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We hope that this statistical methodology will provide a quantitative framework facilitating the unification of our theoretical understanding and empirical observations into a quantitative, multivariate theory of stress. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email journals.permissions@oup.com.MOTIVATION One of the key computational problems in comparative genomics is the reconstruction of genomes of ancestral