Genetic Effects on Microsatellite Diversity in Wild Emmer Wheat (Triticum Dicoccoides) at the Yehudiyya Microsite, Israel

Home , Gene conversion, Genomics, Unequal crossing over

Genetic effects on microsatellite diversity in wild emmer wheat (Triticum dicoccoides) at the Yehudiyya microsite, Israel

Y-C Li1,3, T Fahima1,MSRo¨der2, VM Kirzhner1, A Beiles1, AB Korol1 and E Nevo1 1Institute of Evolution, University of Haifa, Mount Carmel, Haifa 31905, Israel; 2Institute for Plant Genetics and Crop Plant Research, Corrensstrasse 3, 06466 Gatersleben, Germany

This study investigated allele size constraints and clustering, diversity. Genome B appeared to have a larger average and genetic effects on microsatellite (simple sequence repeat number (ARN), but lower variance in repeat number 2 repeat, SSR) diversity at 28 loci comprising seven types of (sARN), and smaller number of alleles per locus than genome tandem repeated dinucleotide motifs in a natural population A. SSRs with compound motifs showed larger ARN than of wild emmer wheat, Triticum dicoccoides, from a shade vs those with perfect motifs. The effects of replication slippage sun microsite in Yehudiyya, northeast of the Sea of Galilee, and recombinational effects (eg, unequal crossing over) on Israel. It was found that allele distribution at SSR loci is SSR diversity varied with SSR motifs. Ecological stresses clustered and constrained with lower or higher boundary. (sun vs shade) may affect mutational mechanisms, influen- This may imply that SSR have functional significance and cing the level of SSR diversity by both processes. natural constraints. Genetic factors, involving genome, Heredity (2003) 90, 150–156. doi:10.1038/sj.hdy.6800190 chromosome, motif, and locus significantly affected SSR

Keywords: SSR variation; allelic cluster; genome effect; mutational mechanism; Triticum dicoccoides; wheat’s progenitor

