Long Microsatellite Alleles in Drosophila melanogaster Have a Downward Mutation Bias and Short Persistence Times, Which Cause Their Genome-Wide Underrepresentation

Corresponding author: Christian Schlötterer, Institut für Tierzucht und Genetik, Veterinärplatz 1, 1210 Vienna, Austria., christian.schloetterer{at}vu-wien.ac.at (E-mail)

Communicating editor: Y.-X. FU

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS AND DISCUSSION LITERATURE CITED

Microsatellites are short tandemly repeated DNA sequence motifs that are highly variable in most organisms. In contrast to mammals, long microsatellites (>15 repeats) are extremely rare in the Drosophila melanogaster genome. To investigate this paucity of long microsatellites in Drosophila, we studied 19 loci with exceptionally long microsatellite alleles. Inter- and intraspecific analysis showed that long microsatellite alleles arose in D. melanogaster only very recently. This lack of old alleles with many repeats indicated that long microsatellite alleles have short persistence times. The size distribution of microsatellite mutations in mutation-accumulation lines suggests that long alleles have a mutation bias toward a reduction in the number of repeat units. This bias causes the short persistence times of long microsatellite alleles. We propose that species-specific, size-dependent mutation spectra of microsatellite alleles may provide a general mechanism to account for the observed differences in microsatellite length between species.

MICROSATELLITES are DNA sequences in which a short motif of 1–6 bases is tandemly repeated. Their inherent instability makes microsatellite loci particular useful for evolutionary and population genetic studies (GOLDSTEIN and SCHLOTTERER 1999 ). Microsatellite mutations are primarily caused by slipped-strand mispairing errors during DNA replication (TAUTZ and SCHLOTTERER 1994 ). Although molecular details of this process are still uncertain, it is assumed that the gain or loss of repeat units is caused by strand displacement of the nascent DNA strand followed by an out of register pairing. Even though most primary slippage events are recognized and corrected by the mismatch repair system, the observed mutation rate is still considerably higher than the base substitution rate (on the order of 10^-4 to 10^-6 per generation; LEVINSON and GUTMAN 1987 ; DALLAS 1992 ; WEBER and WONG 1993 ; SCHUG et al. 1997 , SCHUG et al. 1998A ; WIERDL et al. 1997 ; SCHLOTTERER et al. 1998 ).

A recent comparison to mammals has shown that mutation rates of Drosophila melanogaster microsatellites are substantially lower (KRUGLYAK et al. 1998 ; SCHLOTTERER et al. 1998 ; SCHUG et al. 1997 , SCHUG et al. 1998A ). In a survey of mutation-accumulation lines, SCHLOTTERER et al. 1998 observed nine mutations in 59,524 allele generations. All mutations were detected at a single, exceptionally long microsatellite allele, indicating that the repeat number (length of a microsatellite) is the primary factor influencing microsatellite mutation rates.

KRUGLYAK et al. 1998 analyzed the length distribution of microsatellites in 1 Mb of nonredundant sequence from human, mice, yeast, and Drosophila. Although microsatellite density was similar in humans and Drosophila, the length distribution differed, with long microsatellites being more frequent in humans. To explain the observed microsatellite length distribution, KRUGLYAK et al. 1998 introduced a Markov chain model of microsatellite evolution that incorporated a length-dependent slippage rate (longer microsatellites have a higher slippage rate) and point mutations interrupting the microsatellite. According to this model, the infinite growth of a microsatellite is prevented by base substitutions. Each point mutation in a microsatellite reduces the number of uninterrupted repeats; thus a higher base substitution rate (relative to the slippage rate) leads to shorter microsatellites. To determine the relative slippage rates of microsatellites in different species, KRUGLYAK et al. 1998 fixed the base substitution rate at 1 x 10^-8 (per nucleotide per generation) and fitted the slippage rate to the empirical distribution of microsatellites. Using this approach, they inferred species-specific differences in slippage rates. D. melanogaster, the species with the shortest average microsatellite length, was found to have the lowest slippage rate.

