An Evaluation of Dobzhansky-Muller Incompatibilities in Protein Evolution

This study is focused on the evolution of Dobzhansky-Muller Incompatibilities (DMIs) and Compensated Pathogenic Deviations (CPDs) in protein evolution. DMIs are genetic differences that occur by post zygotic isolation to reduce the overall fitness of an organism. Meanwhile, CPDs are pathogenic mutations that show no adverse effects to the organism as there is an additional mutation somewhere in the sequence that compensates for the deleterious nature of the mutation. Therefore, studying the nature of DMIs and CPDs provides a deeper understanding as to how deleterious events arise throughout the evolution of species. A study conducted by Kondrashov et al. (2002) addressed DMIs in protein evolution by identifying the occurrence of CPDs when the nonhuman orthologs deviated from the reference human ortholog sequence. Kondrashov et al.’s (2002) study was clever in construction, but the methodology was unclear, and the results appeared to be over simplified. To analyze the validity of the Kondrashov et al. (2002) paper, a similar study using restricted parameters and modern bioinformatic databases was conducted for this senior thesis project. To do so, 24 primate orthologs of 32 genes responsible for Mendelian diseases were collected and compared to the pathogenic missense data of humans to identify CPDs. Through computational analysis and the visual representation of protein alignments, 26 valid CPD hits were found. The 26 CPD hits presented in four general patterns: single species CPD, single clade CPD with two or more species, convergent evolution of a CPD, and ancestral CPDs. A statistical analysis was performed to determine whether factors such as the length of the protein, the evolutionary distance between sequences, or the number of pathogenic variants played a role in the number of CPDs found. The relationship between the number of CPDs found and the evolutionary distance between sequences and the amount of pathogenic variant data were found to be statistically significantly correlated. More data and research into primate genomes and the nature of CPDs is required to accurately determine their occurrence. This will help predict how CPDs arise in species and better evaluate the claims made in the Kondrashov et al. (2002) paper.