Effective study design for comparative functional genomics

Comparative studies struggle with the challenge of balancing technical properties with the requirement of obtaining samples from multiple species. Guidelines are needed to minimize the effect of confounders and increase the robustness of the inference. We argue for the paramount importance of extensive record keeping and reporting.

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  1. 1.

    Holloway, A. K., Bruneau, B. G., Sukonnik, T., Rubenstein, J. L. & Pollard, K. S. Accelerated evolution of enhancer hotspots in the mammal ancestor. Mol. Biol. Evol. 33, 1008–1018 (2016).

    CAS  Article  Google Scholar 

  2. 2.

    Blekhman, R., Marioni, J. C., Zumbo, P., Stephens, M. & Gilad, Y. Sex-specific and lineage-specific alternative splicing in primates. Genome Res. 20, 180–189 (2010).

    CAS  Article  Google Scholar 

  3. 3.

    GTEx Consortium. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).

    Article  Google Scholar 

  4. 4.

    Blake, L. E. et al. A comparison of gene expression and DNA methylation patterns across tissues and species. Genome Res. 30, 250–262 (2020).

    CAS  Article  Google Scholar 

  5. 5.

    Gilad, Y. & Mizrahi-Man, O. A reanalysis of mouse ENCODE comparative gene expression data. F1000Res. 4, 121 (2015).

    Article  Google Scholar 

  6. 6.

    Deck, J. et al. The Genomic Observatories Metadatabase (GeOMe): a new repository for field and sampling event metadata associated with genetic samples. PLoS Biol. 15, e2002925 (2017).

    Article  Google Scholar 

  7. 7.

    Kim, S. J. et al. Effects of storage, RNA extraction, genechip type, and donor sex on gene expression profiling of human whole blood. Clin. Chem. 53, 1038–1045 (2007).

    CAS  Article  Google Scholar 

  8. 8.

    Kelly, R. et al. RNA and DNA integrity remain stable in frozen tissue after long-term storage at cryogenic temperatures: a report from the ontario tumour bank. Biopreserv. Biobank 17, 282–287 (2019).

    CAS  Article  Google Scholar 

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The authors thank N. Gonzales, W. Dowd, M. Tobler, L. Barreiro, A. Pai, L. Blake and J. Tung for helpful comments on the manuscript. Y.G is. supported by NIGMS MIRA R35GM131726; J.L.K. is supported by NSF 1557795, 1906015 and 1931650.

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The authors contributed equally to all aspects of the article.

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Correspondence to Yoav Gilad.

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The authors declare no competing interests.

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Kelley, J.L., Gilad, Y. Effective study design for comparative functional genomics. Nat Rev Genet 21, 385–386 (2020). https://doi.org/10.1038/s41576-020-0242-z

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