Given that the model of KRUGLYAK et al. 1998 assumes an equilibrium length distribution, it is not possible to determine how length distributions could shift between organisms. One possibility is that the mutation rate of microsatellites increases, resulting in longer microsatellites. Alternatively, other factors (e.g., selection, mutational biases, and mismatch repair specificity) may cause differences in the repeat number of microsatellites between organisms and these differences, in turn, result in a different microsatellite mutation rate.

To gain further insight into the evolutionary forces shaping microsatellite length distributions and mutation rates, we studied 19 exceptionally long microsatellite loci in D. melanogaster, a species with short microsatellite loci.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS AND DISCUSSION LITERATURE CITED

Microsatellite loci:
Seventeen loci with at least 16 uninterrupted repeats were selected from GenBank. Two additional loci were obtained from a genomic D. melanogaster library (DM12, DM18). The original enrichment protocol (SCHLOTTERER 1998B ) was slightly modified by increasing the stringency of the washing steps (0.1x SSC, 0.1% SDS, 65°) to specifically select for microsatellites with many repeat units. For comparison, 24 short loci for D. melanogaster (5915, G411, Dmtena, DS08011, Z50409, DS09021, DS06335a, DS00146, DS01551, DS09020, DS01340, Drogpad, 6744, Dm2337, Acp26Ab, Dm0620, su.var, tor, DS07289, DS00361c, DS00058/2, DS08088, DS03018, and DS01391) and 30 short loci for D. simulans (sec 1, sec 3, sec 6, sec 7, sec 12, sec 13, 5915, G411, DS00762, DS08011, DS00144, Z50409, DS09021, DS06335a, DS00146, DS01551, Droyanetsb, Drogpad, Dromhc, DS08687a, 6744, Dm2337, Dm0620, tor, DS00361c, DS00541, DS08088, DS03018, DS06335b, and DS00361) with at least 7 uninterrupted repeats were selected as a reference. The primer sequences and amplification conditions are available from the authors' webpage: http://i122server.vu-wien.ac.at.

Drosophila lines:
We assayed microsatellite variability in five European D. melanogaster populations (300 chromosomes) from Austria, Russia, Netherlands, France, and Italy. Five worldwide populations (134 chromosomes) from Israel, Italy, the United States, and Kenya were analyzed in D. simulans. To account for genetic drift during the propagation of isofemale lines, we randomly selected one allele from the African lines. For all other populations, both alleles could be scored, as F₁ individuals were typed.

An 800-bp sequence flanking the microsatellite was analyzed for locus AC004441. Twenty-one long microsatellite alleles (24–30 repeats), 10 short alleles (13–15 repeats), and 5 intermediate alleles with 17 repeats were sequenced in homozygous flies. Because homozygous individuals were rarely observed in F₁ flies, we used isofemale lines originating from Australia, Europe, and North America. The sequenced alleles were chosen to reflect the allele distribution in non-African D. melanogaster populations. We also included one D. simulans individual.

The distribution of microsatellite mutations was analyzed by typing 122 independent mutation-accumulation lines, which were originally generated by NUSSLEIN-VOLHARD et al. 1984 . All 10 loci (4 TA/AT repeats, 6 GT/CA repeats) located on the second chromosome were analyzed in these lines. Calculation of mutation rates was essentially as described in SCHLOTTERER et al. 1998 .

Microsatellite typing:
Genomic DNA was extracted from individual female flies by a high-salt method (MILLER et al. 1988 ). PCR reactions (10-µl) were carried out with 100 ng of genomic DNA, ³²P-labeled forward primer, 1.5 mM MgCl₂, 200 µM dNTPs, 1 µM of each primer, and 0.5 units Taq polymerase. A typical cycling profile consisted of 30 cycles with 50 sec at 94°, 50 sec at 50°–57° (depending on the primer pair), and 50 sec at 72°. All PCR reactions were run with an initial denaturing step of 3 min and a final extension of 45 min at 72° for quantitative terminal transferase activity of the Taq polymerase. PCR products were separated on 7% denaturing polyacrylamide gels (32% formamide, 5.6 M urea) and visualized by autoradiography. The same PCR conditions were also used for cross-species amplification of the microsatellites. PCR products were sized by loading a "slippage ladder" that produced bands every 2 bp (SCHLOTTERER and ZANGERL 1999 ) and a known size standard next to them.