Introduction than expected by chance) in allele size distributions among various allele series of the same locus suggests Microsatellites, or simple sequence repeats (SSR), are the existence of evolutionary constraints on that locus ubiquitously interspersed in eukaryotic genomes (Tautz (Lehmann et al, 1996). Two alternative forces for such and Renz, 1984; Kashi et al, 1997; Kashi and Soller, 1999; nonrandom distribution of allele-size frequency have Li et al, 2002a). SSRs are among the fastest-evolving DNA been proposed: biased mutation and/or selection sequences with high mutation rates, 10À2–10À3 per locus acting on allele size (Garza et al, 1995; Dermitzakis et al, per gamete per generation (Weber and Wong, 1993), 1998). which leads to their high polymorphism in terms of The present study demonstrated constraints and repeat number. It has been suggested that replication clustering of allele size distribution in a natural popula- slippage, sister-chromatid exchanges, unequal crossing tion of wild emmer wheat, Triticum dicoccoides, and over, and gene conversion may cause SSR diversity correlation between SSR diversity and repeat length, (Tautz and Renz, 1984). Among these mutational locus chromosomal location, and genetic effects on mechanisms, replication slippage seems to play a major dinucleotide SSR diversity in a natural population of role in producing new alleles at SSR loci (Levinson and wild emmer wheat from two neighboring (a few meters Gutman, 1987; Wolff et al, 1991; Innan et al, 1997; Stephan apart) and contrasting microclimatic niches, sun, and and Kim, 1998). However, these suggestions need more shade. The microclimatic effect on SSR divergence and critical analysis across species and populations. diversity are described in a complementary paper (Li The distribution of allele sizes in SSR loci, seems to be et al, 2002b). nonrandom. For instance, alleles with long repeats were found to be more mutable than a bulk of the Ccon70 with short repeats (Crozier et al, 1999). Likewise, bimodal Materials and methods distribution of allele size was revealed at many SSR loci Wild emmer wheat, Triticum dicoccoides (Nevo et al, 2002) in some species including human (Rubinsztein et al, is the tetraploid and predominantly self-pollinated 1995), Mimulus guttatus (Awadalla and Ritland, 1997), progenitor of cultivated wheat (Zohary, 1970). This Arabidopsis (Innan et al, 1997), and the ﬁsh Sparus aurata tetraploid species contains two genomes and 28 chromo- (Dermitzakis et al, 1998). The excessive similarity (more somes (2n ¼ 4x ¼ 28, genome AABB). The plant materials used in this analysis are described in detail in Li et al (2002b). Correspondence: E Nevo, Institute of Evolution, University of Haifa, Mt Carmel, Haifa 31905, Israel. E-mail: [email protected] A total of 28 dinucleotide SSR DNA markers (one for 3Current address: Department of Plant Sciences, The University of each chromosomal arm) were chosen for the analysis. Arizona, Tucson, AZ 857-19, USA. The SSR primers used in this study were described by Genetic effects on SSR diversity in wild emmer Y-C Li et al 151 Table 1 SSR motif and chromosomal locations Plaschke et al (1995) and Ro¨der et al (1995, 1998). Table 1 presents the repetitive motif, locus location, and distance Marker Motif Chromosomal from the centromere (D) in bread wheat, T. aestivum. The procedure used to detect SSR polymorphism followed Locationa Distanceb Plaschke et al (1995) and Fahima et al (1998). Fragment sizes were calculated using the Fragment Manager c GWM18 (CA)nGA(TA)k 1BS 5.7 (Pharmacia) computer program by comparing with GWM60 (CA)n 7AS 52.3 internal size standards, which were added to each lane GWM95 (AC)n 2AS 10.8 in the loading buffer. GWM99 (AC)n 1AL 95.3 GWM120 (CT)n(CA)k 2BL 23.7 Analysis of variance (ANOVA) was used to analyze GWM124 (CT)n(GT)k 1BL 82.2 genetic effects on SSR diversity. Multiple regression was GWM136 (CT)n 1AS 38.8 used to measure indirectly contributions of mutational GWM162 (CA)nAA(CA)k 3AL 91.0 mechanisms to SSR diversity in different repeat motifs. GWM169 (GA)n 6AL 49.6 The statistical analyses were performed using the GWM186 (GA)n 5AL 38.4 STATISTICA program (Statsoft, 1996). GWM218 (CT)n 3AS 30.4 GWM219 (GA)n 6BL 40.5 GWM251 (CA)n 4BL 28.9 Results GWM294 (GA)nTA(GA)k 2AL 16.1 GWM332 (GA)n 7AL 53.0 GWM340 (GA)n 3BL 131.4 SSR allele distribution with size clusters and constraints GWM361 (GA)n 6BS 11.4 The distribution of alleles at locus GWM99 showed two GWM368 (AT)n 4BS 8.7 clusters, one with small repeat numbers (7,8), the other GWM389 (CT)n(GT)k 3BS 118.4 with larger repeat numbers (21–24), with a considerable GWM408 (CA) (TA)(CA) (TA) 5BL 73.8 n k m gap of 12 repeats of (AC) between them (Figure 1). GWM415 (GA)n 5AS 25.4 GWM429 (CT)n 2BS 29.0 Similar patterns were observed at loci GWM60, GWM459 (GA)n 6AS 62.5 GWM537, and GWM577 (Figure 1). The allele-size GWM537 (CA)n(TA)k 7BS 43.6 distribution seems to have a low boundary at locus GWM540 (CT)n(CC)(CT)k 5BS 9.3 GWM577 and upper limits at locus GWM537 (Figure 1). GWM577 (CA)n(TA)k 7BL 105.0 At loci GWM415 and GWM601, alleles were limited to GWM601 (CT) 4AS 8.1 n repeat numbers 19 and 17, respectively. Allele sizes at GWM637 (CA)n 4AL 40.1 GWM95, GWM120, and GWM332a varied in the ranges aA, B: genome A and B; S, L: short and long arm. bDistance from the of 15–20, 31–36, and 17–18 repeats, respectively. These centromere (D, in cM), which was estimated according to the map of results suggest that some constraints may exist on repeat Ro¨der et al (1998), the distance of GWM 218 also referred to the map number at SSR loci. The last assumption is especially of Peng et al (2000). cm, n, and k symbolize repeat number. supported by allele distribution at GWM537 (Figure 1).

Figure 1 Allele distributions with clusters and constraint at loci GWM60, GWM99, GWM537, and GWM577.

