Microsatellites and Their Genomic Distribution, Evolution, Function and Applications: a Review with Special Reference to Fish Genetics ⁎ Dimitry A

Aquaculture 255 (2006) 1–29 www.elsevier.com/locate/aqua-online

Review Microsatellites and their genomic distribution, evolution, function and applications: A review with special reference to fish genetics ⁎ Dimitry A. Chistiakov a,b, , Bart Hellemans b, Filip A.M. Volckaert b

a Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, USA b Laboratory of Aquatic Ecology, Katholieke Universiteit Leuven, Ch. de Bériotstraat 32, B-3000 Leuven, Belgium Received 31 March 2005; received in revised form 17 November 2005; accepted 25 November 2005

Abstract

Microsatellites represent codominant molecular genetic markers, which are ubiquitously distributed within genomes. Due to their high level of polymorphism, relatively small size and rapid detection protocols, these markers are widely used in a variety of fundamental and applied fields of life and medical sciences. In the field of aquaculture, microsatellites represent workhorse markers, which are useful for the characterization of genetic stocks, broodstock selection, constructing dense linkage maps, mapping economically important quantitative traits, identifying genes responsible for these traits and application to marker-assisted breeding programmes. In this review, genomic distribution, function, evolution and practical applications of microsatellites are considered, with special emphasis on fish genetics and aquaculture. © 2005 Elsevier B.V. All rights reserved.

Keywords: Evolution; Functional relevance; Genomic distribution; Microsatellite; SSR; Teleostei

Contents

1. Introduction ...... 2 2. Genomic distribution of microsatellites ...... 2 3. Evolution of microsatellites ...... 3 4. Function of microsatellites ...... 5 4.1. DNA structure...... 5 4.2. DNA recombination...... 5 4.3. DNA replication...... 5 4.4. Gene expression...... 5 5. Development of type I (coding) and type II (non-coding) markers...... 7

⁎ Corresponding author. Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, USA. Tel.: +1 513 558 4402; fax: +1 513 558 2141. E-mail address: [email protected] (D.A. Chistiakov).

6. Applications of microsatellites ...... 9 6.1. Genetic mapping ...... 9 6.2. Individual DNA identification and parentage assignment ...... 12 6.3. Phylogeny, population and conservation genetics ...... 13 6.4. Molecular epidemiology and pathology ...... 15 6.5. Quantitative trait loci mapping...... 16 6.6. Marker-assisted selection ...... 18 7. Prospects ...... 20 Acknowledgements ...... 21 References ...... 21

1. Introduction in the smallest bacterial genomes (Gur-Arie et al., 2000). The existence of SSRs in eukaryotic genomes Microsatellites, or simple sequence repeats (SSRs), has been known since the 1970s (Bruford et al., 1996). represent a unique type of tandemly repeated genomic Hamada et al. (1982) demonstrated a large number and sequences, which are abundantly distributed across gen- wide occurrence of these sequences from yeast through omes and demonstrate high levels of allele polymor- to vertebrates. Tautz and Renz (1984) hybridized differ- phism. They are codominant markers of relatively small ent microsatellite sequences to genomic DNA from a size, which can be easily amplified with the polymerase variety of organisms and reported many types of simple chain reaction. These features provide the foundation sequences. for their successful application in a wide range of fun- The majority of microsatellites (30–67%) found are damental and applied fields of biology and medicine, dinucleotides. In the genome of vertebrates, (AC)n is the including forensics, molecular epidemiology, parasito- most common dinucleotide motif. It is 2.3-fold more logy, population and conservation genetics, genetic map- frequent than (AT)n, the second most general type of ping and genetic dissection of complex traits. In the field dinucleotides (Toth et al., 2000). Interestingly, in pri- of fisheries and aquaculture, microsatellites are useful for mates mononucleotide repeats are mostly represented the characterization of genetic stocks, broodstock selec- by poly (A/T) tracts, which are the most frequent classes tion, constructing dense linkage maps, mapping econom- of SSRs (Beckmann and Weber, 1992). In total, higher- ically important quantitative traits and identifying genes order SSR classes (tri-, tetra-, penta-and hexanucluo- responsible for these traits and application in marker- tides) are about 1.5-fold less common in genomic DNA assisted breeding programmes. Although microsatel- of vertebrates than dinucleotides (Toth et al., 2000). In lites are considered selectively neutral markers, they the genome of Japanese pufferfish or fugu Takifugu often represent functionally relevant polymorphisms. rubripes, dinucleotide repeats have the highest relative SSRs contribute to DNA structure, chromatin organi- frequency (34%) followed by tetranucleotides (21%), zation, regulation of DNA recombination, transcription trinucleotides (19%), mononucleotides (16.5%), hexa- and translation, gene expression and cell cycle dyna- nucleotides (6%) and pentanucleotides (3%) (Edwards mics. To date, microsatellites are far from being com- et al., 1998). In total, 1.29% of the genome of Japanese pletely identified and characterised, providing intriguing pufferfish consists of microsatellites. For the closely perspectives for discovery of new properties and cha- related spotted green pufferfish Tetraodon nigroviridis, racteristics of SSRs, which will help the design of SSRs cover 3.21% of the genome (Crollius et al., 2000). new research fields and the practical use of these In fugu, one microsatellite is found every 1.87 kilobases markers. (kb) of DNA, and a CA repeat (the most common type of tandem repeat) occurs every 6.56 kb of DNA. In 2. Genomic distribution of microsatellites three-spined stickleback Gasterosteus aculeatus,CA dinucleotides also are the most common type of micro- Microsatellites are stretches of DNA consisting of satellites, occuring approximately once every 14 kb tandemly repeated short units of 1–6 base pairs (bp) in (Peichel et al., 2001). For comparison, in the human length. SSRs typically span between twenty and a few genome, one microsatellite was found every 6 kb and hundred bases (Beckmann and Weber, 1992). They are one CA repeat occurred every 30 kb of DNA (Beck- ubiquitous in prokaryotes and eukaryotes, present even mann and Weber, 1992). D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 3