DNA sequencing:
For each locus (apart from locus Antp1 for which no individuals homozygous for a single long allele could be obtained), between 5 and 12 alleles covering the entire size spectrum were directly sequenced in D. melanogaster and D. simulans. To determine the ancestral microsatellite structure, one individual from other members of the melanogaster subgroup was also sequenced.

Data analysis:
The program MISAT was used to obtain a maximum-likelihood estimate for the parameter (4N_eµ) by using a Markov chain recursion method (NIELSEN 1997 ). We used 1,000,000 runs through the Markov chain to estimate from allele frequencies of European D. melanogaster populations assuming a strict stepwise mutation model. of X-linked loci was multiplied by ⁴/₃ to account for the smaller effective population size. The program DNASP 2.82 (ROZAS and ROZAS 1997 ) was used to calculate sequence-specific diversity indices. Phylogenetic reconstruction was carried out with the PUZZLE 4.0.1 software (STRIMMER and VON HAESELER 1996 ). TREEVIEW was used for graphical representation of the tree (PAGE 1996 ).

The program GENETREE (GRIFFITHS and TAVARE 1998 ) was used to estimate the age of microsatellite alleles from sequence polymorphism in the flanking region of the micro-satellite (1,000,000 runs). Recombinant sequences were excluded from the analysis. The relative frequencies of short and long alleles, however, still reflected the occurrence of these alleles in natural populations. We used the number of segregating sites (S) as an estimator for the mutation rate. The program returns ages of mutations in units of 2N generations. To calculate the emergence time in years (t) we used the formula t = 2NTT' (where N = effective population size, T = coalescence time, T' = generation time in years). The estimated population size N_e for European D. melanogaster was calculated from the maximum-likelihood value obtained from short microsatellites by solving the formula = 4N_eµ for N_e using the dinucleotide mutation rate of 9.3 x 10^-6 (SCHUG et al. 1998A ).

Sequence analysis:
Nonoverlapping genomic sequences from Saccharomyces cerevisiae, Caenorhabditis elegans, D. melanogaster, and humans were obtained from the following web pages:

• ftp://genome-ftp.stanford.edu/yeast/genome_seq;

• http://www.sanger.ac.uk/Projects/C_elegans/chromosomes.shtml;

• http://www.fruitfly.org/sequence/drosophila-regions.html;

• http://www.ncbi.nlm.nih.gov/genome/seq/.

Only microsatellite sequences with more than four repeats were included in the analysis.

	RESULTS AND DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS AND DISCUSSION LITERATURE CITED

With the recent progress of various genome-sequencing projects, it is possible to compare parameters like microsatellite length and density across taxa. We used the available sequences for yeast, C. elegans, and humans and compared them to D. melanogaster. The average microsatellite length and proportion of long microsatellites were found to be significantly lower in D. melanogaster (Table 1). This underrepresentation of long microsatellites cannot be explained by a general paucity of microsatellite DNA, as microsatellite density is high in D. melanogaster (Table 1). Further support for the scarcity of long microsatellite alleles in D. melanogaster was provided by cloning of DNA fragments that were specifically enriched for long microsatellites. The library was highly redundant and only two loci with >15 repeats were detected among 40 clones. To further investigate the potential causes for the paucity of long microsatellites in the genome of D. melanogaster, we retrieved 17 microsatellites from the sequenced part of the D. melanogaster genome that were longer than 15 dinucleotide repeats. Hence, in total, 19 microsatellites were available that had particularly long alleles.

Long microsatellites have high mutation rates in natural populations of D. melanogaster:
All 19 long microsatellite loci were highly variable in natural populations of D. melanogaster, with 9–36 alleles per locus (Table 2). Heterozygosities averaged over all individuals ranged from 0.235 to 0.951. The average repeat number in our European population sample was 19.02.

