Deciphering causal genomic templates of complex molecular phenotypes

We develop a mathematical theory proposing that complex molecular phenotypes (CMPs, e.g., single-cell gene expression distributions and tissue organization) are produced from templates in the genome. We validate our theory using a procedure termed Causal Phenotype Sequence Alignment (CPSA). CPSA finds a candidate template of a CMP by aligning – without using genetic variation or biological annotations – a phenotypic measurement (e.g., a tissue image) with a reference genome. Given any edit to the CMP (e.g., changing cellular localization), CPSA outputs the genomic loci in the alignment corresponding to the edit. We confirm that three CMPs (single-cell gene expression distributions of the immune system and of embryogenesis, and tissue organization of the tumor microenvironment) have templates: the loci output by CPSA for therapeutically significant edits of these CMPs reveal genes, regulatory regions and active-sites whose experimental manipulation causes the edits. Our theory provides a systematic framework for genetically redesigning CMPs.