Analysis of somatic mutations identifies signs of selection during in vitro aging of primary dermal fibroblasts

Somatic mutations are critical for cancer development and may play a role in age‐related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutch...

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Published inAging cell Vol. 18; no. 6; pp. e13010 - n/a
Main Authors Narisu, Narisu, Rothwell, Rebecca, Vrtačnik, Peter, Rodríguez, Sofía, Didion, John, Zöllner, Sebastian, Erdos, Michael R., Collins, Francis S., Eriksson, Maria
Format Journal Article
LanguageEnglish
Published England John Wiley & Sons, Inc 01.12.2019
John Wiley and Sons Inc
Subjects
Adolescent
Age
Aged, 80 and over
Aging
aging cell
Alleles
Analysis
BRCA2 protein
Cell culture
cell mosaicism
Cells, Cultured
Cellular Senescence - genetics
Child
Child, Preschool
Complementation
DNA - genetics
Exons
Female
Fibroblasts
Fibroblasts - cytology
Fibroblasts - metabolism
Gene frequency
Genes
Genetic aspects
Genetic drift
genome instability
Humans
Male
Mathematical models
molecular biology of aging
Mutation
Nucleotide sequence
Original
Positive selection
Progeria
Sequence Analysis, RNA
Skin - cytology
Skin - metabolism
somatic mutation
tissue heterogeneity
Xeroderma pigmentosum
tissue heterogeneity
genome instability
molecular biology of aging
positive selection
cell mosaicism
aging cell
somatic mutation
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Abstract Somatic mutations are critical for cancer development and may play a role in age‐related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson–Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre‐ and post‐expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging‐related genes. Allele frequencies of 58 somatic mutations differed between the pre‐ and post‐cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, CDKN2A c.53C>T (T18M) and ERCC8 c.*772T>A, were identified in cells from a patient with XPA. The allele frequency of the CDKN2A mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, BRCA2 c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age. De novo somatic mutations are identified in vitro cell culture experiments. We discover three mutations in aging‐related genes displaying signs of positive selection, supporting the model of increased tissue heterogeneity with increased age.
AbstractList Somatic mutations are critical for cancer development and may play a role in age‐related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson–Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre‐ and post‐expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging‐related genes. Allele frequencies of 58 somatic mutations differed between the pre‐ and post‐cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, CDKN2A c.53C>T (T18M) and ERCC8 c.*772T>A, were identified in cells from a patient with XPA. The allele frequency of the CDKN2A mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, BRCA2 c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age.
Somatic mutations are critical for cancer development and may play a role in age-related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson-Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre- and post-expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging-related genes. Allele frequencies of 58 somatic mutations differed between the pre- and post-cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, CDKN2A c.53C>T (T18M) and ERCC8 c.*772T>A, were identified in cells from a patient with XPA. The allele frequency of the CDKN2A mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, BRCA2 c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age.Somatic mutations are critical for cancer development and may play a role in age-related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson-Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre- and post-expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging-related genes. Allele frequencies of 58 somatic mutations differed between the pre- and post-cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, CDKN2A c.53C>T (T18M) and ERCC8 c.*772T>A, were identified in cells from a patient with XPA. The allele frequency of the CDKN2A mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, BRCA2 c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age.
Somatic mutations are critical for cancer development and may play a role in age‐related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson–Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre‐ and post‐expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging‐related genes. Allele frequencies of 58 somatic mutations differed between the pre‐ and post‐cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, CDKN2A c.53C>T (T18M) and ERCC8 c.*772T>A, were identified in cells from a patient with XPA. The allele frequency of the CDKN2A mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, BRCA2 c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age.
Somatic mutations are critical for cancer development and may play a role in age-related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson-Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre- and post-expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging-related genes. Allele frequencies of 58 somatic mutations differed between the pre- and post-cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, CDKN2A c.53C>T (T18M) and ERCC8 c.*772T>A, were identified in cells from a patient with XPA. The allele frequency of the CDKN2A mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, BRCA2 c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age.
Somatic mutations are critical for cancer development and may play a role in age‐related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson–Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre‐ and post‐expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging‐related genes. Allele frequencies of 58 somatic mutations differed between the pre‐ and post‐cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, CDKN2A c.53C>T (T18M) and ERCC8 c.*772T>A, were identified in cells from a patient with XPA. The allele frequency of the CDKN2A mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, BRCA2 c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age. De novo somatic mutations are identified in vitro cell culture experiments. We discover three mutations in aging‐related genes displaying signs of positive selection, supporting the model of increased tissue heterogeneity with increased age.
Audience Academic
Author Erdos, Michael R.
Eriksson, Maria
Rothwell, Rebecca
Rodríguez, Sofía
Zöllner, Sebastian
Didion, John
Vrtačnik, Peter
Collins, Francis S.
Narisu, Narisu
AuthorAffiliation 3 Department of Biosciences and Nutrition, Center for Innovative Medicine Karolinska Institutet Huddinge Sweden
1 National Human Genome Research Institute National Institutes of Health Bethesda MD USA
2 Department of Biostatistics University of Michigan Ann Arbor MI USA
4 Department of Psychiatry University of Michigan Ann Arbor MI USA
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Issue 6
Keywords tissue heterogeneity
genome instability
molecular biology of aging
positive selection
cell mosaicism
aging cell
somatic mutation
Language English
License Attribution
2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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Snippet Somatic mutations are critical for cancer development and may play a role in age‐related functional decline. Here, we used deep sequencing to analyze the...
Somatic mutations are critical for cancer development and may play a role in age-related functional decline. Here, we used deep sequencing to analyze the...
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Enrichment Source
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StartPage e13010
SubjectTerms Adolescent
Age
Aged, 80 and over
Aging
aging cell
Alleles
Analysis
BRCA2 protein
Cell culture
cell mosaicism
Cells, Cultured
Cellular Senescence - genetics
Child
Child, Preschool
Complementation
DNA - genetics
Exons
Female
Fibroblasts
Fibroblasts - cytology
Fibroblasts - metabolism
Gene frequency
Genes
Genetic aspects
Genetic drift
genome instability
Humans
Male
Mathematical models
molecular biology of aging
Mutation
Nucleotide sequence
Original
Positive selection
Progeria
Sequence Analysis, RNA
Skin - cytology
Skin - metabolism
somatic mutation
tissue heterogeneity
Xeroderma pigmentosum
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Title Analysis of somatic mutations identifies signs of selection during in vitro aging of primary dermal fibroblasts
URI https://onlinelibrary.wiley.com/doi/abs/10.1111%2Facel.13010
https://www.ncbi.nlm.nih.gov/pubmed/31385397
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