To quantify the influence of repeat number on microsatellite variability, we characterized the same European populations for 24 additional microsatellite loci, which were not selected for exceptionally long alleles. The compound estimator , which depends on the mutation rate and the effective population size, was used to describe microsatellite variability. While averaged over all long microsatellite loci studied was 46.81 (±12.66), the 24 loci representing shorter microsatellites (mean repeat number = 10.4) had an average of 4.22 (±0.93; Table 3). As all loci were typed in the same populations, the ratio of could be used to determine their relative mutation rates. While the mean repeat number of long loci was almost twice as high as mean repeat length of short loci, is 11.1 times higher in the former loci. This indicates that microsatellite mutability is highly length dependent and the increase in mutation rate is higher than expected under a linear model.

View this table: In this window In a new window   Table 3. Maximum-likelihood estimates of the compound parameter for long and short microsatellites surveyed in natural populations of D. melanogaster and D. simulans

In D. simulans, both groups of loci had very similar repeat numbers and values (Table 3). Given the low sequence divergence and similar genome organization of both species (POWELL 1997 ), we conclude that the loci with the long alleles do not differ from other loci due to, for example, their genomic position. Rather, only the high number of repeats seems to account for their high mutation rate.

Long microsatellite alleles represent the derived state in the melanogaster subgroup:
To study the persistence time of long microsatellites, we analyzed orthologous loci in the melanogaster subgroup. All orthologous PCR products were sequenced and all but one of the orthologous alleles had short microsatellite alleles. To verify this observation, we typed 134 D. simulans chromosomes for all loci that showed long alleles in D. melanogaster. No long microsatellite allele was detected in D. simulans. Applying the parsimony principle, we inferred that the most recent common ancestor of D. melanogaster and the D. simulans triad had a short microsatellite sequence. In more distantly related species, either the size of the microsatellite was reduced or a complex microsatellite structure including point mutations or small indels in the repeat region could be observed. One locus (AC005270) showed a complete loss of the microsatellite in all ancestral species and another locus (DM12) did not amplify in any species except D. melanogaster; hence the ancestral character state is ambiguous for these two loci. In D. sechellia we detected an allele with a pure uninterrupted array of 22 repeat units for a single locus (Dm2337.2). This locus is short (8–11 repeats) in D. simulans and D. mauritiana and interrupted by point mutations in the repeat unit in D. teissieri and D. yakuba. In D. orena the microsatellite structure could not be clearly discerned (longest uninterrupted stretch of 4 repeats). Therefore, we assume that a long microsatellite allele arose twice at this locus during the evolution of the melanogaster subgroup.

The combined evidence from the loci studied suggests that long alleles must have arisen in D. melanogaster and do not represent old alleles.

Long microsatellites are of recent origin within D. melanogaster populations:
Sequencing the flanking region of locus AC004441 in 36 non-African individuals revealed 14 distinct haplotypes (Fig 1). The average nucleotide diversity () was 0.00536. Phylogenetic analysis grouped these 14 haplotypes into three different major lineages (Fig 1 and Fig 2).

View larger version (18K): In this window In a new window Download PPT slide   Figure 1. Polymorphic and diverged sites identified in 36 European D. melanogaster individuals and 1 D. simulans individual. The arrow indicates the position of the microsatellite. *, the haplotype "long" consists of individuals Au12, Au14, Au3, Au5, Au6, Au9, Ita24, C11, C12, C15, C17, C19, C9, B3, B4, B7, and B8.

View larger version (31K): In this window In a new window Download PPT slide   Figure 2. Maximum-likelihood phylogeny based on 855 bp of microsatellite flanking region. Individuals are labeled according to their geographic origin (Au, Australia; B, Boston; C, Chicago; Ita, Italy). Circled areas refer to long (darkly shaded), intermediate (lightly shaded), and short microsatellite alleles.

We classified the microsatellite alleles of locus AC004441 into three different size classes: long, intermediate, and short alleles. Mapping the different microsatellite size classes on the phylogenetic tree based on the flanking sequence indicated that alleles of the three size classes were of different phylogenetic origin. In particular, all long alleles grouped into a single, well-supported clade (Fig 2). This monophyly of long alleles is further supported by a diagnostic base substitution in the microsatellite repeat. All long alleles share an A T substitution in the microsatellite array that is followed by a shorter, invariant stretch of five AT repeats (Table 4). A single short allele (Au2), which is a recombinant between long and short alleles, also shares this microsatellite structure. Two out of 21 long alleles sequenced showed additional point mutations in the repeat. The third size class (the alleles of intermediate size) is characterized by a specific character state (G) at the variable site, thus differentiating between long and intermediate alleles.

