, five or ten copies of a gene such as CYP2D6 code for a P450 enzyme, resulting in additive/mulltiplicative levels of enzyme activity. Thus, patients with several extra copies of this gene will metabolically clear “a CYP2D6 drug” in a matter of minutes instead of hours.

CNVs have been implicated in many human disorders, particularly cancer, in which CNVs promote both tumorigenesis and chemotherapy resistance. CNVs are considered random mutations but often arise through DNA-replication defects; transcription can interfere with replication-fork progression and stability –– leading to increased mutation rates at highly transcribed loci. In the attached paper, authors investigate whether inducible promoters can stimulate CNVs to yield reproducible, environment-specific genetic changes. A general mechanism for environmentally-stimulated CNVs, for example, is seen during copper resistance in budding yeast. By analyzing a large cohort of individual yeast cells, authors demonstrate that a CNV of the copper-resistance gene CUP1 is stimulated by environmental copper. Thus, copper exposure actively drives adaptation to copper-rich environments. Furthermore, quantification of the CNV in individual cells reveals remarkable allelic selectivity in the rate at which specific environments stimulate this CNV.

Authors found that the mechanism underlying this selectivity includes CNV regulation by both promoter activity, and acetylation of histone H3 lysine 56 (H3K56ac) and that H3K56ac is required for CUP1 CNV formation and efficient copper adaptation. The impact of transcription on DNA damage is well understood, but this study shows that the apparently-problematic association forms a pathway by which mutations can be directed to particular genetic loci in particular environments. Moreover, this mutagenic process appears to be regulated through histone acetylation. Stimulated CNVs therefore represent an unanticipated and remarkably controllable pathway, facilitating organismal adaptation to new environments. Quite likely this process is also used by cancer cells to become resistant to chemotherapeutic drugs, and used by animals –– from the fly and worm to mouse and human –– in developing resistance to certain drugs or environmental toxicants.

PloS Biol 2o17; 15: e2001333

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