Evidence for purifying selection acting on silent sites in BRCA1

doi:10.1016/S0168-9525(00)02173-9

Trends in Genetics

Volume 17, Issue 2, 1 February 2001, Pages 62-65

https://doi.org/10.1016/S0168-9525(00)02173-9 Get rights and content

Abstract

In mammals, it is usually assumed that selection cannot be strong enough to act on nucleotide mutations that do not cause a change at the protein level (i.e. ‘silent’ or ‘synonymous’ mutations). Here we report the results of a molecular evolutionary analysis of BRCA1. We find a repeatable pronounced peak in the ratio of nonsynonymous to synonymous substitutions between codons 200–300. Unusually, this peak is caused by a plummet in the silent-site rate of evolution. The most parsimonious interpretation of these data is that purifying selection is acting on silent sites.

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Acknowledgements

We thank the three referees, Z. Yang and A. Eyre-Walker for comments on a previous version of this article. L.D.H. is funded by the Royal Society. C.P. is funded by the TBA programme of the European Science Foundation.

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Cited by (80)

Code inside the codon: The role of synonymous mutations in regulating splicing machinery and its impact on disease
2022, Mutation Research - Reviews in Mutation Research
Citation Excerpt :
Furthermore, it has been discovered that codon choice in human genes varies significantly with distance from splicing sites [38]. Data from a molecular evolutionary investigation of the tumor suppressor gene BRCA1 suggests that the synonymous mutation that has been located close to the ESE region is subject to negative selection [39]. The following sections discuss the effects of synonymous mutations on abnormal splicing and associated human disease conditions (Table 1).
In eukaryotes, precise pre-mRNA processing, including alternative splicing, is essential to carry out the intricate protein translation process. Both point mutations (that alter the translated protein sequence) and synonymous mutations (that do not alter the translated protein sequence) are capable of affecting the splicing process. Synonymous mutations are known to affect gene expression via altering mRNA stability, mRNA secondary structure, splicing processes, and translational kinetics. In higher eukaryotes, precise splicing is regulated by three weakly conserved cis-elements, 5′ and 3′ splice sites and the branch site. Many other cis-acting elements (exonic/intronic splicing enhancers and silencers) and trans-acting splicing factors (serine and arginine-rich proteins and heterogeneous nuclear ribonucleoproteins) have also been found to enhance or suppress the splicing process. The appearance of synonymous mutations in cis-acting elements can alter the splicing process by changing the binding pattern of splicing factors to exonic splicing enhancers or silencer motifs. This results in exon skipping, intron retention, and various other forms of alternative splicing, eventually leading to the emergence of a wide range of diseases. The focus of this review is to elucidate the role of synonymous mutations and their impact on abnormal splicing mechanisms. Further, this study highlights the function of synonymous mutation in mediating abnormal splicing in cancer and development of X-linked, and autosomal inherited diseases.
Manoeuvring protein functions and functional levels by structural excursions
2020, Phenotypic Switching: Implications in Biology and Medicine
The discovery of moonlighting proteins has opened the paradigm of one protein with many functions. Proteins can switch their functions or functional levels through cellular environmental cues and structural changes without altering their amino acid sequences. This chapter describes how three-dimensional (3D) structural features influence protein functions, in a cellular context. It reviews on the implications of factors such as protein–protein interactions, interactions among domains within a multidomain protein, posttranslational modifications, and synonymous codon substitutions on protein functions. Instances of these aspects highlight how cellular environment and 3D structure govern protein actions. Changes in protein functions or functional levels mediated by such nongenetic factors are associated with phenotypic differences related to viral infection, survival in methanol source, cell division, inflammation, and melanoma. Thus, the participation of diverse factors in the regulation of protein function increases complexity to the understanding of cellular mechanisms.
Decoding mechanisms by which silent codon changes influence protein biogenesis and function
2015, International Journal of Biochemistry and Cell Biology
Citation Excerpt :
In support of this idea, Willie and coworkers observed that in human genes, codon preference varied with the distance from splice sites and ESEs (Willie and Majewski, 2004). Molecular evolutionary analysis of the breast cancer-1, early onset (BRCA1) gene has also provided evidence for negative selection against synonymous mutations in ESEs (Hurst and Pal, 2001). It has been estimated that up to 15% of all point mutations causing human genetic disorders disrupt mRNA processing (Krawczak et al., 1992).
Synonymous codon usage has been a focus of investigation since the discovery of the genetic code and its redundancy. The occurrences of synonymous codons vary between species and within genes of the same genome, known as codon usage bias. Today, bioinformatics and experimental data allow us to compose a global view of the mechanisms by which the redundancy of the genetic code contributes to the complexity of biological systems from affecting survival in prokaryotes, to fine tuning the structure and function of proteins in higher eukaryotes. Studies analyzing the consequences of synonymous codon changes in different organisms have revealed that they impact nucleic acid stability, protein levels, structure and function without altering amino acid sequence. As such, synonymous mutations inevitably contribute to the pathogenesis of complex human diseases. Yet, fundamental questions remain unresolved regarding the impact of silent mutations in human disorders. In the present review we describe developments in this area concentrating on mechanisms by which synonymous mutations may affect protein function and human health.
This synopsis illustrates the significance of synonymous mutations in disease pathogenesis. We review the different steps of gene expression affected by silent mutations, and assess the benefits and possible harmful effects of codon optimization applied in the development of therapeutic biologics.
Understanding mechanisms by which synonymous mutations contribute to complex diseases such as cancer, neurodegeneration and genetic disorders, including the limitations of codon-optimized biologics, provides insight concerning interpretation of silent variants and future molecular therapies.
Decoding the effects of synonymous variants
2021, Nucleic Acids Research
Alternative Splicing of RNF180 Genes in Different Species Based on Comparative Genomics Analysis
2020, Research Square
Selection acting on genomes
2019, Methods in Molecular Biology

