Distribution and Effects of Nonsense Polymorphisms in Human Genes
Publication Date
October 14, 2008
Journal
PLOS ONE
Authors
Yumi Yamaguchi Kabata, Makoto K. Shimada, Yosuke Hayakawa, Shinsei Minoshima, et al
Volume
3
Issue
10
Pages
e3393
DOI
http://doi.org/10.1371/journal.pone.0003393
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0003393
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/18852891
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561068
Europe PMC
http://europepmc.org/abstract/MED/18852891
Web of Science
000265121700002
Scopus
54449094545
Mendeley
http://www.mendeley.com/research/distribution-effects-nonsense-polymorphisms-human-genes-4
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Mendeley | Further Information

{"title"=>"Distribution and effects of nonsense polymorphisms in human genes", "type"=>"journal", "authors"=>[{"first_name"=>"Yumi", "last_name"=>"Yamaguchi-Kabata", "scopus_author_id"=>"6508022852"}, {"first_name"=>"Makoto K.", "last_name"=>"Shimada", "scopus_author_id"=>"36106415600"}, {"first_name"=>"Yosuke", "last_name"=>"Hayakawa", "scopus_author_id"=>"16642664000"}, {"first_name"=>"Shinsei", "last_name"=>"Minoshima", "scopus_author_id"=>"7102383696"}, {"first_name"=>"Ranajit", "last_name"=>"Chakraborty", "scopus_author_id"=>"8747937800"}, {"first_name"=>"Takashi", "last_name"=>"Gojobori", "scopus_author_id"=>"35370722600"}, {"first_name"=>"Tadashi", "last_name"=>"Imanishi", "scopus_author_id"=>"7101939542"}], "year"=>2008, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0003393", "pui"=>"352553453", "sgr"=>"54449094545", "scopus"=>"2-s2.0-54449094545", "pmid"=>"18852891", "issn"=>"19326203"}, "id"=>"8be223ea-03bf-382a-a450-7b92739cf526", "abstract"=>"BACKGROUND: A great amount of data has been accumulated on genetic variations in the human genome, but we still do not know much about how the genetic variations affect gene function. In particular, little is known about the distribution of nonsense polymorphisms in human genes despite their drastic effects on gene products.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: To detect polymorphisms affecting gene function, we analyzed all publicly available polymorphisms in a database for single nucleotide polymorphisms (dbSNP build 125) located in the exons of 36,712 known and predicted protein-coding genes that were defined in an annotation project of all human genes and transcripts (H-InvDB ver3.8). We found a total of 252,555 single nucleotide polymorphisms (SNPs) and 8,479 insertion and deletions in the representative transcripts in these genes. The SNPs located in ORFs include 40,484 synonymous and 53,754 nonsynonymous SNPs, and 1,258 SNPs that were predicted to be nonsense SNPs or read-through SNPs. We estimated the density of nonsense SNPs to be 0.85x10(-3) per site, which is lower than that of nonsynonymous SNPs (2.1x10(-3) per site). On average, nonsense SNPs were located 250 codons upstream of the original termination codon, with the substitution occurring most frequently at the first codon position. Of the nonsense SNPs, 581 were predicted to cause nonsense-mediated decay (NMD) of transcripts that would prevent translation. We found that nonsense SNPs causing NMD were more common in genes involving kinase activity and transport. The remaining 602 nonsense SNPs are predicted to produce truncated polypeptides, with an average truncation of 75 amino acids. In addition, 110 read-through SNPs at termination codons were detected.\\n\\nCONCLUSION/SIGNIFICANCE: Our comprehensive exploration of nonsense polymorphisms showed that nonsense SNPs exist at a lower density than nonsynonymous SNPs, suggesting that nonsense mutations have more severe effects than amino acid changes. The correspondence of nonsense SNPs to known pathological variants suggests that phenotypic effects of nonsense SNPs have been reported for only a small fraction of nonsense SNPs, and that nonsense SNPs causing NMD are more likely to be involved in phenotypic variations. These nonsense SNPs may include pathological variants that have not yet been reported. These data are available from Transcript View of H-InvDB and VarySysDB (http://h-invitational.jp/varygene/).", "link"=>"http://www.mendeley.com/research/distribution-effects-nonsense-polymorphisms-human-genes-4", "reader_count"=>39, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>5, "Student > Doctoral Student"=>2, "Researcher"=>14, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>2, "Student > Master"=>6, "Other"=>1, "Student > Bachelor"=>2, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>5, "Student > Doctoral Student"=>2, "Researcher"=>14, "Student > Ph. D. Student"=>3, "Student > Postgraduate"=>2, "Student > Master"=>6, "Other"=>1, "Student > Bachelor"=>2, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>27, "Medicine and Dentistry"=>3, "Psychology"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>27}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Greece"=>1, "Denmark"=>1, "South Africa"=>1, "Germany"=>1, "Russia"=>1}, "group_count"=>0}