Heredity Genetic effects on SSR diversity in wild emmer Y-C Li et al 152 Genetic effect on SSR variation then microsatellite loci, located farther from the centro- Analysis of variance (ANOVA) was used to test the meres should have larger diversity, because recombina- effects of genetic factors (genome, chromosome, and tion is suppressed around the centromeres (Gill et al, motif) (Table 2). The results suggested that genome (A vs 1996). In other words, the ARN and locus distance from B) significantly (Po0.05) affected the average repeat the centromere (D) may affect the genetic diversity at SSR number (ARN), with genome B showing larger ARN loci, allele number (NA) and variance in repeat number (30.2) than genome A (25.1). Genome A showed larger (s2), serving as indirect evidence in favor of one of the variance in repeat number (s2 ¼ 27.8) than genome B explanatory models. Forward stepwise regression was (s2 ¼ 19.0). The SSR ARN on chromosome 1 (including used to estimate contributions of ARN, D, and micro- 2 both 1A and 1B) were significantly (F(6,40) ¼ 3.85, Po0.01) niches to the A and s of different motifs (Table 3). The larger (ARN ¼ 42.5) than those of other chromosomes results indicated that ARN were the most important (ranged from 22 to 31). Microsatellites on chromosome 7 factor for (GA)n loci. Mutational mechanisms (repre- showed the highest variance (s2 ¼ 53.5) in repeat number sented indirectly by ARN, D, and D Â ARN) could 2 2 (F(6,40) ¼ 2.72, Po0.05) compared with those on other significantly affect s at (GA)n loci (R ¼ 0.827, chromosomes. Compound SSRs, such as (CA)n(TA)k, Po0.00005). Niche could also alone (r ¼ 0.466, Po0.05) (CT)n(GT)k, and (CT)n(CA)k, appeared to have signifi- or through interaction niche Â ARN (r ¼À0.538, Po0.05) 2 cantly (F(6,47) ¼ 2.88, Po0.01) larger ARN (433) than affect the s of (GA)n loci. Both the mutational mechan- simple or perfect SSRs, such as (GA)n and (AT)n. isms and ecological effects could significantly determine 2 2 (ARN ¼ 24–29). The SSRs with (CA)n showed the the s of (GA)n loci (R ¼ 0.889, Po0.00005). In (CA)n smallest ARN ( ¼ 20, Li et al, 2002b). Locus effect was SSRs, D Â ARN and microniche were highly responsible highly significant (Po0.00005, Table 2) for number of alleles (NA), ARN, and s2. Locus GWM294 showed the largest NA (13), whereas each of GWM415 and GWM601 Table 2 Analysis of variance for genetic effects on microsatellite variation (number of alleles per locus, NA; average repeat number, displayed only one allele. Locus GWM136 appeared to ARN; and variance in repeat number of microsatellites) have the largest ARN (70.0) and GWM99 the smallest ARN (10.0). Loci GWM332a and GWM332b showed the Genetic factora F ratio smallest (0.27–0.55) and largest (97.6–127.0) s2, respec-

tively (Li et al, 2002b). (df1,df2) NA ARN Variance

Mutational mechanism for producing SSR variation Genome 1, 40 3.865c 4.987*b 0.474 Replication slippage (Levinson and Gutman, 1987; Wolff Chromosome 6, 40 1.886 3.848** 2.716* et al, 1991; Innan et al, 1997) and unequal crossing over Genome Â 6, 40 5.896*** 0.470 3.059* chromosome (Harding et al, 1992) were regarded as mechanisms for Motif 6, 47 1.473 2.877** 1.059 generating new alleles or diversity at SSR loci. With Locus 26, 27 37.717**** 114.132**** 7.957**** replication slippage, a longer repeat would tend to have larger diversity, since the chance of replication errors is aInteraction of some genetic factors could not be estimated because higher for a longer sequence (Levinson and Gutman, of incomplete design. bSigniﬁcance: *, **, ***, ****Po0.05, 0.01, 1987; Wolff et al, 1991). If recombination is important, 0.0005, 0.00005. cPo0.10.

Table 3 Multiple regression of the genetic factors, microniche and their interactions as independent variables with number of alleles per locus (NA) and variance (s2) in repeat number in the Yehudiyya population of T. dicoccoides as dependent variables

Motif No. cases Step Enter variablea NA Step Enter variable s2 in repeat number

rb R2,c rb R2

(GA)n 22 1 ARN 0.427* 0.182* 1 ARN 0.862**** 0.602**** 2DÂ ARN À0.738*** 0.723**** 3 D 0.696** 0.827**** 4 Niche Â ARN À0.538* 0.858**** 5 Niche 0.466* 0.889****

d (CA)n 10 1 D Â ARN 0.856** 0.621** 1 — —— 2 Niche 0.628* 0.770**

(CT)n 10 1 — — — 1 D Â ARN À0.989**** 0.987**** 2 ARN 0.996**** 0.989**** 3 D 0.994**** 0.997**** 4 Niche Â ARN À0.969**** 0.999****

(CA)n(TA)k 81DÂ ARN 0.975*** 0.924*** 1 D Â ARN 0.838* 0.703* 2 Niche Â ARN 0.651* 0.950***

aARN: average repeat number; D: locus distance from the centromere (cM), Â : interaction. br: partial correlation coefficient at the last step with significance of t-test. cR2: coefficient of multiple determination with significance of F test for multiple correlation. *, **, ***, **** Po0.05, 0.01, 0.0005, 0.00005. d—: no significant factors entered the multiple regression.