Microsatellites can be found anywhere in the ge- flounder and Japanese pufferfish (Venkatesh and Bren- nome, both in protein-encoding and noncoding DNA ner, 1997). (Toth et al., 2000). In eukaryotic organisms, SSRs have In contrast to other types of repeat motifs, triplets are been shown to be in excess in noncoding regions com- found in both coding and non-coding genomic regions pared to a random distribution pattern (Metzgar et al., with a high frequency (Wren et al., 2000; Morgante et 2000). They are relatively rare in coding DNA, ranging al., 2002). In all vertebrates, (G+C)-rich motifs (e.g., between 7–10% in higher plants (Wang et al., 1994; CCG, CAG) are the most common among trinucleo- Varshney et al., 2002) and between 9–15% in verte- tides. These repeats dominate in exons, whereas they brates (Moran, 1993; Jurka and Pethiyagoda, 1995; Van are less common in intronic sequences (Toth et al., Lith and Van Zutphen, 1996). Only 11.6% of a total of 2000). In humans, the expansion of trinucleotides, 6042 microsatellites were found in protein-coding encoding polyproline (CCG)n, polyarginine (CGG)n, regions in the genome of Japanese pufferfish (Edwards polyalanine [(GCC)n and (GCG)n] and polyglutamine et al., 1998). A relatively low frequency of SSRs in (CAG)n tracts within exons has been described. Such coding regions could be explained by negative selection expansions can lead to various neurodegenerative and against frameshift mutations in the translated sequences neuromuscular disorders, including myotonic distrophy, (Metzgar et al., 2000; Li et al., 2004). fragile X syndrome, Huntington's disease and spinocer- Di- and tetranucleotide motifs are mostly clustered ebellar ataxia (Jasinska et al., 2003; Brown and Brown, in noncoding regions. In vertebrates, they are distrib- 2004). Naturally occurring triplet repeat instability of uted 42- and 30-fold less frequently in exons than in transcribed sequences occurs not only in humans, but intronic sequences and intergenic regions, respectively also in lower vertebrates. For example, length variabil- (Toth et al., 2000). Analysis of perfect dimeric SSRs ity of the signal peptide-encoding region of the mela- showed that the length distribution of microsatellite noma receptor tyrosine kinase (XMRK) gene has been tracts with five and more repeat units in noncoding described in the swordtail genus Xiphophorus (Schartl regions fits the unbiased single-step mutation model et al., 1998). The signal peptide contains a variable (Bell and Jurka, 1997). This model suggests that number of CTG repeats, which may differ in length repeats change length by plus or minus one unit with even between closely related individuals. The XMRK equal probabilities, and that base substitutions destroy locus, encoding a sex-linked oncogene, and responsible long perfect repeats, producing two shorter tracts of for melanoma formation, is located in a highly unstable perfect repeats (see later). As a consequence, long genomic region (Froschauer et al., 2001). Variability in dimeric motifs are highly unstable within expressed the signal peptide could influence the efficiency of the sequences, while in noncoding regions most dinucleo- functional protein export through the cell membrane tide repeats can have surprisingly long stretches, prob- and therefore affect fitness traits of individuals expres- ably due to the high tolerance of noncoding DNA to sing the melanoma phenotype. In channel catfish, vari- mutations (Dokholyan et al., 2000). The potential size able (ACC)n repeats encoding a polythreonine tract expansion of di- or tetranucleotide microsatellites in have been found within the RAD23B gene, which is untranslated regions (UTRs) and introns could lead to important in the nucleotide excision repair system (Liu disruption of native protein and/or formation of new et al., 2001). A polymorphic (CAA)n trinucleotide motif genes with frame-shift (Liu et al., 1999a). These pat- encoding a polyglutamine stretch was observed in the terns suggest that random distribution of such di- and sex-linked NROB1 (DAX1) gene of the European sea tetranucleotide SSRs are strongly selected against bass Dicentrarchus labrax (Chistiakov and Hellemans, (Bachtrog et al., 1999). unpublished data). Dinucleotide repeats in 5′- and 3′-UTRs have been described within genes of a variety of fish species, 3. Evolution of microsatellites including channel catfish Ictalurus punctatus (Liu et al., 1999a), Atlantic salmon Salmo salar (Grimholt et The key feature of SSRs as molecular markers is al., 2002), zebrafish Danio rerio (Gerhard et al., 2000), their hypermutability and, hence, their hypervariability Japanese flounder Paralichthys olivaceus (Hirono et al., in species and populations. The microsatellite mutation 2000) and Nile tilapia Oreochromis niloticus (Mansour rate is estimated at 10− 2–10− 6 per locus per generation et al., 1998). Dinucleotide SSRs are also found in (Ellegren, 2000), which is several orders of magnitude introns. For example, intronic dinucleotide microsatel- greater than that of regular nonrepetitive DNA (10− 9; lites have been detected in the growth hormone gene of Li, 1997). Analysis of (AC)n microsatellites in five Nile tilapia, barramundi Lates calcarifer, Japanese vertebrate classes (mammals, birds, reptiles, amphibians 4 D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 and fishes) showed that length is a major factor influ- mechanisms are probably involved in the instability of encing mutation rate. A directional mutation toward an tri-and dinucleotides in yeast (Richard and Dujon, increase in microsatellite length was also observed 1997), polarity of substitutions within repeats in (CA)n (Neff and Gross, 2001). stretches in ovine and bovine genomes (Brohede and Two models (DNA polymerase slippage and unequal Ellegren, 1999), conservation of the dinucleotide micro- recombination) have been suggested to explain microsatellite locus Loc6 in lamniform sharks (Martin et al., satellite generation and evolution. The first model 2002) and evolution of intronic microsatellites and involves transient dissociation of the replicating DNA some haplotypes within orthologous Rhesus (RH) strands with subsequent reassociation (Schlötterer and genes in vertebrates (Okuda and Kajii, 2002). Tautz, 1992; Richards and Sutherland, 1994). The Slipped-strand mispairing during DNA replication is slipped structure can be stabilized by hairpin, triplex likely to represent the predominant mutational mecha- or quadruplex arrangement of DNA strands (Sinden, nism for microsatellites (Schlötterer and Tautz, 1992). It 1999). (CCG)n ×(CGC)n, (AGG)n ×(CCT)n and some results in the nascent strand having a different number other triplet motifs are shown to have high hairpin- of repeats from the template strand once DNA replica- forming potential and, therefore, could form stable al- tion is complete. This mutation process allows the same ternative structures, which are implicated in the triplet microsatellite allele to arise multiple times, thereby expansion diseases (Usdin, 1998; Sinden, 1999). Since generating size homoplasy. Homoplasy represents sim- DNA repeat regions represent preferred target sites for ilarity of traits or genes for reasons other than coances- mutations during DNA replication, microsatellite stabil- try (e.g., convergent evolution, parallelism, evolutionary ity is controlled at multiple steps in vivo through the reversals, horizontal gene transfer, gene duplications). DNA mismatch repair (MMR) system, as shown for Homoplasy can violate a basic assumption of the analy- Escherichia coli, yeast and humans (Sia et al., 1997). sis of genetic markers, in which variants of similar MMR proteins are found in a wide variety of taxa and phenotype (e.g., base pair size) are assumed to derive are responsible for the correction of replication mistakes from a common ancestor (Sanderson and Hufford, and suppresion of the recombination between diverged 1996). sequences (Kolodner and Marsischky, 1999). If the Various mutational models that account for this ho- MMR system is defective, coding sequences with tan- moplasy have been proposed. The stepwise mutational dem repeats become subject to mutations, for example model (SMM) assumes that all mutational events in- in tumour tissues (Sia et al., 1997). High-frequency volve a change in a single repeat only (Kimura and microsatellite instability, therefore, plays a pivotal role Ohta, 1978; Bell and Jurka, 1997), whereas the two- in carcinogenesis (Atkin, 2001). Both minor and major phase mutational model (TPM) allows a proportion of MMR genes contain short (A)n tracts in their coding mutations to involve changes greater than single repeats regions, which are highly vulnerable to spontaneous (Di Rienzo et al., 1994). In contrast, the infinite-allele deletion or insertion mutations, that could result in the model (IAM) refuses homoplasy events, suggesting that inactivation of the MMR gene and hence cause MMR every mutation results in the creation of a new allele deficiency (Chang et al., 2001). (Kimura and Crow, 1964). Determining which muta- Although a number of experimental findings argue in tional model is most appropriate is important, because favour of the above model, nonreciprocal recombina- estimation of microsatellite-specific genetic distances tion (gene conversion) also may play a role in genetic among populations relies on the underlying assump- instability of some SSRs, including triplet motifs tions of the chosen model. (Jakupciak and Wells, 2000). Gene conversion mechan- During DNA replication, longer stretches of repeated isms were found to be involved in the differentiation units pose more of a problem to DNA polymerase than and evolution of paralogous sequences (duplicated loci do shorter stretches, making longer alleles more prone within species) in members of the family Salmonidae to slipped-strand mispairing. In addition, larger numb- derived from tetraploidization. This observation was ers of repeats provide more opportunities for misalign- taken from the comparative sequence analysis of a ment during the reannealing of the nascent strand simple microsatellite locus Str1INRA, which contains (Eisen, 1999). Therefore, there is thought to be a long flanking sequences, including both coding and rough threshold of minimum repeat number below noncoding regions, in different species of subfamily which a microsatellite is not likely to mutate or be Salmoninae (Angers et al., 2002). Replication slippage variable. Estimations of slippage frequency during po- and recombination could interact, affecting stability of lymerase chain reaction (PCR) showed that such a microsatellite loci. For example, such “repair-slippage” threshold exists and is equal to four and eight repeats D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 5