The emergence time of the long alleles was determined using the coalescence approach (GRIFFITHS and TAVARE 1998 ). On the basis of an estimated effective population size of 1.13 x 10⁵ [N_e = 4.22/(4 x 9.3 x 10^-6)] and 5–10 generations per year, we conclude that the most recent common ancestor of the allelic class to which all long alleles belong occurred 13.9–27.8 thousand years ago. The long alleles were the youngest class of alleles at locus AC004441, further supporting their recent origin.

Long microsatellite alleles have the tendency to lose repeat units:
Cross-species comparisons and within-population studies indicated that long alleles do not persist for long times in the Drosophila genome. Therefore, we were interested whether the microsatellite mutation spectrum provides an explanation for this observation. We screened all 10 long microsatellites mapping to the second chromosome in 122 mutation-accumulation lines described by SCHLOTTERER et al. 1998 . In total, we detected eight mutations at four different loci (Table 5; Fig 3). While the number of upward and downward mutations was identical, the downward mutations encompassed larger steps than upward mutations. Hence, on average each mutation resulted in a loss of 1.4 repeats. This result is very similar to the observation by SCHLOTTERER et al. 1998 , who observed an average loss of 1.7 repeats per mutation. A combined analysis of both data sets indicated that repeat losses were significantly more frequent than repeat gains (P = 0.037, Mann-Whitney U-test). Resampling of the observed mutations also provided strong support of a downward mutation bias (P < 0.05).

View larger version (33K): In this window In a new window Download PPT slide   Figure 3. Size distribution of observed mutations in mutation-accumulation lines at four microsatellite loci.

With the small effective population sizes at which the mutation-accumulation lines were propagated, we can rule out that this mutation bias is the result of selection against long alleles. To overcome genetic drift in the vials, unrealistic selection coefficients would have to be assumed. Thus, the observed mutational bias of long microsatellite alleles is a neutral phenomenon.

Experiments in yeast indicated that the mutation spectrum of cloned microsatellites changes with the repeat number (WIERDL et al. 1997 ; SCHLOTTERER 1998A ). While mutations of short microsatellites (7.5–16.5 repeats) were slightly biased toward a gain of repeat units, mutations of microsatellites with >25 repeat units were significantly biased toward a lower number of repeats. On average, yeast microsatellites >25 repeats lost 2 repeat units per mutation (Table 6). Thus, the occurrence of a downward mutation bias of long microsatellite alleles in both species suggests a general mechanism to constrain the length of microsatellites.

Previous surveys of the D. melanogaster genome (SCHUG et al. 1998B ; BACHTROG et al. 1999 ) also indicated that dinucleotide microsatellites longer than 15 repeats are extremely rare (<0.6%). In yeast, however, the percentage of dinucleotide microsatellites longer than 15 repeats is about five times higher than in Drosophila (Table 1). Furthermore, yeast microsatellites are on average 6% longer than D. melanogaster ones (Table 1). This difference between D. melanogaster and yeast could be explained if the mutation spectrum of microsatellites changes at a different length. While our data support such a model of species-specific and size-dependent mutation spectra, it has to be emphasized that our data are based on a small number of observations and the yeast data are obtained from a plasmid-based system. Previous results indicated that the mutational behavior of genomic microsatellites differs from those cloned into a plasmid (HENDERSON and PETES 1992 ). Nevertheless, species-specific, size-dependent mutation spectra of microsatellite alleles may also account for the well-described variation in microsatellite length between different species (AMOS 1999 ). Each species may have its own critical length at which the mutational behavior of a microsatellite changes, thus resulting in a species-specific microsatellite length distribution.