Heredity Genetic effects on SSR diversity in wild emmer Y-C Li et al 153 2 for the NA (R ¼ 0.770, Po0.01). At (CT)n SSRs, sig- so, a negatively skewed allele frequency distributions nificant effects on s2 in repeat number were displayed toward long SSRs with a relatively sharp cutoff length, by mutational mechanisms (ARN, D and D Â ARN; are expected (Amos, 1999). The allele distribution at R2 ¼ 0.997, Po0.00005) and the interaction niche Â ARN GWM537 (Figure 1) fits these expectations. (r ¼À0.969, Po0.0005). In (CA)n(TA)k SSRs, ARN Â D In the evolutionary model of simple tandem repetitive and niche Â ARN affected NA (R2 ¼ 0.950, Po0.0005), DNA proposed by Stephan and Cho (1994), natural whereas the ARN Â D interaction was significant for s2 selection is expected to play an essential role in (R2 ¼ 0.703, Po0.05). These results implied the impor- controlling the length of a nucleotide string in minisa- tance of mutational mechanisms and other factors for tellite and SSR DNA. Natural stresses may accelerate producing and maintaining population variation. These replication errors (Jackson et al, 1998) and recombination factors may vary among different motifs of SSRs. The intermediates (Korol et al, 1994; Afzal et al, 1995), or results also suggest that in addition to internal mechan- decrease the ability of DNA mismatch-repair mechanisms, external microniche factors may directly or isms (Radman et al, 1995; Brentnall et al, 1996; Jackson indirectly affect SSR diversity. et al, 1998) so as to increase SSR diversity. Natural stress could also select the favorable alleles or eliminate deleterious mutants, thereby changing the level and Discussion pattern of SSR diversity (Hartl and Clark, 1997). A biased mutation process could also regulate repeat Constraints on allele sizes number. However, the only bias in mutation observed Our results demonstrated significant skewness to the has been predominance of upward mutations. Garza et al right of allele distributions at a variety of loci, combined (1995) modeled a symmetric process in which the same with a clear boundary and/or a large gap on the type of bias affects large and small alleles. Stephan distribution, suggesting that constraints may exist on and Cho (1994) suggested that replication slippage repeat number at SSR loci, as shown by previous studies work on SSRs but unequal crossing over cannot act on (Deka et al, 1994; Garza et al, 1995; Dermitzakis et al, 1998; very short tandem arrays like SSRs. Our study suggested Pollock et al, 1998). Two possible mechanisms for that the mechanisms for generating new alleles constraining allele sizes are biased mutation and selec- may differ in different motif types. Replication slippage tion on the SSR loci themselves (Garza et al, 1995; seems to be the most important mechanism for (GA)n Zhivotovsky et al, 1997; Dermitzakis et al, 1998). Accord- SSRs, and the interaction of replication slippage and ing to our results, it seems that natural constraints may unequal crossing over appears to be an important factor act on both short and long arrays in wild populations of for diversity of (CA)n, (CT)n, and (CA)n(TA)k SSRs. T. dicoccoides. If so, the short and long repeats may have This interaction can occur during DNA replication functional meaning, and natural selection may prevent involved in recombination-dependent DNA repair: them from overstepping certain minimum or maximum strand exchange between two homologous chromosomes thresholds. This pattern was displayed by the distribu- may create a region of mismatched (heteroduplex) tions of repeat numbers at GWM60, GWM99, GWM537, DNA. These regions undergo replication-dependent and GWM577 with motifs (CA)n and (CA)n(TA)k. The correction; hence, slippage mechanism may also work two microclimatic niches were significant factors for in recombination tracts involving SSR arrays. One may the number of alleles at (CA)n and (CA)n(TA)k SSRs further speculate that the level of slippage errors varies suggesting that these repeats may have some functional along the chromosome together with the rate of regulatory meaning (Li et al, 2002b). recombination (Li et al, 2002a). King and Soller (1999) also suggested that many SSRs Notably, in a selfer, recombination is largely ineffective are functionally integrated into the genome, so that such in creating new haplotypes, that is, the effective rate of changes in tract length can exert a quantitative regula- recombination between polymorphic loci is much lower tory effect on gene transcription activity. It has been than the absolute rate (Narain, 1966). However, in the shown that (TC)n, (GA)n, and (TA)n control transcription case of unequal crossing over even between equivalent activity of Ultrabithorax, hsp26, and actin5C genes in chromosomes, repeat number will be changed. Drosophila. Similarly, a (TG)n repeat modulates the transcription activity of a prolactin gene of rat (reviewed Clusters of SSR alleles in Kashi et al, 1997; Kashi and Soller, 1999; Trifonov, In our study, we found clusters of alleles with some gaps 2003). In human, mouse, and rat (GT)n repeats could X nine repeats at the GWM60, 99, 537, and 577 loci. This enhance gene activity not only from sites residing close phenomenon may have implications for the evolution of to promoter sequences, but also from distant positions, SSRs with respect to mutational models and homoplasy such as introns or 30-flanking regions (Stallings et al, among alleles. SSR mutation rate is positively correlated 1991). For SSR arrays that might indeed be involved in to repeat length (Wierdl et al, 1997; Primmer et al, 1998); it gene regulation, therefore, one could expect that selec- is also allele-specific (Schlo¨tterer et al, 1998). It has been tion constrains the reduction and/or expansion in repeat shown that for a given locus, propensity to generate number in certain positions inside some minimum mutations could be different among alleles (Wierdl et al, thresholds, as suggested by GWM577 (Figure 1). For 1997). For example, the types of alterations observed in the SSR repeats involved in chromosome organization long and short (GT)n tracts in wild-type strains with (Cuadrado and Schwarzacher, 1998), and dinucleotide mismatch repair system were different in two ways. repeats correlated with regional variation in the rate of First, tracts with nX51 bp (including flanking region) recombination (Schug et al, 1998), one could assume that had significantly larger deletions of length change than selection limits the increase in the repeat number under those with np33 bp. Second, for the 99- and 105-bp some maximum thresholds that may be motif-specific. If tracts, almost all events involving single repeats were