for (CA/GT)n dinucleotides and (A/T)n motifs, respec- an important role in the organization of the chromo- tively (Shinde et al., 2003). Measurements in slime some structure. mold Neurospora found that microsatellites are expected to be variable if they have a mean of 5.1 4.2. DNA recombination repeats (Dettman and Taylor, 2004). SSRs are considered hot spots for recombination 4. Function of microsatellites (Jeffreys et al., 1998). Dinucleotide motifs are preferen- tial sites for recombination events due to their high SSRs typically represent selectively neutral DNA affinity for recombination enzymes (Biet et al., 1999). markers. However, multiple studies proved the func- Some SSR sequences, such as GT, CA, CT, GA and tional relevance of a significant number of SSRs. others, may influence recombination directly through their effects on DNA structure (Biet et al., 1999). The 4.1. DNA structure orthologous rhesus (Rh) genes, which are responsible for the determination of the blood group in higher Microsatellites are involved in forming a wide vari- vertebrates, were found to contain multiple microsatel- ety of unusual DNA structures with simple and complex lites in their introns (Okuda et al., 2000). These SSRs loop-folding patterns. Double-stranded alternating pu- were shown to be associated with the assignment of rine and pyrimidine sequences such as the (dC−dA)× some Rh phenotypes, and to be involved in the molec- (dG−dT)32 form left-handed Z-DNA structures in vitro ular evolution of the human Rh gene family and its (Rich et al., 1984). Several microsatellite sequences, orthologs in other eukaryotes and Archaea via replica- such as (GAA)n, (AC)n and composite (GT)n ×(GA)n tion slippage and recombination (gene conversion) simple repeats, also exhibit non-B-DNA structural mechanisms (Fujiwara et al., 1999; Okuda and Kajii, properties (Epplen et al., 1996). 2002). Telomeric and centromeric chromosome regions have been shown to be rich in long arrays of a variety 4.3. DNA replication of mono-, di-, tri-, tetra-and hexanucleotide motifs. Satellite sequences enriched by AT-dinucleotides have SSRs may influence DNA replication. For example, been found in the centromeric DNA of various gobiid in rat cells, DNA amplification is terminated within a species (Canapa et al., 2002). They are considered specific fragment which consists of a d(GA)27 ×d(TC)27 important for the control of centromeric chromatin tract. This sequence is situated at the end of an amplicon compactness in these fishes. A cryptic RRY(i) micro- and forms a loop, which serves as a stop signal for DNA satellite located close to the centromeric region of an polymerase (Li et al., 2002). acrocentric chromosome pair was characterized in At- Human genes encoding important cell fidelity and lantic salmon (Martinez et al., 2001). The expanded growth factors, such as the B-cell leukemia/lymphoma stretches of a simple repeat sequence (TTAGGG)n ori- 2(BCL2)-associated X protein, insulin-like growth fac- ented in the 5′ to 3′ direction towards the end of tor 2 receptor (IGF2R), breast cancer early onset protein eukaryotic chromosomes constitute a substantial por- 2(BRCA2) and transforming growth factor beta 2 tion of the repetitive DNA in telomeric regions (Hen- (TGF-β2), contain short repeated sequences. MMR de- derson, 1995). For example, the telomeric repeat in the ficiency causes frame-shift mutations, resulting in both Nile tilapia varies in size from 4 to 10 kb (Chew et al., insertions and deletions of repeat units within these 2002). Telomere-associated repeats can be related to sequences that affect these genes and could therefore nucleolus organizing regions (NORs), as seen in rain- initiate tumorigenesis (Johannsdottir et al., 2000). These bow trout Oncorhynchus mykiss (Abuin et al., 1996), observations suggest that microsatellites can affect lake trout Salvelinus namaycush (Reed and Phillips, enzymes controlling mutation rate and cell cycles 1995) and Nile tilapia (Foresti et al., 1993). The (Chang et al., 2001). (TTAGGG)n hexamer sequence is recognized by ribo- nucleoprotein polymerase, a telomerase, which synthe- 4.4. Gene expression sizes telomere repeats onto the chromosome ends to overcome the loss of sequences during DNA replica- Numerous data show that SSRs located in promoter tion, whereas other proteins prevent nucleolytic degra- regions can influence gene expression. The 5' upstream dation and confer stability of chromosomes (Fang and region of the insulin gene of Nile tilapia contains a Sech, 1995; Martins et al., 2004). Therefore, SSRs play microsatellite close to the same position of a unique 6 D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 minisatellite found only in humans and primates (Man- sequences for binding a variety of expression-regulating sour et al., 1998). The human insulin minisatellite is proteins, as was shown for certain (GT)n or mixed GT/ highly polymorphic, and some of its alleles were shown GA stretches of intronic simple repeats. They have been to regulate the expression of the insulin gene (Melloul et preserved in immunologically relevant genes for at least al., 2002). An analogous function might be predicted 70 million years and bind nuclear protein regulatory for the insulin microsatellite in Nile tilapia. In Japanese molecules with high affinities (Epplen et al., 1993; pufferfish, many SSRs have been found in the transcrip- 1996). A number of such SSR repeats could also corre- tion factor-binding sites of promoter regions of many late with the strength and affinity of the protein binding important genes (Edwards et al., 1998). These SSRs (Winter and Varshavsky, 1989). could affect the sequence of the binding site and there- Microsatellites situated in the 3′-UTR could affect fore influence its affinity for the binding of a gene expression through their influence on the stability corresponding regulatory transciption factor. The tran- of transcribed products. This role was found for a GA- scription-regulating activity of the (CT)n tract in pro- rich repeatitive DNA segment in the 3′-UTR of the rat moters of the HSP26 gene encoding a 26 kDa heat- polymeric immunoglobulin receptor gene (Fabregat et shock protein in Drosophila (Sandaltzopoulos et al., al., 2001) and the chicken elastin gene (Hew et al., 1995), the gene for glyceraldehyde-3-phospate dehy- 2000). Long stretches of such polypurine and pyrimi- drogenase in Aspergillus (Punt et al., 1990) and the dine repeat motifs at 3′-UTRs could destabilize the piypt1 gene of Phytophtora (Chen and Roxby, 1997) structure of the 3′-end of a mRNA molecule and could serve as examples. The CT-element lying close to hence facilitate its availability for degradation by intra- the transcription start point of these genes was shown to cellular exonucleases (Wang et al., 2002). Otherwise, be the target sequence for binding transcription factors such repeats could affect mRNA stability, representing and might be important in determining the frequency of binding sites for translation factors, as has been de- transcription initiation (Chen and Roxby, 1997). scribed for an AU-rich sequence in the 3′-UTR of In many cases, SSR repeat number could significant- mRNA for human plasminogen activator inhibitor ly influence gene expression level. Such an effect was type 2 (Maurer et al., 1999). described for a dinucleotide (CA/GT)n microsatellite in In the European eel Anguilla anguilla, a highly var- the Nile tilapia prolactin 1 (PRL1) promoter (Streelman iable region was found at the 3′-UTR of the TSHB gene and Kocher, 2002). Individuals homozygous for long encoding thyrotropin β subunit (Pradet-Balade et al., microsatellite alleles express less PRL1 in freshwater, 1998). The region includes repeat units, which contain but more in half-seawater than fish with other geno- CTG double