Distinct Mutational Behaviors Differentiate Short Tandem Repeats from Microsatellites in the Human Genome

Ananda, Guruprasad; Walsh, Erin; Jacob, Kimberly D.; Krasilnikova, Maria M.; Eckert, Kristin A.; Chiaromonte, Francesca; Makova, Kateryna D.

doi:10.1093/gbe/evs116

Cited by 58 publications

(92 citation statements)

References 74 publications

(143 reference statements)

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“…We have developed a simple probabilistic model of polymerase slippage that explains these correlations and accurately predicts indel rates across the observed range, as a function of local sequence similarity. The good quantitative fit supports the idea that polymerase slippage by itself can explain the remarkable rate heterogeneity among stable nonrepetitive sequence, indelprone homopolymers (Ananda et al 2013), multiallelic tandem repetitive sites, and highly unstable microsatellites. Interpretation of the inferred model parameter indicates that polymerase slippage most frequently involves the formation of ''loops'' of 1-4 bp, although longer loops also occur; once formed these loops are generally unstable, but may become stabilized by the presence of sequence identity at the misaligned locus of ;6 bp or more, leading to indel formation.…”

Section: Discussionsupporting

confidence: 68%

The origin, evolution, and functional impact of short insertion–deletion variants identified in 179 human genomes

et al. 2013

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Short insertions and deletions (indels) are the second most abundant form of human genetic variation, but our understanding of their origins and functional effects lags behind that of other types of variants. Using population-scale sequencing, we have identified a high-quality set of 1.6 million indels from 179 individuals representing three diverse human populations. We show that rates of indel mutagenesis are highly heterogeneous, with 43%-48% of indels occurring in 4.03% of the genome, whereas in the remaining 96% their prevalence is 16 times lower than SNPs. Polymerase slippage can explain upwards of three-fourths of all indels, with the remainder being mostly simple deletions in complex sequence. However, insertions do occur and are significantly associated with pseudo-palindromic sequence features compatible with the fork stalling and template switching (FoSTeS) mechanism more commonly associated with large structural variations. We introduce a quantitative model of polymerase slippage, which enables us to identify indel-hypermutagenic protein-coding genes, some of which are associated with recurrent mutations leading to disease. Accounting for mutational rate heterogeneity due to sequence context, we find that indels across functional sequence are generally subject to stronger purifying selection than SNPs. We find that indel length modulates selection strength, and that indels affecting multiple functionally constrained nucleotides undergo stronger purifying selection. We further find that indels are enriched in associations with gene expression and find evidence for a contribution of nonsense-mediated decay. Finally, we show that indels can be integrated in existing genome-wide association studies (GWAS); although we do not find direct evidence that potentially causal protein-coding indels are enriched with associations to known disease-associated SNPs, our findings suggest that the causal variant underlying some of these associations may be indels.

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Section: Discussionsupporting

confidence: 68%

The origin, evolution, and functional impact of short insertion–deletion variants identified in 179 human genomes

et al. 2013

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“…Repeat expansion in coding regions can alter protein function which can also result in new function 36 . It is perhaps due to these reasons that presence of SSRs in exons compared with introns is low in the present study, which corroborates studies on different genes and genomes 22,28,62,72,75 . Some trinucleotide repeats may add new coding regions and affect size or add new functions to proteins 76 .…”

Section: Repeats In Exons/intronssupporting

confidence: 92%

“…Further, the repeats do not have greater than 75% CG richness, which agrees with other studies where the GC rich repeats are not abundant in genomes, particularly in coding sequences 23,48,74,86 . Few C/G rich repeats in human keratin genes could be due to the propensity for mutations 28,74,[87][88][89] even though some mammalian genes have higher ratio of C/G repeats of certain lengths 74 . Human KRT31 exon has a tetranucleotide repeat CTCC(n) which lies in the region that is known for variation as per the Ensembl version 75.…”

Section: Repeat Cg Richnessmentioning

confidence: 99%

“…Repeat length: Longer repeats are polymorphic 27 , have higher chances of mutations interrupting the length 65 , tend to have higher slippage rates 28 and are deleted in dividing cells 70 . Since the hair keratin genes are also expressed in actively dividing cells (the hair bulb), it is possibly due to this reason and propensity for higher slippage rate, that most repeats are not long in the hair keratin genes.…”