Assuming that the average mutation rate of dinucleotide microsatellites determined by SCHUG et al. 1998A represents the typical mutation rate of short microsatellites, it is possible to estimate the average mutation rate of microsatellite loci with long alleles. Because of these loci is ~11.1 times higher than of typical short microsatellites, their average mutation rate is also 11.1 times higher (assuming the same mutational behavior). Thus, we estimated the average mutation rate of microsatellite loci with long alleles to be 1.03 x 10^-4. This mutation rate is within the range of observed average microsatellite mutation rates in humans (WEBER and WONG 1993 ). Hence, microsatellite mutation rates in D. melanogaster are on average lower than in mammals, but long alleles have mutation rates similar to those observed in mammals. Thus, if microsatellite mutation rates are not species specific, they cannot explain the observed variation in microsatellite length distribution in different species. Most likely, the differences in microsatellite length between species are caused by species-specific, size-dependent mutation spectra. The approach of KRUGLYAK et al. 1998 to incorporate point mutations to explain the microsatellite length distribution cannot fully account for the evolution of long microsatellites in D. melanogaster because the persistence times of most long alleles are too short for multiple base substitutions to occur in the microsatellite repeat.

It remains speculative why the mutational behavior of microsatellites changes with their length in a species-specific manner. Because of the well-recognized importance of the mismatch repair system (EISEN 1999 ) and some other factors involved in DNA replication, they provide good candidates for determining species-specific differences.

An alternative model that included sister chromatid exchange as a factor influencing microsatellite evolution has recently been suggested by FALUSH and IWASA 1999 . Using computer simulations they showed that even with an upwardly biased mutational process for microsatellite alleles, the persistence time of long alleles remains short due to sister chromatid exchange. Because the persistence time was proportional to the rate of sister chromatid exchange in their model, it is conceivable that species-specific rates of sister chromatid exchange may be responsible for the observed difference in size distribution. It should be noted, however, that a previous study did not detect an influence of recombination rate on the length of microsatellite loci (BACHTROG et al. 1999 ). Hence, if sister chromatid exchange is influencing the length distribution of D. melanogaster microsatellites, their rates should differ from recombination rates.

	ACKNOWLEDGMENTS

We are grateful to the laboratory of C. Nüsslein-Volhard, the Umea and the Bloomington Stock Centers, J. David, R. Achmann, A. Korol, D. Slezak, and R. C. Woodruff for providing flies. Special thanks to E. Müller for help with the development of the C-code determining the microsatellite distribution in genomic sequences. S. Weiss provided many helpful comments on the manuscript. This work was supported by grants of the Fonds zur Förderung der wissenschaftlichen Forschung (FWF) to C.S.

Manuscript received October 15, 1999; Accepted for publication March 24, 2000.

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				M. Perez, F. Cruz, and P. Presa Distribution Properties of Polymononucleotide Repeats in Molluscan Genomes J. Hered., January 1, 2005; 96(1): 40 - 51. [Abstract] [Full Text] [PDF]

				M. D. Prasad, M. Muthulakshmi, M. Madhu, S. Archak, K. Mita, and J. Nagaraju Survey and Analysis of Microsatellites in the Silkworm, Bombyx mori: Frequency, Distribution, Mutations, Marker Potential and Their Conservation in Heterologous Species Genetics, January 1, 2005; 169(1): 197 - 214. [Abstract] [Full Text] [PDF]

				R. Sainudiin, R. T. Durrett, C. F. Aquadro, and R. Nielsen Microsatellite Mutation Models: Insights From a Comparison of Humans and Chimpanzees Genetics, September 1, 2004; 168(1): 383 - 395. [Abstract] [Full Text] [PDF]

				P. Almeida and C. Penha-Goncalves Long Perfect Dinucleotide Repeats Are Typical of Vertebrates, Show Motif Preferences and Size Convergence Mol. Biol. Evol., July 1, 2004; 21(7): 1226 - 1233. [Abstract] [Full Text] [PDF]

				Y. Lai and F. Sun The Relationship Between Microsatellite Slippage Mutation Rate and the Number of Repeat Units Mol. Biol. Evol., December 1, 2003; 20(12): 2123 - 2131. [Abstract] [Full Text] [PDF]

				M. O. Kauer, D. Dieringer, and C. Schlotterer A Microsatellite Variability Screen for Positive Selection Associated With the "Out of Africa" Habitat Expansion of Drosophila melanogaster Genetics, November 1, 2003; 165(3): 1137 - 1148. [Abstract] [Full Text] [PDF]