repeats at their ends. The CTG double types. Interestingly, a similar activity was previously repeats are able to form unusual helix structures within reported by Naylor and Clark (1990) for TG/CA repeat double-stranded DNA (Chastain and Sinden, 1998). sequences in the promoter of the rat prolactin gene. It Such configurations may, therefore, promote genetic suggests the conservation of the regulatory function for instability and be responsible for heterogeneity in the CA/GT microsatellites in the PRL1 promoter over 300 number and length of the thyrotropin β mRNA in the million years of vertebrate evolution. European eel (Pradet-Balade et al., 1997). Transcribed microsatellites located in 5′ untranslated The above evidence suggests that SSR variation can regions (UTRs) could form specific and unusual DNA produce either drastic or quantitative variations in gene structures. In that case, the length of the repeat region expression. Because of genomic overabundance and could affect the translation level from the target mRNA. high mutability of SSRs, changes in SSR array size The apparent correlation between gene expression and may serve as a rich source of variation in fitness-related the number of tandem GAA repeat motifs was observed traits in natural populations (Kashi et al., 1997; Streel- for the GAA repeat region which regulates expression man and Kocher, 2002). Its role may be especially of the M9/pMGA gene family in the avian intracellular important for population survival and adaptation to parasite Mycoplasma gallisepticum (Liu et al., 2000). spatially and temporarily varying environmental condi- Intronic SSRs also can affect gene transcription. For tions (Blankenship et al., 2002). The presence of so- example, such an effect was measured for the tetrameric called contingency loci in many bacterial species may microsatellite located in intron 1 of the human tyrosine explain how microsatellite variability influences the hydroxylase gene (Meloni et al., 1998) and the (CA)n adaptive evolution of microbial pathogens (Metzgar dinucleotide repeat in the first intron of the human and Wills, 2000). These loci, containing tandem repeats epidermal growth factor receptor gene (Gebhardt et within either a coding sequence or a promoter, can be al., 1999). SSRs in introns might serve as target hypermutable. Altered numbers of repeats thus cause D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 7 switches in the reading frame of translation or changes species to another and therefore to use SSR markers for in the level of promoter activity. The contingency loci population genetics, parentage analysis and other appli- are specifically associated with genes controlling the cations without having to invest in the isolation of antigenic type and/ or phase state of pathogenic bacteria polymorphic microsatellites (Cairney et al., 2000; (Bayliss et al., 2001). Examples of genes carrying these Leclerc et al., 2000). The presence of highly conserved hypermutable repeats include those encoding surface flanking regions has been reported for some microsa- polysaccharides of Haemophilus influenzae, variable tellite loci in cetaceans (Schlötterer et al., 1991), turtles surface lipoproteins of Mycoplasma hyorhinis and (FitzSimmons et al., 1995) and fishes (Rico et al., 1996; opacity proteins of Neisseria sp.(Yogev et al., 1991; Angers and Bernatchez, 1996), allowing cross-amplifi- Bayliss et al., 2001). The hypervariability of these genes cation from species that diverged as long ago as 470 allows clonal lineages to switch rapidly between sero- million years. types and thereby evade clearance by the host immune Type I markers are more difficult to develop (Liu et system, or to switch rapidly between different pheno- al., 1999b). While non-gene sequences are free to mu- typic ‘phases’ required for the invasion of multiple tate, causing higher levels of polymorphism, sequences tissue types (Moxon et al., 1994). within protein-coding regions generally show lower levels of polymorphism because of functional selection 5. Development of type I (coding) and type II pressure. The most effective and rapid way for produc- (non-coding) markers ing type I microsatellites is the sequencing of clones from cDNA libraries. Both 5′- and 3′-ends of a cDNA O'Brien (1991) divided molecular markers into type clone can be sequenced to produce expressed sequence I markers associated with genes of known functions and tags (ESTs). An EST represents a short, usually 200– type II markers associated with anonymous genomic 600 bp-long nucleotide sequence, which represents a sequences. Microsatellites usually represent type II mar- uniquely expressed region of the genome. If the EST kers, since they commonly are located in noncoding harbours any polymorphic type I marker [usually SSR intergenic regions. The fastest and simplest way to and/or single nucleotide polymorphism (SNP)], it can detect and characterize a large number of such type II be mapped (see later). cDNA libraries can be routinely microsatellites lies in the construction of small-insert sequenced, rapidly producing a bulk of ESTs, with genomic libraries enriched in arrays of tandem repeats which to organize an EST collection. Such collections (Zane et al., 2002). The enrichment technique usually provide a robust sequence resource that can be used for includes selective hybridization of fragmented genomic gene discovery, genome annotation and comparative DNA with a tandem repeat-containing oligonucleotide genetics (Rudd, 2003; Dunham, 2004; Ng et al., 2005). probe and further PCR amplification of the hybridiza- EST sequences are archived in a special branch of tion products. Libraries highly enriched by tandem the GenBank nucleotide database (dbEST) (http://www. repeats have been constructed for many organisms, ncbi.nlm.nih.gov/dbEST/index.html)(Wheeler et al., including fishes. The high frequency of tandem repeats 2004). In November 2005, the EST database contained in fish genomes provides a good opportunity to obtain more than 31.3 million sequence entries from around libraries significantly enriched in microsatellites. For 500 species. The numbers of ESTs for fish species are example, libraries containing 74%, 95% and 96% summarized in Table 1; most of species listed represent clones with (CA)n repeats have been developed for the model organisms or economically important fishes. Mediterranean angler fish Lophius sp. (Garoia et al., SSRs can be searched for in these EST sequence 2003), gilthead sea bream Sparus aurata (Zane et al., databases. However, the major drawback for effective 2002), and Nile tilapia (Carleton et al., 2002), respec- and rapid development of type I SSRs is access to tively. A library usually contains 1000–4000 recombi- sufficient sequence information. As shown in Table 1, nant clones. Screening of these clones typically yields for the channel catfish, around 45,000 EST sequences 10–15% unique polymorphic SSRs, resulting in the have been developed. This provides a serious source for production of 100–500 non-redundant variable micro- extracting thousands of sequences containing putative satellites from a single library (Zane et al., 2002). SSRs with the possibility of developing several In addition, type II markers can be rapidly developed hundreds of polymorphic microsatellite markers. For from SSRs isolated previously from closely related example, sequence analysis of 1909 ESTs from a skin species (Bruford et al., 1996). Cross-species amplifica- cDNA library of Ictalurus punctatus revealed the pres- tion of SSRs provides a possibility to superimpose the ence of 89 (4.7% of 1909) microsatellite-containing genetic information or a genetic linkage map from one genes (Karsi et al., 2002). Screening of 1201 ESTs 8 D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29