Section: Repeat Cg Richnessmentioning

confidence: 99%

“…SSRs are considered hypermutable sequences where mutations could be due to insertions, deletions of a motif or of a single nucleotide in a motif 22,25 . Expansion or contraction of SSRs generally happens during DNA replication and is frequent on the lagging strand 21,[26][27][28][29] . SSR length mutations may modify genes 21,30,31 and or cause disorders whether repeats are present in exons, introns or un-transcribed regions 23,[32][33][34][35][36][37][38][39][40] .…”

Section: Introductionmentioning

confidence: 99%

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Few Simple Sequence Repeats in Human Hair

2017

JCBSC

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Abstract:Keratin genes are subgroup of intermediate filament (IF) genes. Keratins expressed in hair are called "hair keratins". Comparison of keratin gene sequences and structural organization has been done earlier but no study has been undertaken that compares human hair keratin genes with orthologues in chimp, orangutan, macaque and platypus, with specific references to simple sequence repeats (SSRs) or microsatellites. This study seeks presence of SSRs in human hair keratin genes and compares their positions in orthologue genes. Although the structural organization of keratin genes is largely conserved, as reported in other studies; some human keratin genes show differences in the number of exons and the lengths of exons/introns, when compared with the orthologues. The present study shows few SSRs in human hair keratin genes, where only one repeat is found in exon of Type I keratin gene KRT31, while additional repeats are present in introns. Some repeats are longer in the human genes whereas some indicate reduction in length compared with orthologues. Many repeats are present in regions that are known for intronic variations. This study revisits the comparisons of structural organization of human hair keratin genes and compares them with the orthologues. The SSRs found here could be useful for monitoring variations in human hair keratin genes that may happen due to hypermutable nature of SSRs.

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Evolution of MicrosatelliteDNA

Jentzsch¹,

Bagshaw²,

Buschiazzo³

et al. 2013

Encyclopedia of Life Sciences

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Microsatellites are highly mutable nucleotide arrays composed of short motifs repeated in tandem. They are ubiquitously distributed in bacterial and eukaryotic genomes and their abundance and mutability has made them a widely used genetic marker for a variety of applications. One aim of the study of microsatellite evolution is to predict their mutational patterns in order to make them more accurate markers of genetic distance between species or individuals. Applications that use microsatellites as markers work under the basic assumption that microsatellite mutations are simple and random. However, this assumption contrasts with the observed variability of mutation rates across microsatellite loci. Several factors such as array size and sequence motif have been shown to influence microsatellite mutation rates, but research into their evolution is also complicated by the fact that some microsatellites function to regulate gene expression and possibly other genomic functions, and may therefore be subject to selective pressure. Key Concepts: Microsatellites are arrays of tandemly repeated 1–6 bp sequence motifs. They are highly abundant in all organisms studied, and they are also highly polymorphic as a result of frequent change of length mutations. The traditional view of microsatellites as neutrally evolving junk DNA is overly simplistic, which sometimes affects the accuracy of studies that use them as genetic markers. Many complex processes interact to govern the frequency with which microsatellites mutate, including array length, sequence motif and flanking sequence. Increasing evidence indicates that a subset of microsatellites function to regulate gene expression, and perhaps also interchromosomal recombination, and the evolution of these microsatellites is therefore influenced by selection. The mutability of microsatellites, the fact that their mutations are easily reversible, and their abundance and conservation in regulatory regions suggest that they may make a significant contribution to the diversity and adaptation of species, but much work remains to establish the extent of their functional importance.

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Distinct Mutational Behaviors Differentiate Short Tandem Repeats from Microsatellites in the Human Genome

Cited by 58 publications

References 74 publications

The origin, evolution, and functional impact of short insertion–deletion variants identified in 179 human genomes

The origin, evolution, and functional impact of short insertion–deletion variants identified in 179 human genomes

Few Simple Sequence Repeats in Human Hair

Evolution of MicrosatelliteDNA

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