Heredity Genetic effects on SSR diversity in wild emmer Y-C Li et al 154 additions; for the smaller tracts, both additions and (Gill et al, 1996), may increase the effects of selective deletions of single repeats were common (Wierdl et al, sweep (see Hedrick, 1980) and background selection 1997). Such a size-dependent mutation seems to be able (Liu et al, 1999). Therefore, distance of microsatellite to form bimodal allele distribution. loci from the centromeres (D) may affect the level Based on the assumption that replication slippage is of SSR variance in repeat size. In this study, we the main mechanism, and on empirical data that observed significant correlation between the D and mutations in SSR repeats are biased with a tendency to variance in repeat size for dinucleotide SSRs in make the array grow larger (Weber and Wong, 1993; three populations of wild emmer wheat at Yehudiyya Amos et al, 1996), Dermitzakis et al (1998) also proposed a (Spearman’s rank order correlation rs ¼ 0.393, n ¼ 54, possible process of how this clustering was generated in Po0.005). The simplest interpretation of such SSRs. In this model, at two linked loci, allele size- correlation between recombination and D is an effect of constraints (natural selection or mutation bias) eliminate background selection or selective sweeps. Similarly, repeat number randomly from short or long arrays with both background selection and selective sweeps may equal possibilities. In such a case, long arrays lose contribute to the correlation between DNA sequence repeats with the same rate as short ones, but gains variation at 18 dinucleotide microsatellites and repeats faster than the short arrays. If this mechanism is recombination in Drosophila (Schug et al, 1998). The allowed to act for long, it may generate two clusters of relative contribution of background selection versus about the same size, but at the two extremes. selective sweeps to the correlation depends on the mutation rate of SSRs. However, it is not easy to Genetic factors affecting SSR variation distinguish between these two explanations of back- In our study of T. dicoccoides, the significant effects of ground selection and selective sweeps (reviewed in Li genome, chromosome, and motif on SSR diversity were et al, 2002a). found. In many cases, compound motifs tended to have larger repeat number than simple (or perfect) motifs. This is explicable by assuming that a compound motif, Conclusion for example, (CT)n(GT)k, may have more chances to gain In conclusion, our study demonstrated allele size a new repeat unit of either (CT)n or (GT)k than a simple cluster and constraint at some SSR loci, and significant motif, such as (CT)n. Compound or imperfect SSRs seem effects of genome, chromosome, SSR motif and locus for to manifest more complex evolutionary patterns than do SSR diversity in the Yehudiyya microsite population of perfect SSRs (Ortı´ et al, 1997). Some previous studies wild emmer wheat. Genome B and those SSRs with suggested that imperfection in repeated regions might compound motifs showed longer repeats. This may cause a decrease in the mutation rate of SSR loci (Garza result from specific evolutionary origin or evolutionary et al, 1995). We also found that some imperfect SSR loci, feature. The revealed patterns by multiple regression such as GWM361 and GWM415, showed a low level of may reflect the fact that the relative importance of diversity. Imperfection in repeated regions possibly different mutational mechanisms (replication slippage constrains the mutation process and stabilizes some and unequal crossing over) in generating new alleles at SSRs. Some evidence suggested that compound SSRs SSR loci varies between motifs. Background selection may conform more closely to the ‘infinite alleles’ model and selective sweeps may also influence SSR variation, (Estoup et al, 1995) because of the larger number of since wild emmer wheat is a selfer and some of the potentially achievable allelic states (Goldstein et al, 1995; GWM loci studied are located not far away from Angers and Bernatchez, 1997). The genome effect on SSR the centromere. Microniche conditions may affect the diversity in this study could be explained by different level and the pattern of SSR diversity directly, through evolutionary patterns between compound and perfect microclimatic selection posing some ‘constraints’ on SSRs, since most loci in genome B assayed here are the repeat numbers at different loci, and by modula- compound SSRs, whereas most of the loci in genome A are ting the mutation/recombination mechanisms (Li et al, perfect SSRs. The difference in locus distribution of 2002a, b). compound or simple SSRs may arise from different evolutionary origins of genomes A and B in wheat. The A genome was derived from T. urartu,andtheBgenome Acknowledgements from an ancient S genome species that was similar to the present T. speltoides (Friebe and Gill, 1996). The A genome The authors thank Dr V Korzun and Ms K Wendehake as a whole appears to have experienced a faster rate of for their excellent help, and the Graduate School, evolution than the B and D genomes (Sallares and Brown, University of Haifa for financial support to this study 1999). Hence, one may expect that SSRs in genome A also whose microsatellite work was conducted in Germany at evolve faster than in genome B. This expectation seems to the laboratory of the Institute for Plant Genetics and be supported by the higher variance in repeat number of Crop Plant Research. This research is part of the PhD SSRsingenomeAthaningenomeB,andbyahigher research project of the first author. The research was proportion of perfect (and less stable) SSRs in genome A financially supported by an equipment grant of The than in B. Out of 95 and 115 SSR loci mapped on genomes Israel Science Foundation (No. 9048/99); and by the A and B, 31.6 and 52.2%, respectively, are compound or German–Israeli Cooperation Project (DIP project funded imperfect (Ro¨der et al, 1998). by the BMBF and supported by BMBF’s International Bureau at the DLR). This work was also supported by the Selective sweeps and background selection Israeli Discount Bank Chair of Evolutionary Biology and Low recombination rate, like in selfing species as wild the Ancell–Teicher Research Foundation for Genetics and emmer wheat or around centromeres of chromosomes Molecular Evolution.