Table 1 Fish taxa ranked by the number of ESTs available (November 2005) Speciesa Familya # of ESTsb # of SSRsc Other sequencesc Totalc Danio rerio (zebrafish) Cyprinidae 689,581 6055 362,754 1,052,335 Oncorhynchus mykiss (rainbow trout) Salmonidae 239,327 968 2972 243,267 Oryzias latipes (Japanese medaka) Adrianichthyidae 221,546 2 117,865 339,413 Gasterosteus aculeatus (three-spined stickleback) Gasterosteidae 170,994 140 10,223 181,357 Salmo salar (Atlantic salmon) Salmonidae 113,002 1696 1434 116,132 Fundulus heteroclitus (mummichog) Fundilidae 55,116 83 494 55,693 Ictalurus punctatus (channel catfish) Ictaluridae 44,476 3921 1614 50,011 Haplochromis chilotes (cichlid fish) Cichlidae 35,747 – 1 35,748 Takifugu rubripes (Japanese pufferfish) Tetraodontidae 25,850 430 66,805 93,085 Eptatretus burgeri (inshore hagfish) Myxinidae 23,884 – 147 24,031 Haplochromis sp. (red tail sheller) Cichlidae 14,073 ––14,073 Leucoraja erinacea (little skate) Rajidae 11,260 – 609 11,869 Squalus acanthias (piked dogfish) Scualidae 10,878 8 134 11,020 Petromyzon marinus (sea lamprey) Petromyzontidae 10,617 11 550 11,178 Cyprinus carpio (common carp) Cyprinidae 10,612 29 1614 12,255 Ictalurus furcatus (blue catfish) Ictaluridae 10,524 – 25 10,549 Platichthys flesus (European flounder) Pleuronectidae 5,573 29 225 616 Paralichtys olivaceus (Japanese flounder) Paralichtyidae 3874 87 368 4329 Astatotilapia burtoni (cichlid fish) Cichlidae 3670 – 90 3760 Hippoglossus hippoglossus (Atlantic halibut) Pleuronectidae 3146 29 180 3355 Oncorhynchus tshawytscha (chinook salmon) Salmonidae 2301 78 591 2970 Carassius auratus (goldfish) Cyprinidae 2080 21 789 2890 Dicentrarchus labrax (European seabass) Moronidae 1770 208 286 1264 Coregonus clupeaformis (lake whitefish) Salmonidae 1691 31 13 1735 Pseudopleuronectes americanus (winter flounder) Pleuronectidae 1663 – 185 1668 Osmerus mordax (rainbow smelt) Salmonidae 1587 – 15 1600 Sparus aurata (gilthead seabream) Sparidae 1518 26 487 2007 Gadus morhua (Atlantic cod) Gadidae 1422 12 1599 2954 Perca fluviatilis (European perch) Percidae 1097 1 97 1195 Epinephelus coioides (orange-spotted grouper) Serranidae 1007 1 167 1193 Xiphophorus maculatus (Southern platyfish) Poeciliidae 847 266 167 1280 Oncorhynchus nerka (sockeye salmon) Salmonidae 664 43 186 893 Opsanus beta (gulf toadfish) Batrachoidiae 619 – 21 640 Seriola quinqueradiata (five-ray yellowtail) Carangidae 558 5 178 741 Ctenopharyngodon idella (grass carp) Cyprinidae 531 1 186 718 Oreochromis niloticus (Nile tilapia) Cichlidae 294 235 3,543 4,072 Anguilla japonica (Japanese eel) Anguillidae 196 37 323 556 Gillichtys mirabilis (long-jawed mudsucker) Gobiidae 109 – 1110 Tetraodon fluviatilis (green pufferfish) Tetraodontidae 99 – 89 188 Austrofundulus limnaeus (annual killifish) Ruvilidae 91 – 16 107 Salvelinus alpinus (Arctic charr) Salmonidae 63 12 220 295 Gillichthysseta (goby) Gobiidae 62 – 59 121 Torpedo marmorata (spotted ray) Torpedinidae 41 – 123 164 Siniperca chuatsi (Chinese perch) Percichthyidae 32 – 109 141 Chiloscyllium plagiosum (white-spotted bambooshark) Hemiscylliidae 17 – 926 Poecilia reticulata (guppy) Poeciliidae 15 137 339 491 Cyclopterus lumpus (lumpsuker) Cyclopteridae 12 – 17 29 Paramisgurnus dabryanus (Chinese loach) Cobitidae 11 1 24 36 Xiphophorus maculatus x Xiphophorus helleri Poeciliidae 6 –– 6 (Southern platyfish x green swordtail) Periophthalmus modestus (shuttles hoppfish) Gobiidae 4 – 48 Eptatretus cirrhatus (New Zealand hagfish) Myxinidae 24 3 9 Labeo rohita (rohu) Cyprinidae 22155 88 Catla catla (Indian major carp) Cyprinidae 11914 34 Geotria australis (pouched lamprey) Petromyzontidae 1 – 89 Lethenteron japonicum (Japanese lampey) Petromyzontidae 1 – 87 88 Oncorhynchus keta (chum salmon) Salmonidae 1 16 335 351 Notes to Table 1: aTaxonomic assignment was performed through the NCBI taxonomy database (http://www.ncbi.nlm.nih.gov/Taxonomy/taxonomyhome.html, Wheeler et al., 2004). D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 9 from a channel catfish brain cDNA library yielded 88 extensive genome coverage and relative abundance, (7.3%) clones with microsatellites (Liu et al., 2001). microsatellites have been successfully applied in a Most brain microsatellites represented dinucleotides lo- wide variety of research fields and practical disciplines cated in 3′-UTRs. However, 12 (14%) SSRs were tetra- (Powel et al., 1996). meric, whereas 20 (23%) clones contained trinucleotide repeats. A recent bioinformatic analysis of 43,033 ESTs 6.1. Genetic mapping from channel catfish revealed 4855 ESTs (11.3%) containing microsatellites (Serapion et al., 2004). 1312 of Genetic mapping represents one of the major re- these ESTs fell into 569 contigs (e.g., locations within a search fields in which microsatellite markers have chromosome map, where contiguous DNA segments been applied. SSRs remain the markers of choice for overlap) and the remaining 3534 ESTs were singletons the construction of linkage maps, because they are (e.g., unmapped to contigs, with unknown position in a highly polymorphic (and highly informative) and re- chromosome map). A total of 4103 unique microsatel- quire a small amount of DNA for each test (Fig. 1). lite-containing genes were identified. The dinucleotide Methods for microsatellite detection can be readily au- CA/TG and GA/TC pairs were the most abundant tomated. A disadvantage of microsatellites is that they among EST-derived microsatellites (Serapion et al., are mostly anonymous DNA fragments (Cullis, 2002). 2004). However, type II (noncoding) microsatellites are very A typical strategy for the development of EST- helpful for building a dense linkage map framework derived microsatellite markers (data mining) includes into which type I (coding) markers can then be preliminary analysis of EST sequences from the DNA incorporated. database to remove poly(A) and poly(T) stretches. Compared to type II markers, mapping type I mar- These mononucleotide repeats are very common in kers directly shows the location of genes within the ESTs developed from the 3′-ends of cDNA clones linkage map. The coding markers often represent genet- and correspond to the poly(A)-tails in eukaryotic ic variations associated with interesting or economically mRNA. Sequences are further screened for putative significant phenotypes. Therefore, enrichment of the SSRs. This supports identification of all SSR-contain- linkage map by type I loci greatly benefits the mapping ing EST sequences. Following the identification of and characterization of genes responsible for medically, microsatellite-containing ESTs, flanking primers should agriculturally and evolutionarily important complex be designed to amplify a microsatellite. In order to traits. This also provides a good opportunity for mark- hypothesize about putative functions of SSR-containing er-assisted selection (MAS) in commercially significant genes, these sequences are needed for comparison to species (Poompuang and Hallerman, 1997; Waldbieser the database of amino acid sequences (Kantety et al., and Wolters, 1999). For economically important fishes, 2002; Thiel et al., 2003). UniProt/Swiss-Prot is an EST-derived microsatellites have been isolated and used annotated protein sequence database (http://www.ebi. for genetic mapping in Atlantic salmon (Koop and ac.uk/swissprot/) which is extremely helpful for these Davidson, 2005), channel catfish (Liu et al., 2001; purposes. Waldbieser et al., 2001; Karsi et al., 2002), European sea bass (Chistiakov, pers. data), Nile tilapia (Cnaani et 6. Applications of microsatellites al., 2002), rainbow trout (Sakamoto et al., 2000) and zebrafish (Knapik et al., 1998). SSRs are often highly polymorphic due to variation Linkage maps are known as recombination maps and in the number of repeats (Amos and Pemberton, 1992). define the order and distance of loci along a chromo- They can be simply and rapidly detected by the poly- some on the basis of inheritance in families or mapping merase chain reaction (PCR) using two unique oligonu- populations. During meiosis, one random copy of each cleotide primers that flank the microsatellite and hence chromosome pair is passed on to the gamete. Therefore, define the microsatellite locus. Because of their multi- grandparental copies of genes located on different chro- allelic nature, codominant inheritance, small length, mosomes are inherited independently, whereas genes on

