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Related Concept Videos

Frequency-dependent Selection01:21

Frequency-dependent Selection

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When the fitness of a trait is influenced by how common it is (i.e., its frequency) relative to different traits within a population, this is referred to as frequency-dependent selection. Frequency-dependent selection may occur between species or within a single species. This type of selection can either be positive—with more common phenotypes having higher fitness—or negative, with rarer phenotypes conferring increased fitness.
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Comparing Copy Number Variations and SNPs02:26

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Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...
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Nonsense-mediated mRNA Decay02:27

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The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
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Single Nucleotide Polymorphisms-SNPs01:05

Single Nucleotide Polymorphisms-SNPs

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A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
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Related Experiment Video

Updated: Jul 6, 2025

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

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Quantifying negative selection on synonymous variants.

Mikhail Gudkov1, Loïc Thibaut2, Eleni Giannoulatou1

  • 1Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia.

HGG Advances
|January 9, 2024
PubMed
Summary
This summary is machine-generated.

Synonymous genetic variants, previously thought "silent," can negatively impact health. This study reveals that some synonymous variants face significant negative selection, particularly those affecting codon optimality or splice sites.

Keywords:
codon optimalitynegative selectionsynonymous variantsvariant deleteriousness

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Area of Science:

  • Genetics
  • Population Genetics
  • Molecular Biology

Background:

  • DNA sequencing generates numerous genetic variants, complicating disease association studies.
  • Synonymous variants, which do not alter amino acid sequences, were historically considered benign.
  • Emerging research indicates that some synonymous variants can be deleterious despite their "silent" nature.

Purpose of the Study:

  • To quantify the negative selective pressure on various classes of synonymous genetic variants.
  • To investigate the factors driving negative selection in synonymous variants.
  • To understand the population-level impact of synonymous variants on human health and disease.

Main Methods:

  • Analysis of synonymous singleton variants in human exomes from the gnomAD dataset.
  • Application of a modified mutability-adjusted proportion of singletons (MAPS) metric to assess purifying selection.
  • Testing various predictors to explain selection score variability in synonymous variants.

Main Results:

  • Synonymous variants are not uniformly benign; some classes experience stronger negative selection than others.
  • Variants reducing codon optimality are under stronger negative selection compared to those increasing it.
  • Synonymous variants associated with splice-site alterations (loss or gain) are also significantly affected by selection.

Conclusions:

  • Negative selection acts on specific classes of synonymous variants, challenging the notion of their benign nature.
  • Codon optimality and splice site integrity are key factors influencing the selective pressure on synonymous variants.
  • Understanding these selective pressures provides crucial insights into the role of synonymous variants in human health and disease.