Heredity Genetic effects on SSR diversity in wild emmer Y-C Li et al 155 References Kashi Y, King D, Soller M (1997). Simple sequence repeats as a source of quantitative genetic variation. Trends Genet 13: Afzal V, Feeney L, Thomas GH, Volpe JP, Cleaver JE. (1995). 74–78. Sister chromatid exchanges in cells defective in mismatch, Kashi Y, Soller M (1999). Functional roles of microsatellites and post-replication and excision repair. Mutagenesis 10: 457–462. minisatellites. In: Goldstein DB, Schlotterer C (eds) Micro- Amos W (1999). A comparative approach to the study of satellites: Evolution and Application, Oxford University Press: microsatellite evolution. In: Goldstein DB, Schlo¨tterer C (eds) Oxford. pp 10–23. Microsatellites: Evolution and Applications, Oxford Press: King AG, Soller M (1999). Variation and fidelity: the evolution Oxford. pp 66–79. of simple sequence repeats as functional elements in Amos W, Sawcer SJ, Feaker RW, Rubinstein DC (1996). adjustable genes. In: Wasser SP (ed) Evolutionary Theory and Microsatellites show mutational bias and heterozygote Processes: Modern Perspective, Papers in Honor of Eviatar Nevo, instability. Nat Genet 13: 390–391. Kluwer Academic Publishers: The Netherlands. pp 65–85. Angers B, Bernatchez L (1997). Complex evolution of a Korol AB, Preygel IA, Preygel SI (1994). Recombination Variability salmonid microsatellite locus and its consequences in and Evolution. Chapman & Hall: London. inferring allelic divergence from size information. Mol Biol Lehmann T, Hawley WA, Collins FH (1996). An evaluation of Evol 14: 230–238. evolutionary constraints on microsatellite loci using null Awadalla P, Ritland K (1997). Microsatellite variation and alleles. Genetics 144: 1155–1163. evolution in the Mimulus guttatus species complex with Levinson G, Gutman GA (1987). Slipped-strand mispairing: a contrasting mating systems. Mol Biol Evol 14: 1023–1034. major mechanism for DNA sequence evolution. Mol Biol Evol Brentnall TA, Crispin DA, Bronner MP, Cherian SP, Hueffed M, 4: 203–221. Rabinovitch PS et al (1996). Microsatellite instability in Li YC, Korol AB, Fahima T, Beiles A, Nevo E (2002a). nonneoplastic mucosa from patients with chronic ulcerative Microsatellites: Genomic distribution, putative functions, colitis. Cancer Res 56: 1237–1240. and mutational mechanisms (a review). Mol Ecol 11: 2543– Crozier RH, Kaufmann B, Carew ME, Crozier YC (1999). 2565. Mutability of microsatellites developed for the ant Campono- Li YC, Ro¨der MS, Fahima T, Kirzhner VM, Beiles A, Korol AB tus consobrinus. Mol Ecol 8: 271–276. et al (2002b). Climatic effects on microsatellite diversity in Cuadrado A, Schwarzacher T (1998). The chromosomal wild emmer wheat, Triticum dicoccoides, at Yehudiyya organization of simple sequence repeats in wheat and rye microsite. Heredity 89: 127–132. genomes. Chromosoma 107: 587–594. Liu Z, Tan G, Li P, Dunham RA (1999). Transcribed dinucleotide Deka R, Shriver MD, Yu LM, Jin L, Aston CE, Chakraborty R microsatellites and their associated genes from channel et al (1994). Conservation of human chromosome 13 poly- catfish Ictalurus punctatus. Biochem Biophys Res Commun 259: 190–194. morphic microsatellite (CA)n repeats in chimpanzees. Geno- mics 22: 226–230. Narain P (1966). Effect of linkage on homozygosity of a Dermitzakis ET, Clark AG, Batargias C, Magoulas A, Zouros E population under mixed selfing and random mating. Genetics (1998). Negative covariance suggests mutation bias in a two- 54: 303–314. locus microsatellite system in fish Sparus aurata. Genetics 150: Nevo E, Korol AB, Beiles A, Fahima T (2002). Evolution of Wild 1567–1575. Emmer and Wheat Improvement. Population Genetics, Genetic Estoup A, Garnery L, Solignac M, Cornuet JM (1995). Micro- Resources, and Genome Organization of Wheats Progenitor, satellite variation in honey bee (Apis mellifera L.) populations: Triticum dicoccoides. Springer: Berlin. hierarchical genetic structure and test of the infinite allele Ortı´ G, Pearse D, Avise JC (1997). Phylogenetic assessment of and stepwise mutation models. Genetics 140: 679–695. length variation at a microsatellite locus. Proc Natl Acad Sci Fahima T, Ro¨der MS, Grama A, Nevo E (1998). Microsatellite USA 94: 10745–10749. DNA polymorphism and divergence in Triticum dicoccoides Peng JH, Korol AB, Fahima T, Ro¨der MS, Li YC, Ronin YI et al. accessions highly resistant to yellow rust. Theor Appl Genet (2000) Molecular genetic maps in wild emmer wheat, 96: 187–195. Triticum dicoccoides: genome-wide coverage, massive negative Friebe B, Gill BS (1996). Chromosome banding and genome interference, and putative quasi-linkage. Genome Res 10: analysis in diploid and cultivated polyploid wheats. In: 1509–1531. Jauhar PP (ed) Methods of Genome Analysis in Plants, CRC Plaschke J, Ganal MW, Ro¨der MS (1995). Detection of genetic Press, Inc.: Boca Raton, FL. pp 39–60. diversity in closely related bread wheat using microsatellite Garza JC, Slatkin M, Freimer NB (1995). Microsatellite allele markers. Theor Appl Genet 91: 1001–1007. frequencies in humans and chimpanzees, with implications Pollock DD, Bergman A, Feldman MW, Goldstein DB (1998). for constraints on allele size. Mol Biol Evol 12: 594–630. Microsatellite behavior with range constraints: parameter Gill KS, Gill BS, Endo TR, Taylor T (1996). Identification and estimation and improved distances for use in phylogenetic high-density mapping of gene-rich regions in chromosome reconstruction. Theor Popul Biol 53: 256–271. group 1 of wheat. Genetics 144: 1883–1891. Primmer CR, Saino N, Mller AP, Ellegren H (1998). Unraveling Goldstein DB, Linares RA, Cavalli-Sforza LL, Feldman MW the processes of microsatellite evolution through analysis of (1995). An evaluation of genetic distances for use with germ line mutations in barn swallows Hirundo rustica. Mol microsatellite loci. Genetics 139: 463–471. Biol Evol 158: 1047–1054. Harding RM, Boyce AJ, Clegg JB (1992). The evolution of Radman M, Matic I, Hallida Y, Taddei F (1995). Editing DNA tandemly repetitive DNA: recombination rules. Genetics 132: replication and recombination by mismatch repair: from 847–859. bacterial genetics to mechanisms of predisposition to cancer Hartl DL, Clark AG (1997). Principles of Population Genetics, 3rd in humans. Philos Trans R Soc Lond B 347: 97–103. edn. Sinauer Associates, Inc., Publishers: Sunderland, MA. Ro¨der MS, Korzun V, Wendehake K, Plaschke J, Tixier MH, Hedrick PW (1980). Hitchhiking: a comparison of linkage and Leroy P et al (1998). A microsatellite map of wheat. Genetics partial selfing. Genetics 94: 791–808. 149: 2007–2023. Innan H, Terauchi R, Miyashita NT (1997). Microsatellite Ro¨der MS, Plaschke J, Ko¨nig SU, Bo¨rner A, Sorrells ME, polymorphism in natural populations of wild plant Arabi- Tanksley SD et al (1995). Abundance variability and dopsis thaliana. Genetics 146: 1441–1452. chromosomal location of microsatellites in wheat. Mol Gen Jackson AL, Chen R, Loeb LA (1998). Induction of microsatellite Genet 246: 327–333. instability by oxidative DNA damage. Proc Natl Acad Sci USA Rubinsztein DC, Leggo J, Coetzee GA, Irvine RA, Buckley M, 95: 12468–12473. Ferguson-Smith MA (1995). Sequence variation and size