Notes to Table 1: aTaxonomic assignment was performed through the NCBI taxonomy database (http://www.ncbi.nlm.nih.gov/Taxonomy/taxonomyhome.html, Wheeler et al., 2004). bDabData are taken from the dbEST database (http://www.ncbi.nlm.nih.gov/dbEST/dbEST_summary.html). cData are taken from GenBank database (http://www.ncbi.nlm.nih.gov/Genbank/GenbankSearch.html). 10 D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29

Fig. 1. Fifty F1 progeny and both parents (male and female) of European sea bass (Dicentrarchus labrax) from the linkage mapping panel Venezia Fbis (Chistiakov et al., 2005). The parents share microsatellite allele 171 and are diagnostic for the alleles 179 and 187 at locus DLA0014 (mapped to linkage group 13). At the right are indicated the marker sizes of the standard (M) (in bp). the same chromosome are not inherited independently, (AFLPs) (Vos et al., 1995)(Table 2). SSRs and but are passed on together or “linked”. Only genes AFLPs represent DNA markers, which are extremely located next to each other are tightly linked. Crossing- useful for constructing a primary framework map that over results from physical exchange of chromosome could be further enriched with type I markers (ESTs, segments between two homologous chromosomes of SNPs, genes). Zebrafish and rainbow trout linkage meiosis. Recombination results in the exchange of maps can serve as examples of such “map evolution”. grandparental alleles of genes further apart on that chro- For example, Woods et al. (2000) used 616 of 2000 mosome (Hartl and Jones, 2001). microsatellites mapped by Shimoda et al. (1999) to During linkage map construction, co-segregating build a linkage map additionally enriched with 1503 markers are placed into linkage groups, and the propor- coding markers. tion of recombinants detected between linked markers is The number of linkage groups in a linkage map does used as a measure of distance between them. Genetic not always match the haploid number of chromosomes distance is usually measured in centimorgans (cM), (Table 2). It may be due to the structure of the popula- where 1 cM is equivalent to 1% recombination between tion used for construction of the map and the low markers. Gene mapping algorithms analyse the co-seg- genome coverage of the markers mapped. regation of markers in the families and assemble the For some aquaculture species, such as rainbow trout markers into linkage groups, followed by selecting the (Sakamoto et al., 2000), zebrafish (Singer et al., 2002), most likely order of markers within the same linkage Japanese flounder (Coimbra et al., 2003), tilapia group (Hartl and Jones, 2001). (Agresti et al., 2000), Arctic charr (Woram et al., Examples of microsatellite-based linkage maps for 2004) and European sea bass (Chistiakov et al., 2005), some important teleost fish species are listed in Table 2. sex-specific maps have been developed (Table 2). Link- Consolidated linkage maps have been published for age map length differs between sexes. In species with fishes, such as Arctic charr Salvenius alpinus (Woram the XY sex determination system, the female map is et al., 2004), Atlantic salmon (Moen et al., 2004a, b), usually longer than the male map because of higher rainbow trout (Sakamoto et al., 2000; Nichols et al., recombination rates in females compared to males. In 2003a, b), Xiphophorus sp. (Walter et al., 2004), zebra- zebrafish and rainbow trout, the male recombination fish (Woods et al., 2000), Japanese flounder (Coimbra rate close to the centromere is greatly reduced compared et al., 2003) and Nile tilapia (Kocher et al., 1998; to the female (Sakamoto et al., 2000; Singer et al., Agresti et al., 2000)(Table 2). These maps comprise 2002). The molecular basis of suppression in recombi- different types of markers, with a major contribution of nation remains unclear. Lindahl (1991) proposed some SSRs and amplified fragment length polymorphisms general explanations, while Sakamoto et al. (2000) D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 11

