Improved measures for evolutionary conservation that exploit taxonomy distances

Abstract

Selective pressures on protein-coding regions that provide fitness advantages can lead to the regions' fixation and conservation in genome duplications and speciation events. Consequently, conservation analyses relying on sequence similarities are exploited by a myriad of applications across all biosciences to identify functionally important protein regions. While very potent, existing conservation measures based on multiple sequence alignments are so pervasive that improvements to solutions of many problems have become incremental. We introduce a new framework for evolutionary conservation with measures that exploit taxonomy distances across species. Results show that our taxonomy-based framework comfortably outperforms existing conservation measures in identifying deleterious variants observed in the human population, including variants located in non-abundant sequence domains such as intrinsically disordered regions. The predictive power of our approach emphasizes that the phenotypic effects of sequence variants can be taxonomy-level specific and thus, conservation needs to be interpreted accordingly.

A variety of changes, including CRISPR/Cas9‐mediated deletions, in CENH3 lead to haploid induction on outcrossing

“…This requires consideration not only of position of the amino acid in question, but also the nature of the specific amino acid change. Many programs exist that are intended to predict severity of mutant alleles, taking into consideration, to varying degrees, the nature of the change in R group (sometimes in context of tertiary structure), the frequency at which such changes are found in natural populations of the same species, and evolutionary conservation across kingdoms (Malhis et al , 2019). One such program is SIFT (sorting intolerant from tolerant; Ng and Henikoff, 2003).…”

ACE 2 Coding Variants: A Potential X-linked Risk Factor for COVID-19 Disease

“…We retrieved CADD scores from a downloaded version of CADD v1.4; the Phred-scaled CADD score 21 is reported for position and allele combination. We also used the online tool LIST 22 to estimate deleteriousness of coding amino acid substitutions in ACE2. Three-dimensional modelling used MolSoft.…”

Deep phylogeny of cancer drivers and compensatory mutations

“…As the body of available gene and protein expression data grows, this in silico approach for the identification of compensators can be augmented through validation of the functional effects of the drivers by utilizing transcriptome and proteome analyses. Separation of pairwise associations from noise in the MSA can be challenging 59 – 61 , motivating the development of new methods 62 . Here we present a coherent approach to quantitatively assess relevance of such associations (see “Methods” for details).…”