Triangulation of the human, chimpanzee, and Neanderthal genome sequences identifies potentially compensated mutations

Zhang, Pei; Krawczak, Michael; Ball, Edward V.; Mort, Matthew; Kehrer‐Sawatzki, Hildegard; Cooper, David Neil

doi:10.1002/humu.21389

Cited by 12 publications

(16 citation statements)

References 49 publications

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“…The frequency of these compensatory mutations depends on the time elapsed from the common ancestor and the data in Table I show that there is a correlation between the frequency of CPDs and the diversity of the homologues used to detect CPDs. For example, our dataset (10) (where we apply no constraint on the sequence identity between functionally equivalent homologues) shows a higher ratio of CPDs compared with the dipteran-only (26) or mammalianonly (9,11,33) datasets.…”

Section: Expert Opinionmentioning

confidence: 98%

“…Deleterious mutations also referred to as diseaseassociated mutations (DAMs) (9) are SAAPs that result in high-penetrance disease phenotypes.…”

Section: Terminologymentioning

confidence: 99%

“…Compensated pathogenic deviations (CPDs) have also been referred to as 'potential compensated mutations' (9). Their existence was first discussed by Kimura (4), who termed them 'compensatory neutral mutations' while the term CPD was first defined by Kondrashov et al (11).…”

Section: Terminologymentioning

confidence: 99%

“…This type of compensation is easier to detect, especially in analyses where only recently diverged homologues are considered (9,11,26). Two examples of one-on-one compensations are shown in the Case Study presented below.…”

Section: Compensatory Mutations In Evolutionmentioning

confidence: 99%

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Compensated pathogenic deviations

Barešić

Martin

2011

BioMolecular Concepts

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Deleterious or ‘disease-associated’ mutations are mutations that lead to disease with high phenotype penetrance: they are inherited in a simple Mendelian manner, or, in the case of cancer, accumulate in somatic cells leading directly to disease. However, in some cases, the amino acid that is substituted resulting in disease is the wild-type native residue in the functionally equivalent protein in another species. Such examples are known as ‘compensated pathogenic deviations’ (CPDs) because, somewhere in the second species, there must be compensatory mutations that allow the protein to function normally despite having a residue which would cause disease in the first species. Depending on the nature of the mutations, compensation can occur in the same protein, or in a different protein with which it interacts. In principle, compensation can be achieved by a single mutation (most probably structurally close to the CPD), or by the cumulative effect of several mutations. Although it is clear that these effects occur in proteins, compensatory mutations are also important in RNA potentially having an impact on disease. As a much simpler molecule, RNA provides an interesting model for understanding mechanisms of compensatory effects, both by looking at naturally occurring RNA molecules and as a means of computational simulation. This review surveys the rather limited literature that has explored these effects. Understanding the nature of CPDs is important in understanding traversal along fitness landscape valleys in evolution. It could also have applications in treating diseases that result from such mutations.

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Section: Expert Opinionmentioning

confidence: 98%

“…Deleterious mutations also referred to as diseaseassociated mutations (DAMs) (9) are SAAPs that result in high-penetrance disease phenotypes.…”

Section: Terminologymentioning

confidence: 99%

Section: Terminologymentioning

confidence: 99%

Section: Compensatory Mutations In Evolutionmentioning

confidence: 99%

See 2 more Smart Citations

Compensated pathogenic deviations

Barešić

Martin

2011

BioMolecular Concepts

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“…Another way of describing this is that nucleotide substitutions that are known to be pathogenic in humans are just five times less likely to be observed in other species than substitutions for which no pathogenic association is known. Genome-wide studies, e.g., using the chimpanzee genome [50], the rhesus genome [51], or the Neanderthal genome [52], have confirmed such a high rate. The reason for the vast majority of the cases is probably that one or several other substitutions-often in the same protein-compensate the effect [53].…”

Section: Apoe As An Example For Compensatory Mutationsmentioning

confidence: 99%

Functional primate genomics—leveraging the medical potential

Enard

2012

J Mol Med

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Within biomedicine, comparative genomics is crucial for interpreting human genetic variants and building proper animal models. As our closest relatives, primates are of particular relevance in this frame work. Here, I review principles and concrete examples of this approach. Since one can expect that generating the necessary genomic DNA sequences will not be the major limiting factor in the near future, I argue that in analogy to human biomedicine, comprehensive phenotyping of different primates will be a crucial next step to tap the full potential of comparative genomics. Especially the possibility to generate pluripotent stem cells from primates should allow extending the comparative approach to many medically relevant questions.

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Compensatory Evolution in Disease‐Associated Genes

Azevedo

2015

Encyclopedia of Life Sciences

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Genetic diseases are caused by amino acid replacements at functionally important positions of protein sequences. These positions are conserved at the interspecific level, indicating that their replacement would be expected to be deleterious between homologous sequences. However, several examples of human disease‐associated mutations have been found in the genomes of non‐human species. Following the model of compensatory evolution, the acceptability of human deleterious mutations in other species is strictly dependent on the presence of a compensatory partner variant that is able to compensate for the negative effect of the mutation. The co‐occurrence of a compensated mutation and its compensatory partner has now been documented for a large number of proteins involved in human genetic disease, thereby increasing theoretical and experimental support for the model of compensatory evolution at the same time as providing us with an improved understanding of the molecular and selective forces underlying the mechanism of amino acid interaction. Key Concepts A high number of human disease‐associated mutations are found in non‐human species. Many human disease‐associated mutations are compensated in non‐human species by epistatic interactions with a compensatory variant. The deleterious impact of a variant depends on the genetic background where it occurs. The basis of molecular compensation results from the structural interaction between amino acid variants.

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Triangulation of the human, chimpanzee, and Neanderthal genome sequences identifies potentially compensated mutations

Cited by 12 publications

References 49 publications

Compensated pathogenic deviations

Compensated pathogenic deviations

Functional primate genomics—leveraging the medical potential

Compensatory Evolution in Disease‐Associated Genes

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