Table 2 Microsatellite-based-linkage maps of some economically important marine species Species Linkage map Diploid Reference chromosome Number of markers mapped Number of Length, cM number (2n)a linkage groups Arctic charr 327 (184 SSRs+129 AFLPs+13 46 3900 (male) 80 Woram et al., 2004 (Salvenius alpinus) ESTs+phenotypic marker Sex) 9920 (female) Atlantic salmon Male—251 (31 SSRs+215 AFLPs) 31 103 60 Moen et al., 2004a (Salmo salar) Female—230 (31 SSRs+199 AFLPs) 25 910 Channel catfish 263 (19 type I SSRs+243 32 1958 56 Waldbieser et al., (Ictalurus punctatus) type II SSRs+1 EST) 2001 Yellowtail (Seriola sp.) Male (S. lalandi): 175 SSRs 21 548.3 48 Ohara et al., 2005 Female (S. quinqueradiata): 25 473.3 122 SSRs Three-spined stickleback 227 SSRs 26 886 42 Peichel et al., 2001 (Gasterosteus aculeatus) Nile tilapia 162 (59 STRs+103 AFLPs) 30 704 44 Kocher et al., 1998 (Oreochromis niloticus) Male (O. aureus×O. niloticus F1): 24 1632 Agresti et al., 2000 214 (60 SSRs+154 AFLPs) Female (O. mossambicus): 14 514 62 (13 SSRs+42 AFLPs) Hybrid O. aureus× 525 SSRs+21 genes 24 1311 Lee et al., 2005 O. niloticus Rainbow trout 208 (191 SSRs+3 RAPD+7 29 463.2 (male) 60 Sakamoto et al., (Oncorhynchus mykiss) genes+7 allozymes) 2000 1152.8 (female) 1359 (973 AFLPs+226 SSRs+ 40 (30 major) 4590 Nichols et al., 72 VNTRs+38 SINE markers+ 2003a 29 genes+12 minisatellites+ 5 RAPD+4 allozymes) European sea bass 162 SSRs 25 815 48 Chistiakov et al., (Dicentrarchus labrax) 2005 567 (male) 906 (female) Red sea bream Male: 100 SSRs 26 609.1 48 Inami et al., 2005 (Pagrus major) Female: 89 SSRs 28 (female) 708.5 (female) Platyfish (Xiphophorus sp.) 290 (256 SSRs+22 allozymes+ 24 2178 48 Walter et al., 2004 11 genes) Zebrafish (Danio rerio) 102 SSRs 25 1320 50 Knapik et al., 1996 705 SSRs 25 2350 Knapik et al., 1998 2119 (616 SSRs+1503 genes 25 2400 Woods et al., 2000 and ESTs) 2000 SSRs 25 2295 Shimoda et al., 1999 141 SSRs 25 2582.7 (female) Singer et al., 2002 942.5 (male) 1635.6 (sex-averaged) Japanese flounder Male—231 (82 SSRs+149 AFLPs) 25 741.1 48 Coimbra et al., 2003 (Paralichtys olivaceus) Female—304 (101 SSRs+203 AFLPs) 27 670.4 aData are taken from the Animal Genome Size Database (http://www.genomesize.com/fish.htm). Abbreviations: AFLP, amplified fragment lentgth polymorphism; VNTR, variable number of tandem repeats; STS, sequence tagged site; RAPD, randomly amplified polymorphic DNA; IRS, internal repetitive sequence. focused their suggestions for salmonids on the model of pered in fish species due to the absence of heteromorphic tetravalent formation, which hinders crossovers be- sex chromosomes (Traut and Winking, 2001), variabil- tween homologous chromosomes via structural con- ity of genetic sex determination (Volff and Schartl, straints in distal regions in males. 2001) and ability to switch sex depending on the envi- Fishes have some of the most complex sex determi- ronmental conditions (Baroiller and D'Cotta, 2001). nation systems known in the animal kingdom (Schartl, However, applying microsatellites provides a good op- 2004). Identification of sex-determining loci is ham- portunity to find a sex-determining locus due to 12 D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 specific features in the heterogametic sex such as an nomically significant species such as bluegill sunfish obvious reduction in recombination between markers Lepomis macrochirus (Neff, 2001), red sea bream linked to the sex-determination region in male com- Pagrus major (Doyle et al., 2001), turbot Scophthalmus pared to female meioses (Naruse et al., 2000) and maximus (Castro et al., 2004), chinook salmon Oncor- the consistently heterozygous status of males for hynchus tshawytscha and rainbow trout (Bentzen et al., unique alleles in this region (Peichel et al., 2004). 2001), Atlantic salmon (Norris et al., 2000; King et al., Using this approach, a sex-determining locus has 2001), European sea bass and gilthead sea bream been found in medaka Oryzias latipes (Naruse et (Kotoulas and Tsigenopoulos, pers. comm.). al., 2000) and three-spined stickleback (Peichel et Due to the small size of SSRs, they are relatively al., 2004), species without distinct sex chromosomes. stable in degraded DNA (Schneider et al., 2004). This is one reason why polymorphic SSRs are widely used 6.2. Individual DNA identification and parentage in forensic science for individual DNA identification. assignment In addition, they show a high degree of allelic variability, and hence uniqueness. An interesting example Microsatellites represent codominant single-locus of the application of microsatellites to resolve a case of DNA markers. For each SSR, a progeny inherits one fishing tournament fraud in Finland was reported by allele from the male parent and another allele from the Primmer et al. (2000). Genotyping data provided a female parent. This simple inheritance pattern can ex- highly significant power for excluding the possibility plain the extreme popularity of polymorphic SSR loci in (PN0.9999) of a 5.5 kg Atlantic salmon originating paternity testing. Using a panel of several microsatellite from the fishing competition location, Lake Saimaa loci, a unique combined SSR genotype profile can be (south east Finland). Assignment of the suspect fish produced for each individual tested. The genotype pro- to neighbouring natural samples was done with three file is highly discriminating, which suggests that a ran- methods: using a Bayesian-based approach, based on dom individual would have a low probability of reference population allele frequencies and based on matching a given genotype. genetic distance, all using the software GeneClass Microsatellites are extensively exploited for paternity (Cornuet et al., 1999). When presented with this evi- and relatedness analysis of natural populations, hatchery dence, the offender confessed to purchasing the salmon broodstocks and trade control of fish products, including at a local fish shop, and criminal charges were made. A those from aquaculture (Liu and Cordes, 2004). Appro- similar strategy could be also used, for example, in priate mathematical tools are available to evaluate ge- cases of illegal poaching, fraud with food authenticity netic relatedness and inheritance in these systems and the mix-up of commercial fish catches (Fig. 3), in (Luikart and England, 1999; Blouin, 2003; Jones and order to assign or exclude individuals from originating Ardren, 2003). A suitable methodology should be cho- from a claimed population (Poetsch et al., 2000). sen for accurate and correct analysis of genotyping data In addition, microsatellite loci remain relatively sta- to reconstruct parentage and pedigree structure in wild ble in bone remnants and dental tissue, providing the populations and broodstocks. Existing analytical basis for the successful application of ancient DNA for packages combine several different approaches in par- molecular analysis (Burger et al., 1999). Successful entage analysis such as merging likelihood techniques extraction and amplification of nuclear DNA from with tools assessing statistical confidence in parental the β-globin gene region containing a polymorphic assignments that provides a significant power in par- (AT)χ(T)γ microsatellite from 12,000 year-old human entage reconstruction (Jones and Ardren, 2003). bone specimens has been reported (Beraud-Colomb et An example of successful application of microsatel- al., 1995). Application of microsatellites obtained from lite markers in relatedness testing was described by historical fish scale collections has helped to explain Herbinger et al. (1995), who analyzed a rainbow trout demographic declines in abundance, which resulted in broodstock in a small hatchery in Canada. Using only the complete collapse of populations of lake trout in the four of five microsatellite markers, they were able to upper Laurentian Great Lakes of North America during match 91% of offspring to one or two parental couples the past 40 years (Guinand et al., 2003). Other cases of 100 possible parental pairs (ten sires×ten dams) and, where DNA from old fish scales was used to characterise in addition, to estimate parental effects on progeny historic populations involve northern pike Esox lucius growth and survival. Applications of SSRs have been (Miller and Kapuscinski, 1996; Larsen et al., 2005) and reported to determine paternity and reproductive contri- brown trout Salmo trutta (Hansen, 2002). Also the mem- bution in wild and farmed populations of various eco- brane lining of fish otoliths contains DNA, which can be D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 13 used to genotype historic populations (Atlantic cod primers for amplifying homologous loci in divergent Gadus morhua: Hutchinson et al., 2003; New Zealand taxa are evident. Even when it is possible to amplify snapper Pagrus auratus: Hauser et al., 2002). something in divergent taxa, the sequences may not be Analysis of nuclear microsatellites from ancient similar enough to permit confident assessment of orthol- human and animal remnants represents an essential ogy. Flanking regions of microsatellites have proven step to understand the genetic diversity in current popu- their value in establishing phylogenetic relationships lations and to provide substantial perspectives for the between species and families, because they evolve analysis of archeological issues, establishment of an- much more slowly than numbers of tandem repeats. cient baselines, heritable diseases, determination of re- For example, a phylogeny of cichlid fishes was studied latedness and establishment of genealogies in based on information from DNA sequences of the flank- prehistoric populations (Zierdt et al., 1996). ing region of a (CA)n microsatellite locus TmoM27, which showed particular conservation in several 6.3. Phylogeny, population and conservation genetics lineages of cichlids diverged more than 80–100 million years ago (Zardoya et al., 1996). Analysis revealed that The molecular structure and genetic variability of the repeat region was nearly lost in the ancestor to microsatellites is extensively exploited in evolutionary cichlids and then amplified extensively in African taxa studies of a wide variety of fish species. The vast ma- (Streelman et al., 1998). Indian and Malagasy cichlids jority of these studies attempt to infer phylogenetic formed a basal, paraphyletic group, while African and relationships from microsatellite data at levels below Neotropical cichlids were both monophyletic and sister the species level (Goldstein et al., 1999; Heath et al., groups (Zardoya et al., 1996; Streelman et al., 1998). 2001; Reusch et al., 2001) or for recently diverged The authors suggested that marker TmoM27 could be species (McCartney et al., 2003; Stamford and Taylor, widely applied in phylogenetic studies in other perci- 2004), using variability within stretches of tandem form fishes. repeats, which evolve significantly more rapidly than Phylogeographical applications of microsatellites are flanking regions. However, the high incidence of homo- eminently suitable, where population structure is ob- plasy (e.g., false equality of alleles based on independent served over a large geographical scale (Koskinen et mutation to the same size) with increasing evolutionary al., 2002; Gum et al., 2005)(Fig. 2). The latter study distance, may undermine the confidence of the inferred on grayling Thymallus thymallus shows that there is phylogenetic hypotheses, compromise the accuracy and strong admixture among major lineages in contact limit the depth of phylogenetic inference (Jarne and zones between drainages zones. Microsatellites are Lagoda, 1996). Another obvious problem with using even more revealing over shorter geographical dis- SSRs for phylogenetic inference is that primers devel- tances, where a few cases of panmixia (Dannewitz et oped from one taxon may not work well on all the taxa al., 2005) and numerous cases of isolation by distance for which genotypes are required. Although cross- patterns (Ruzzante et al., 1999; O'Reilly et al., 2004), species ampification is common, limits on the utility of clinal variation (Nielsen et al., 2004), fragmentation

