Limits...
The amino-acid mutational spectrum of human genetic disease.

Vitkup D, Sander C, Church GM - Genome Biol. (2003)

Bottom Line: Computational methods were recently used to predict deleterious effects of nonsynonymous human mutations and polymorphisms.The overall disease spectrum mainly reflects the mutability of the genetic code.We estimate that the rate of nonsynonymous mutations with a negative impact on human health is less than one per diploid genome per generation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Lipper Center for Computational Genetics and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT

Background: Nonsynonymous mutations in the coding regions of human genes are responsible for phenotypic differences between humans and for susceptibility to genetic disease. Computational methods were recently used to predict deleterious effects of nonsynonymous human mutations and polymorphisms. Here we focus on understanding the amino-acid mutation spectrum of human genetic disease. We compare the disease spectrum to the spectra of mutual amino-acid mutation frequencies, non-disease polymorphisms in human genes, and substitutions fixed between species.

Results: We find that the disease spectrum correlates well with the amino-acid mutation frequencies based on the genetic code. Normalized by the mutation frequencies, the spectrum can be rationalized in terms of chemical similarities between amino acids. The disease spectrum is almost identical for membrane and non-membrane proteins. Mutations at arginine and glycine residues are together responsible for about 30% of genetic diseases, whereas random mutations at tryptophan and cysteine have the highest probability of causing disease.

Conclusions: The overall disease spectrum mainly reflects the mutability of the genetic code. We corroborate earlier results that the probability of a nonsynonymous mutation causing a genetic disease increases monotonically with an increase in the degree of evolutionary conservation of the mutation site and a decrease in the solvent-accessibility of the site; opposite trends are observed for non-disease polymorphisms. We estimate that the rate of nonsynonymous mutations with a negative impact on human health is less than one per diploid genome per generation.

Show MeSH

Related in: MedlinePlus

The relative mutation probabilities as a function of mutation site conservation and solvent accessibility. Relative mutation probability as a function of (a) evolutionary conservation of the mutation site (measured using relative entropy), and (b) solvent accessibility of the mutation site in the protein structure. Because the overall probability that a random mutation will cause a genetic disease or be observed as a polymorphism is not known, the probabilities have only relative meaning within each mutation class (disease, synonymous, nonsynonymous). To show different trends clearly, the relative probabilities were normalized to 1 within each class. Conservation of mutation sites in evolution was characterized by the relative entropy using close sequence homologs (see Materials and methods). The solvent accessibility of mutation sites was calculated using the program NACESS [41]. An increase in the degree of evolutionary conservation increases the probability of deleterious mutations and decreases the probability of nonsynonymous benign SNPs (a). An increase in the degree of solvent accessibility decreases the probability of deleterious mutations and increases the probability of nonsynonymous benign SNPs (b). Synonymous mutations do not change amino-acid sequences and are predominantly neutral. Consequently, the probability that a synonymous mutation will be deleterious is relatively constant across sites.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC329120&req=5

Figure 5: The relative mutation probabilities as a function of mutation site conservation and solvent accessibility. Relative mutation probability as a function of (a) evolutionary conservation of the mutation site (measured using relative entropy), and (b) solvent accessibility of the mutation site in the protein structure. Because the overall probability that a random mutation will cause a genetic disease or be observed as a polymorphism is not known, the probabilities have only relative meaning within each mutation class (disease, synonymous, nonsynonymous). To show different trends clearly, the relative probabilities were normalized to 1 within each class. Conservation of mutation sites in evolution was characterized by the relative entropy using close sequence homologs (see Materials and methods). The solvent accessibility of mutation sites was calculated using the program NACESS [41]. An increase in the degree of evolutionary conservation increases the probability of deleterious mutations and decreases the probability of nonsynonymous benign SNPs (a). An increase in the degree of solvent accessibility decreases the probability of deleterious mutations and increases the probability of nonsynonymous benign SNPs (b). Synonymous mutations do not change amino-acid sequences and are predominantly neutral. Consequently, the probability that a synonymous mutation will be deleterious is relatively constant across sites.

Mentions: To complement the analysis of the amino-acid mutation matrices, we investigated how the probabilities of benign SNPs and disease mutations depend on the properties of the mutation site. Several recent studies have focused on developing evolutionary and structural approaches to predict potentially deleterious human mutations [1-4,18,19]. Here, we focus on understanding the relative mutation probabilities (see Materials and methods). Our results are in general agreement with the previous studies. The relative probabilities of disease mutations and benign SNPs are shown in Figure 5a as a function of the interspecies evolutionary conservation of the mutation site. The conservation was characterized by the relative entropy measure using homologs with more than 30% sequence identity. The probability that a random mutation will cause a genetic disease increases monotonically with an increase in the degree of site conservation, while the probability of observing nonsynonymous benign SNPs shows the opposite trend. The synonymous benign SNPs do not change amino acids and should be predominantly neutral. As a result, their probability is uniform across sites.


