Somatic mutations and cellular aging: two-dimensional DNA typing of rat fibroblast clones

Slagboom, P. Eline; Mullaart, E.; Droog, S.; Vijg, Jan

doi:10.1016/0921-8734(91)90022-4

Cited by 7 publications

(4 citation statements)

References 33 publications

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“…Moreover, these analytical tools estimate technical error based on STR genotypes from sequenced homozygous or haploid genomes, ignoring somatic alleles within individuals (which are expected for STRs even in primary tissues, occurring at rates 10 4 –10 5 times higher than SNV somatic mutations) [73–76]. Probabilistic error models have been formulated to quantify variation arising from technical sources [37,38], but in the face of somatic STR variation, these models presumably require substantial read coverage to call germ-line STR genotypes with confidence.…”

Section: Analytical Tools and Genotyping Methods Continue To Strugglementioning

confidence: 99%

“…This somatic STR variation is particularly noticeable in tumor tissues, but is also measurable in primary tissues [73,87]. While these findings immediately led to systems of classification for tumor types and clones [76,88,89], the investigation of somatic STR variation (or MSI) may also inform us about general phenotypic states and disease susceptibility.…”

Section: Somatic Str Variation May Be a Sensitive Marker For Increasementioning

confidence: 99%

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The overdue promise of short tandem repeat variation for heritability

2014

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Section: Analytical Tools and Genotyping Methods Continue To Strugglementioning

confidence: 99%

Section: Somatic Str Variation May Be a Sensitive Marker For Increasementioning

confidence: 99%

The overdue promise of short tandem repeat variation for heritability

2014

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“…Moreover, these analytical tools estimate technical error based on STR genotypes from sequenced homozygous or haploid genomes, ignoring somatic alleles within individuals (which are expected for STRs even in primary tissues, occurring at rates 10 4 -10 5 times higher than SNV somatic mutations) [73–76]. Probabilistic error models have been formulated to quantify variation arising from technical sources [37,38], but in the face of somatic STR variation, these models presumably require substantial read coverage to call germ-line STR genotypes with confidence.…”

Section: Analytical Tools and Genotyping Methods Continue To Strugglementioning

confidence: 99%

“…It has been appreciated for some time that the high STR mutation rate leads to somatic variation within individuals in addition to germ-line variation between individuals [71]. This somatic STR variation is particularly noticeable in tumor tissues, but is also measurable in primary tissues [73,87]. While these findings immediately led to systems of classification for tumor types and clones [76,88,89], the investigation of somatic STR variation (or MSI) may also inform us about general phenotypic states and disease susceptibility.…”

Section: Somatic Str Variation May Be a Sensitive Marker For Increasementioning

confidence: 99%

The overdue promise of short tandem repeat variation for heritability

Press

Carlson

Queitsch

2014

Preprint

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Short tandem repeat (STR) variation has been proposed as a major explanatory factor in the heritability of complex traits in humans and model organisms. However, we still struggle to incorporate STR variation into genotype-phenotype maps. Here, we review the promise of STRs in contributing to complex trait heritability, and highlight the challenges that STRs pose due to their repetitive nature. We argue that STR variants are more likely than single nucleotide variants to have epistatic interactions, reiterate the need for targeted assays to accurately genotype STRs, and call for more appropriate statistical methods in detecting STR-phenotype associations. Lastly, we suggest that somatic STR variation within individuals may serve as a read-out of disease susceptibility, and is thus potentially a valuable covariate for future association studies. Keywordsshort tandem repeats; microsatellites; heritability; epistasis; sequencing technologies The 'missing heritability' of complex diseases and STR variationComplex diseases such as diabetes, various cancers, cardiovascular disease, and neurological disorders cluster in families, and are thus considered to have a genetic component [1][2][3] (Glossary). The identification of these genetic factors has proven challenging; although genome-wide association (GWA) studies have identified many genetic variants that are associated with complex diseases, these generally confer less disease risk than expected from empirical estimates of heritability. This discrepancy, termed the 'missing heritability', has been attributed to many factors [1][2][3][4][5][6]. A trivial explanation is that shared environments among relatives may artificially inflate estimates of heritability. However, missing heritability may also be due to variants in the human genome that are currently inaccessible at a population scale [1,2]. One such class of variation is short tandem repeat (STR) unit number variation. Some have previously suggested that adding STR © 2014 Elsevier Ltd. All rights reserved.Corresponding author: Queitsch, C. (queitsch@uw.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [25][26][27][28][29]. Together, these findings suggest that STR variation has the potential to dramatically revise the heritability estimates attributable to genetic factors. NIH Public AccessThe high STR mutation rate also leads to substantial somatic variation of STR loci within individuals. In fact, this somatic variation, also called microsatellite instability (MSI), has been used for decades as a biomarker for different classes of cancer [30]. Recent studi...

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