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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/919114"], "description"=>"<p>Nonsense SNPs with known pathological effects.</p>", "links"=>[], "tags"=>["snps", "pathological"], "article_id"=>589568, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.t007", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nonsense_SNPs_with_known_pathological_effects_/589568", "title"=>"Nonsense SNPs with known pathological effects.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-10-14 02:39:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/919229"], "description"=>"a<p>Number of genes with a molecular function in the 581 genes in which nonsense SNPs causing NMD were found.</p>b<p>Expected number of genes that have a biological function in a sample of 581 genes, assuming a proportion of genes with a molecular function in all human genes.</p>c<p>Enrichment of a biological term in the genes for nonsense SNPs was statistically evaluated as a upper probability in a hypergeometric distribution.</p>", "links"=>[], "tags"=>["genes", "having", "nonsense", "snps", "causing"], "article_id"=>589676, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.t008", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_bias_of_genes_having_nonsense_SNPs_causing_NMD_/589676", "title"=>"Functional bias of genes having nonsense SNPs causing NMD.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-10-14 02:41:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/918898"], "description"=>"<p>Top: Scheme of analysis pipeline of polymorphisms with gene structure. Bottom: Screen shots taken from ‘Transcript View’ in H-InvDB that show classified SNPs and their positions (blue bars) in the <i>CASP12</i> gene.</p>", "links"=>[], "tags"=>["polymorphisms"], "article_id"=>589354, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.g001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Analysis_of_polymorphisms_with_gene_structure_/589354", "title"=>"Analysis of polymorphisms with gene structure.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-10-14 02:35:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/919036"], "description"=>"<p>Polymorphisms mapped on single positions were analyzed with 36,712 protein-coding genes.</p>", "links"=>[], "tags"=>["indels", "intron", "genomic"], "article_id"=>589489, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.t001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SNPs_and_indels_in_exon_intron_and_other_genomic_regions_/589489", "title"=>"SNPs and indels in exon, intron and other genomic regions.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-10-14 02:38:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/919189"], "description"=>"<p>Bold letters show nucleotide changes by transition.</p>*<p>P<0.005 by chi-square test.</p>", "links"=>[], "tags"=>["codon", "nonsense"], "article_id"=>589643, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.t005", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Frequency_of_each_type_of_codon_change_for_nonsense_SNPs_/589643", "title"=>"Frequency of each type of codon change for nonsense SNPs.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-10-14 02:40:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/919076"], "description"=>"a<p>This prediction is based on that mRNA would be destroyed if a stop codon occurs in the 5′ side of the boundary, which is 50–55 nucleotides upstream from the 3′ end of the second to last exon. Here, the nonsense SNPs located in the 5′ side of the boundary, which was set at 50 nucleotides upstream from the 3′ end of the second to last exon, were predicted to cause NMD.</p>b<p>This number includes SNPs in genes consisting of only one exon.</p>c<p>P = 0.0033 by Fisher's exact test.</p>", "links"=>[], "tags"=>["snps"], "article_id"=>589532, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.t006", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nonsense_SNPs_and_prediction_of_NMD_/589532", "title"=>"Nonsense SNPs and prediction of NMD.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-10-14 02:38:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/919001"], "description"=>"a<p>These two gene sets are the same as <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003393#pone-0003393-t002\" target=\"_blank\">Table 2</a>.</p>b<p>Possible read-through SNPs in which alleles coding stop codons were ancestral type. This may be due to existence of shorter ORFs in the ancestral population.</p>c<p>Possible nonsense SNPs in which alleles coding stop codons were derived alleles. This may be due to existence of longer ORFs in the ancestral population.</p>d<p>The densities of nonsense SNPs in ORFs were calculated based on the numbers of potential nucleotide sites for nonsense mutations in coding regions.</p>", "links"=>[], "tags"=>["causing", "changes", "amino", "acids"], "article_id"=>589450, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.t003", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SNPs_causing_changes_between_amino_acids_and_stop_codons_/589450", "title"=>"SNPs causing changes between amino acids and stop codons.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-10-14 02:37:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/919264"], "description"=>"a<p>Number of genes with a molecular function in the 602 genes in which nonsense SNPs causing NMD were found.</p>b<p>Expected number of genes that have a biological function in a sample of 602 genes, assuming a proportion of genes with a molecular function in all human genes.</p>c<p>Enrichment of a biological term in the genes for nonsense SNPs was statistically evaluated as a upper probability in a hypergeometric distribution.</p>", "links"=>[], "tags"=>["genes", "having", "nonsense", "snps", "causing"], "article_id"=>589719, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.t009", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_bias_of_genes_having_nonsense_SNPs_not_causing_NMD_/589719", "title"=>"Functional bias of genes having nonsense SNPs not causing NMD.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-10-14 02:41:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/918967"], "description"=>"a<p>Representative transcripts in 23,717 genes whose function were defined or suggested (similarity category I–III) and genes annotated as conserved hypothetical proteins (similarity category IV).