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Trends in Genetics

Abstract

Section snippets

Acknowledgements

References (23)

Silent sites in Drosophila genes are not neutral – evidence of selection among synonymous codons

Mol. Biol. Evol.

Circumsporozoite protein genes of malaria parasites (Plasmodium spp.): evidence for positive selection on immunogenic regions

Genetics

Positive Darwinian selection promotes charge profile diversity in the antigen binding cleft of class I MHC molecules

Mol. Biol. Evol.

Adaptive evolution of the tumour suppressor BRCA1 in humans and chimpanzees

Nat. Genet.

Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution

Mol. Biol. Evol.

Molecular evidence for natural-selection

Annu. Rev. Ecol. Syst.

DNA-sequence evolution: the sounds of silence

Philos. Trans. R. Soc. London Ser. B

An analysis of codon usage in mammals: selection or mutation bias?

J. Mol. Evol.

The causes of synonymous rate variation in the rodent genome: can substitution rates be used to estimate the sex bias in mutation rate?

Genetics

Evidence of selection on silent site base composition in mammals: Potential implications for the evolution of isochores and junk DNA

Genetics

Selection on silent sites in the rodent H3 histone gene family

Genetics

Cited by (80)

Code inside the codon: The role of synonymous mutations in regulating splicing machinery and its impact on disease

Manoeuvring protein functions and functional levels by structural excursions

Decoding mechanisms by which silent codon changes influence protein biogenesis and function

Decoding the effects of synonymous variants

Alternative Splicing of RNF180 Genes in Different Species Based on Comparative Genomics Analysis

Selection acting on genomes

Trends in Genetics

Research UpdateEvidence for purifying selection acting on silent sites in BRCA1

Abstract

Section snippets

Acknowledgements

Mol. Biol. Evol.

Circumsporozoite protein genes of malaria parasites (Plasmodium spp.): evidence for positive selection on immunogenic regions

Genetics

Positive Darwinian selection promotes charge profile diversity in the antigen binding cleft of class I MHC molecules

Mol. Biol. Evol.

Adaptive evolution of the tumour suppressor BRCA1 in humans and chimpanzees

Nat. Genet.

Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution

Mol. Biol. Evol.

Molecular evidence for natural-selection

Annu. Rev. Ecol. Syst.

DNA-sequence evolution: the sounds of silence

Philos. Trans. R. Soc. London Ser. B

An analysis of codon usage in mammals: selection or mutation bias?

J. Mol. Evol.

The causes of synonymous rate variation in the rodent genome: can substitution rates be used to estimate the sex bias in mutation rate?

Genetics

Evidence of selection on silent site base composition in mammals: Potential implications for the evolution of isochores and junk DNA

Genetics

Selection on silent sites in the rodent H3 histone gene family

Genetics

Research Update
Evidence for purifying selection acting on silent sites in BRCA1