				S. Souames, E. Bonnivard, C. Bazin, and D. Higuet High Mutation Rate of TPE Repeats: A Microsatellite in the Putative Transposase of the hobo Element in Drosophila melanogaster Mol. Biol. Evol., November 1, 2003; 20(11): 1826 - 1832. [Abstract] [Full Text] [PDF]

				D. Dieringer and C. Schlotterer Two Distinct Modes of Microsatellite Mutation Processes: Evidence From the Complete Genomic Sequences of Nine Species Genome Res., October 1, 2003; 13(10): 2242 - 2251. [Abstract] [Full Text] [PDF]

				C. L. Ross, K. A. Dyer, T. Erez, S. J. Miller, J. Jaenike, and T. A. Markow Rapid Divergence of Microsatellite Abundance Among Species of Drosophila Mol. Biol. Evol., July 1, 2003; 20(7): 1143 - 1157. [Abstract] [Full Text] [PDF]

				J. C. Whittaker, R. M. Harbord, N. Boxall, I. Mackay, G. Dawson, and R. M. Sibly Likelihood-Based Estimation of Microsatellite Mutation Rates Genetics, June 1, 2003; 164(2): 781 - 787. [Abstract] [Full Text] [PDF]

				P. Calabrese and R. Durrett Dinucleotide Repeats in the Drosophila and Human Genomes Have Complex, Length-Dependent Mutation Processes Mol. Biol. Evol., May 1, 2003; 20(5): 715 - 725. [Abstract] [Full Text] [PDF]

				M. T. Webster, N. G. C. Smith, and H. Ellegren Microsatellite evolution inferred from human- chimpanzee genomic sequence alignments PNAS, June 25, 2002; 99(13): 8748 - 8753. [Abstract] [Full Text] [PDF]

				J. Brohede, C. R. Primmer, A. Moller, and H. Ellegren Heterogeneity in the rate and pattern of germline mutation at individual microsatellite loci Nucleic Acids Res., May 1, 2002; 30(9): 1997 - 2003. [Abstract] [Full Text] [PDF]

				D. Metzgar, L. Liu, C. Hansen, K. Dybvig, and C. Wills Domain-Level Differences in Microsatellite Distribution and Content Result from Different Relative Rates of Insertion and Deletion Mutations Genome Res., March 1, 2002; 12(3): 408 - 413. [Abstract] [Full Text] [PDF]

				C. Schlotterer A Microsatellite-Based Multilocus Screen for the Identification of Local Selective Sweeps Genetics, February 1, 2002; 160(2): 753 - 763. [Abstract] [Full Text] [PDF]

				M. Kauer, B. Zangerl, D. Dieringer, and C. Schlotterer Chromosomal Patterns of Microsatellite Variability Contrast Sharply in African and Non-African Populations of Drosophila melanogaster Genetics, January 1, 2002; 160(1): 247 - 256. [Abstract] [Full Text] [PDF]

				G. Queney, N. Ferrand, S. Weiss, F. Mougel, and M. Monnerot Stationary Distributions of Microsatellite Loci Between Divergent Population Groups of the European Rabbit (Oryctolagus cuniculus) Mol. Biol. Evol., December 1, 2001; 18(4): 2169 - 2178. [Abstract] [Full Text]

				G. Queney, N. Ferrand, S. Weiss, F. Mougel, and M. Monnerot Stationary Distributions of Microsatellite Loci Between Divergent Population Groups of the European Rabbit (Oryctolagus cuniculus) Mol. Biol. Evol., December 1, 2001; 18(12): 2169 - 2178. [Abstract] [Full Text] [PDF]

				P. P. Calabrese, R. T. Durrett, and C. F. Aquadro Dynamics of Microsatellite Divergence Under Stepwise Mutation and Proportional Slippage/Point Mutation Models Genetics, October 1, 2001; 159(2): 839 - 852. [Abstract] [Full Text] [PDF]

M. V. Katti, P. K. Ranjekar, and V. S. Gupta Differential Distribution of Simple Sequence Repeats in Eukaryotic Genome Sequences Mol. Biol. Evol., July 1, 2001; 18(7): 1161 - 1167. [Abstract] [Full Text] [PDF]