</p>b<p>Representative transcripts in all protein-coding genes (36,712) including genes in similarity category I–IV plus similarity category V–VII (hypothetical protein, hypothetical short protein, and pseudogene candidate, respectively).</p>c<p>Densities of polymorphisms are shown in brackets as average number of polymorphisms per site. The average lengths of the 5′UTR, ORF and 3′UTR regions in 23717 genes were 303.9 bp, 1343.5 bp, and 877.6 bp, respectively. The densities of SNPs for synonymous, nonsynonymous and nonsense SNPs in ORFs were calculated based on the numbers of potential nucleotide sites for synonymous, nonsynonymous and nonsense mutations in coding regions. The density of nonsense SNPs is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003393#pone-0003393-t003\" target=\"_blank\">Table 3</a>.</p>d<p>SNPs causing changes between amino acids and stop codons.</p>", "links"=>[], "tags"=>["snps", "exon"], "article_id"=>589419, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.t002", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Classified_SNPs_in_exon_regions_/589419", "title"=>"Classified SNPs in exon regions.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-10-14 02:36:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/919150"], "description"=>"a<p>These two gene sets are the same as <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003393#pone-0003393-t002\" target=\"_blank\">Table 2</a>.</p>b<p>Densities of polymorphisms are shown in brackets as average number of polymorphisms per site.</p>c<p>Three indels were located on both of ORF and UTR.</p>", "links"=>[], "tags"=>["deletions", "exon"], "article_id"=>589604, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0003393.t004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Insertions_and_deletions_in_exon_regions_/589604", "title"=>"Insertions and deletions in exon regions.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-10-14 02:40:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/454025", "https://ndownloader.figshare.com/files/454188"], "description"=>"<div><h3>Background</h3><p>A great amount of data has been accumulated on genetic variations in the human genome, but we still do not know much about how the genetic variations affect gene function. In particular, little is known about the distribution of nonsense polymorphisms in human genes despite their drastic effects on gene products.</p><h3>Methodology/Principal Findings</h3><p>To detect polymorphisms affecting gene function, we analyzed all publicly available polymorphisms in a database for single nucleotide polymorphisms (dbSNP build 125) located in the exons of 36,712 known and predicted protein-coding genes that were defined in an annotation project of all human genes and transcripts (H-InvDB ver3.8). We found a total of 252,555 single nucleotide polymorphisms (SNPs) and 8,479 insertion and deletions in the representative transcripts in these genes. The SNPs located in ORFs include 40,484 synonymous and 53,754 nonsynonymous SNPs, and 1,258 SNPs that were predicted to be nonsense SNPs or read-through SNPs. We estimated the density of nonsense SNPs to be 0.85×10<sup>−3</sup> per site, which is lower than that of nonsynonymous SNPs (2.1×10<sup>−3</sup> per site). On average, nonsense SNPs were located 250 codons upstream of the original termination codon, with the substitution occurring most frequently at the first codon position. Of the nonsense SNPs, 581 were predicted to cause nonsense-mediated decay (NMD) of transcripts that would prevent translation. We found that nonsense SNPs causing NMD were more common in genes involving kinase activity and transport. The remaining 602 nonsense SNPs are predicted to produce truncated polypeptides, with an average truncation of 75 amino acids. In addition, 110 read-through SNPs at termination codons were detected.</p><h3>Conclusion/Significance</h3><p>Our comprehensive exploration of nonsense polymorphisms showed that nonsense SNPs exist at a lower density than nonsynonymous SNPs, suggesting that nonsense mutations have more severe effects than amino acid changes. The correspondence of nonsense SNPs to known pathological variants suggests that phenotypic effects of nonsense SNPs have been reported for only a small fraction of nonsense SNPs, and that nonsense SNPs causing NMD are more likely to be involved in phenotypic variations. These nonsense SNPs may include pathological variants that have not yet been reported. These data are available from Transcript View of H-InvDB and VarySysDB (<a href=\"http://h-invitational.jp/varygene/\">http://h-invitational.jp/varygene/</a>).</p></div>", "links"=>[], "tags"=>["effects", "nonsense", "polymorphisms", "genes"], "article_id"=>149439, "categories"=>["Molecular Biology", "Evolutionary Biology", "Genetics"], "users"=>["Yumi Yamaguchi-Kabata", "Makoto K. Shimada", "Yosuke Hayakawa", "Shinsei Minoshima", "Ranajit Chakraborty", "Takashi Gojobori", "Tadashi Imanishi"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0003393.s001", "https://dx.doi.org/10.1371/journal.pone.0003393.s002"], "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Distribution_and_Effects_of_Nonsense_Polymorphisms_in_Human_Genes/149439", "title"=>"Distribution and Effects of Nonsense Polymorphisms in Human Genes", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-10-14 02:37:19"}

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Relative Metric

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