Heredity Genetic effects on SSR diversity in wild emmer Y-C Li et al 156 ranges of CAG repeats in the Machado–Joseph disease, Stephan WM, Kim Y (1998). Persistence of microsatellite arrays spinocerebellar ataxia type 1 and androgen receptor genes. in ﬁnite populations. Mol Biol Evol 15: 1332–1336. Hum Mol Genet 4: 1585–1590. Tautz D, Renz M (1984). Simple sequences are ubiquitous Sallares R, Brown TA (1999). PCR-based analysis of the repetitive components of eukaryotic genomes. Nucleic Acid intergenic spacers of the Nor loci on the A genomes of Res 12: 4127–4138. Triticum diploids and polyploids. Genome 42: 116–128. Trifonov EN (2003). Tuning function of tandemly repeating Schlo¨tterer C, Ritter R, Harr B, Brem G (1998). High mutation sequences: a molecular device for fast adaptation. Gene (in press). rate of a long microsatellite allele in Drosophila melanogaster Weber JL, Wong C (1993). Mutation of human short tandem provides evidence for allele-speciﬁc mutation rates. Mol Biol repeats. Hum Mol Genet 2: 1123–1128. Evol 15: 1269–1274. Wierdl M, Dominska M, Thomas DP (1997). Microsatellite Schug MD, Hutter CM, Noor MAF, Aquadro CF (1998). instability in yeast: dependence on the length of the Mutation and evolution of microsatellites in Drosophila microsatellite. Theor Popul Biol 53: 272–283. melanogaster. Genetica 102/103: 359–367. Wolff RK, Plaeke R, Jeffreys AJ, White R (1991). Unequal Stallings RL, Ford AF, Nelson D, Torney DC, Hildebrand CE, crossing over between homologous chromosomes is not the Moyzis RK (1991). Evolution and distribution of (GT)n major mechanism involved in the generation of new alleles at repetitive sequences in Mammalian genomes. Genomic 10: VNTR loci. Genomics 5: 382–384. 807–815. Zhivotovsky LA, Feldman MW, Grishechkin SA (1997). Biased Statsoft, Inc. (1996). STATISTICA for Windows (Computer Program mutations and microsatellite variation. Mol Biol Evol 14: 926– Manual), Statsoft, Inc.: Tulsa, OK. 933. Stephan W, Cho S (1994). Possible role of natural selection in the Zohary D (1970). Centers of diversity and centers of origin. In: formation of tandem-repetitive noncoding DNA. Genetics Frankel OH, Bennet E. (eds) Genetic Resources in Plants – Their 136: 333–341. Exploration and Conservation, Blackwell: Oxford. pp 33–42.

Heredity