The amino-acid mutational spectrum of human genetic disease.

Vitkup D, Sander C, Church GM - Genome Biol. (2003)

The relative mutation probabilities as a function of mutation site conservation and solvent accessibility. Relative mutation probability as a function of (a) evolutionary conservation of the mutation site (measured using relative entropy), and (b) solvent accessibility of the mutation site in the protein structure. Because the overall probability that a random mutation will cause a genetic disease or be observed as a polymorphism is not known, the probabilities have only relative meaning within each mutation class (disease, synonymous, nonsynonymous). To show different trends clearly, the relative probabilities were normalized to 1 within each class. Conservation of mutation sites in evolution was characterized by the relative entropy using close sequence homologs (see Materials and methods). The solvent accessibility of mutation sites was calculated using the program NACESS [41]. An increase in the degree of evolutionary conservation increases the probability of deleterious mutations and decreases the probability of nonsynonymous benign SNPs (a). An increase in the degree of solvent accessibility decreases the probability of deleterious mutations and increases the probability of nonsynonymous benign SNPs (b). Synonymous mutations do not change amino-acid sequences and are predominantly neutral. Consequently, the probability that a synonymous mutation will be deleterious is relatively constant across sites.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC329120&req=5

Figure 5: The relative mutation probabilities as a function of mutation site conservation and solvent accessibility. Relative mutation probability as a function of (a) evolutionary conservation of the mutation site (measured using relative entropy), and (b) solvent accessibility of the mutation site in the protein structure. Because the overall probability that a random mutation will cause a genetic disease or be observed as a polymorphism is not known, the probabilities have only relative meaning within each mutation class (disease, synonymous, nonsynonymous). To show different trends clearly, the relative probabilities were normalized to 1 within each class. Conservation of mutation sites in evolution was characterized by the relative entropy using close sequence homologs (see Materials and methods). The solvent accessibility of mutation sites was calculated using the program NACESS [41]. An increase in the degree of evolutionary conservation increases the probability of deleterious mutations and decreases the probability of nonsynonymous benign SNPs (a). An increase in the degree of solvent accessibility decreases the probability of deleterious mutations and increases the probability of nonsynonymous benign SNPs (b). Synonymous mutations do not change amino-acid sequences and are predominantly neutral. Consequently, the probability that a synonymous mutation will be deleterious is relatively constant across sites.
Mentions: To complement the analysis of the amino-acid mutation matrices, we investigated how the probabilities of benign SNPs and disease mutations depend on the properties of the mutation site. Several recent studies have focused on developing evolutionary and structural approaches to predict potentially deleterious human mutations [1-4,18,19]. Here, we focus on understanding the relative mutation probabilities (see Materials and methods). Our results are in general agreement with the previous studies. The relative probabilities of disease mutations and benign SNPs are shown in Figure 5a as a function of the interspecies evolutionary conservation of the mutation site. The conservation was characterized by the relative entropy measure using homologs with more than 30% sequence identity. The probability that a random mutation will cause a genetic disease increases monotonically with an increase in the degree of site conservation, while the probability of observing nonsynonymous benign SNPs shows the opposite trend. The synonymous benign SNPs do not change amino acids and should be predominantly neutral. As a result, their probability is uniform across sites.

Bottom Line: Computational methods were recently used to predict deleterious effects of nonsynonymous human mutations and polymorphisms.The overall disease spectrum mainly reflects the mutability of the genetic code.We estimate that the rate of nonsynonymous mutations with a negative impact on human health is less than one per diploid genome per generation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Lipper Center for Computational Genetics and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT

Background: Nonsynonymous mutations in the coding regions of human genes are responsible for phenotypic differences between humans and for susceptibility to genetic disease. Computational methods were recently used to predict deleterious effects of nonsynonymous human mutations and polymorphisms. Here we focus on understanding the amino-acid mutation spectrum of human genetic disease. We compare the disease spectrum to the spectra of mutual amino-acid mutation frequencies, non-disease polymorphisms in human genes, and substitutions fixed between species.

Results: We find that the disease spectrum correlates well with the amino-acid mutation frequencies based on the genetic code. Normalized by the mutation frequencies, the spectrum can be rationalized in terms of chemical similarities between amino acids. The disease spectrum is almost identical for membrane and non-membrane proteins. Mutations at arginine and glycine residues are together responsible for about 30% of genetic diseases, whereas random mutations at tryptophan and cysteine have the highest probability of causing disease.

Conclusions: The overall disease spectrum mainly reflects the mutability of the genetic code. We corroborate earlier results that the probability of a nonsynonymous mutation causing a genetic disease increases monotonically with an increase in the degree of evolutionary conservation of the mutation site and a decrease in the solvent-accessibility of the site; opposite trends are observed for non-disease polymorphisms. We estimate that the rate of nonsynonymous mutations with a negative impact on human health is less than one per diploid genome per generation.

Show MeSH
Related in: MedlinePlus