Microsatellite evolution: polarity of substitutions within repeats and neutrality of flanking sequences

Brohede, Jesper; Ellegren, Hans

doi:10.1098/rspb.1999.0712

Cited by 79 publications

(51 citation statements)

References 46 publications

(37 reference statements)

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“…In sequenced clones having more than three repeats, primers were designed from the regions flanking the microsatellites, using the primer design program, Primer3 (Rozen and Skaletsky, 1998). Primers were designed with resulting products no larger then 200 bp to reduce the frequency of inadvertently detecting mutations in the flanking region (Brohede and Ellegren, 1999).…”

Section: Library Constructionmentioning

confidence: 99%

Identification and characterization of microsatellite markers in the Chagas disease vector Triatoma dimidiata

Anderson¹,

Lai²,

Dotson³

et al. 2002

Infection, Genetics and Evolution

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Section: Library Constructionmentioning

confidence: 99%

Identification and characterization of microsatellite markers in the Chagas disease vector Triatoma dimidiata

Anderson¹,

Lai²,

Dotson³

et al. 2002

Infection, Genetics and Evolution

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“…A number of different errors in measuring allele length are possible due to the combined effects of misaligned flanking sequences, single-base substitutions, mutations in nearby microsatellites, and actual length changes. For example, point substitutions close to the end of repeat arrays, which have been shown to be more common than expected (41), could cause the array to appear shorter because of a length change, when no actual change has occurred. In addition, the presence of repetitive DNA can cause errors to occur in the alignment because of the higher incidence of length mutations.…”

Section: Methodsmentioning

confidence: 99%

Microsatellite evolution inferred from human– chimpanzee genomic sequence alignments

Webster

Smith

Ellegren

2002

Proc. Natl. Acad. Sci. U.S.A.

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122

117

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Most studies of microsatellite evolution utilize long, highly mutable loci, which are unrepresentative of the majority of simple repeats in the human genome. Here we use an unbiased sample of 2,467 microsatellite loci derived from alignments of 5.1 Mb of genomic sequence from human and chimpanzee to investigate the mutation process of tandemly repetitive DNA. The results indicate that the process of microsatellite evolution is highly heterogeneous, exhibiting differences between loci of different lengths and motif sizes and between species. We find a highly significant tendency for human dinucleotide repeats to be longer than their orthologues in chimpanzees, whereas the opposite trend is observed in mononucleotide repeat arrays. Furthermore, the rate of divergence between orthologues is significantly higher at longer loci, which also show significantly greater mutability per repeat number. These observations have important consequences for understanding the molecular mechanisms of microsatellite mutation and for the development of improved measures of genetic distance.T he human genome is composed of 40-50% repetitive DNA, an important class being simple tandem repeats or microsatellite DNA sequences (1). Microsatellites are iterations of short (1-6 bp) sequence motifs, repeat numbers generally being less than 30 (2). They are spread over the genome with an estimated average density of one locus per 2-30 kb, the frequency being dependent on the criteria used for defining a microsatellite locus (1, 3). Similar microsatellite densities have also been documented for other eukaryotic genomes (4). Microsatellites are instrumental as genetic linkage markers in genome mapping projects (5) and have also found widespread use for evolutionary and population genetics studies in many species (6, 7), including humans (8).Microsatellites differ from most other DNA sequences in their high degree of polymorphism, with heterozygosities commonly exceeding 70%. As they generally seem to be free of selective constraints, it is evident that the extensive degree of genetic variability requires a high underlying mutation rate. Estimates of the human genomic mutation rate are in the range of 10 Ϫ4 to 10 Ϫ2 per meiosis (9), several orders of magnitude higher than that of unique DNA sequences (10, 11). It is commonly assumed that microsatellite mutations arise from replication slippage (slipped strand mispairing), a process thought to result in the gain or loss of one or a few repeat units (12)(13)(14). A microsatellite locus may initially evolve from the random occurrence of a few repeat units embedded within unique sequence and subsequently, after several steps of repeat expansion, reach a stage of an appreciable number of repeats. In theory, such expansion can proceed indefinitely in the absence of selection unless there are mechanisms that direct mutations toward contractions (15)(16)(17) or that make loci collapse (e.g., point mutations or large deletions; ref. 18).Based on the assumption that replication slippage is the main cause...

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“…Homoplasy can affect population genetic analyses like inflating estimates of gene flow and genetic differentiation (Adams et al 2004;Curtu et al 2004). Brohede and Ellegren (1999) analyzed a number of sheep and ovine microsatellite orthologs and found a tendency for point mutations to be enriched in microsatellite ends and in the immediate microsatellite flanking regions. A larger data set of human-chimpanzee orthologs was analyzed for flanking sequence divergence by Vowles and Amos (2006), who also found a higher substitution rate in the flanking positions closest to repeat regions.…”

Section: Genome Researchmentioning

confidence: 99%

Genome-wide analysis of microsatellite polymorphism in chicken circumventing the ascertainment bias

Brandström

Ellegren

2008

Genome Res.

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Studies of microsatellites evolution based on marker data almost inherently suffer from an ascertainment bias because there is selection for the most mutable and polymorphic loci during marker development. To circumvent this bias we took advantage of whole-genome shotgun sequence data from three unrelated chicken individuals that, when aligned to the genome reference sequence, give sequence information on two chromosomes from about one-fourth (375,000) of all microsatellite loci containing di-through pentanucleotide repeat motifs in the chicken genome. Polymorphism is seen at loci with as few as five repeat units, and the proportion of dimorphic loci then increases to 50% for sequences with ∼10 repeat units, to reach a maximum of 75%-80% for sequences with 15 or more repeat units. For any given repeat length, polymorphism increases with decreasing GC content of repeat motifs for dinucleotides, nonhairpin-forming trinucleotides, and tetranucleotides. For trinucleotide repeats which are likely to form hairpin structures, polymorphism increases with increasing GC content, indicating that the relative stability of hairpins affects the rate of replication slippage. For any given repeat length, polymorphism is significantly lower for imperfect compared to perfect repeats and repeat interruptions occur in >15% of loci. However, interruptions are not randomly distributed within repeat arrays but are preferentially located toward the ends. There is negative correlation between microsatellite abundance and single nucleotide polymorphism (SNP) density, providing large-scale genomic support for the hypothesis that equilibrium microsatellite distributions are governed by a balance between rate of replication slippage and rate of point mutation.

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Microsatellite evolution: polarity of substitutions within repeats and neutrality of flanking sequences

Cited by 79 publications

References 46 publications

Identification and characterization of microsatellite markers in the Chagas disease vector Triatoma dimidiata

Identification and characterization of microsatellite markers in the Chagas disease vector Triatoma dimidiata

Microsatellite evolution inferred from human– chimpanzee genomic sequence alignments

Genome-wide analysis of microsatellite polymorphism in chicken circumventing the ascertainment bias

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