North Sea Adriatic Sea M

105 bp 100 bp

94 bp

75 bp

50 bp

Fig. 2. Microsatellite genotypes (scored at dinucleotide locus F14) of common soles (Solea solea) collected in the North Sea (n=27) and Adriatic Sea (n=29). Homozygotes are indicated with an arrow. A larger number of individuals from the North Sea population are heterozygous because of the higher allelic diversity. At the right are indicated the marker sizes of the standard (M) (in bp). 14 D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29

(Lemaire et al., 2005), hybridisation (Gum et al., 2005) size homoplasy problems in PCR-based microsatellite and cryptic speciation (Fillatre et al., 2003) have been assays may affect the inference of recent population identified (see later). In those cases, differences in the history (Estoup et al., 2002). Homoplasy may contrib- microsatellite allelic composition of populations are ute to biased genetic analyses of natural populations converted into evolutionary distances. Microsatellite and, hence, limit the use of microsatellites for the iden- genotypes are particularly helpful to detect structure in tification of conservation units. closely related populations, regardless of whether they Genome-wide scans using microsatellite markers are in evolutionary equilibrium. could be applied for a search of locus-specific signa- The levels of genetic diversity between fish popula- tures of positive directional selection in natural populations revealed with microsatellite markers are much tions of any species for which a high-density genetic higher than those obtained with phenotypic or allozyme map is available (Storz, 2005). The expansion and fix- markers (Miller and Kapuscinski, 1996; Shaw et al., ation of adaptive mutations is associated with joint 1999; Triantafyllidis et al., 2002; Corujo et al., 2004). fixation of linked neutral variants, or genetic hitch-hik- Compared with allozyme markers, microsatellites ex- ing. Genetic hitch-hiking results in a reduced level of hibit higher levels of polymorphism and abundance in polymorphism and a skewed distribution of allele fre- genomic DNA (Schlötterer, 2000). Most microsatellites quencies at linked neutral markers (Kim and Stephan, are considered neutral markers, whereas allozymes are 2000). The basic starategy of how to use whole-genome sometimes the target for natural selection. In that case, screens to detect loci under positive selection, was no deviation from the expectations under a neutral explained and referred to as hitch-hiking mapping model is expected by selection acting on the microsa- (Harr et al., 2002). For example, a whole-genome tellite itself. However, if a microsatellite locus is linked screen of DNA polymorphisms was recently performed to a genomic region which is the target for natural in humans and found evidence for selective sweeps, or selection, then this microsatellite will show deviation loci which are driven by positive adaptive selection, in from neutral expectation (Schlötterer et al., 1997; non-African populations (Storz et al., 2004). Lemaire et al., 2000). In selected cases, it is possible to identify candidate SSR loci are more sensitive than allozymes for the genes, which are responsible for divergent selection in evaluation of the dynamics of populations, including natural populations (Hendry et al., 2000; Santiago and demographic bottlenecks (Spencer et al., 2000; Guinand Caballero, 2005). A multilocus scan of microsatellite and Scribner, 2003; Ramstad et al., 2004), population variation in a southeast Asian population of the malaria size fluctuations and effective population sizes (Gold et parasite Plasmidium falciparum identified evidence for al., 2001; Bérubé et al., 2002; Waples, 2002). Common a selective sweep within a 100-kb region on chromo- measures of genetic diversity are heterozygosity (the some 4 containing the dihydrofolate reductase (dhfr) proportion of heterozygous individuals in the popula- gene; point mutations in this gene are known to be tion), allelic diversity (number of alleles at a locus in the responsible for resistance to the antimalarial drug pyri- population), and the proportion of polymorphic loci methamine (Nair et al., 2003). (Pujolar et al., 2005). Marked decreases in the observed For spatially separated populations that inhabit dif- heterozygosity and reduced number of observed alleles ferent environments or sympatric populations that use of tested SSRs might be attributed to the action of different ecological niches, is it possible to find chro- population genetic bottlenecks. Since they evolve mosome regions conferring adaptive biodiversity by 102–103 times faster than single-copy nuclear DNA, comparing relative levels of differentiation among mul- they are a powerful tool for analyzing recent and con- tiple unlinked loci (Charlesworth et al., 1997). The temporary events (Ellegren, 2000). For example, occurrence of highly polymorphic microsatellites in screening of microsatellites linked to the Y chromo- the untranslated regions of ESTs is a potentially useful some enabled observation of fine genetic structure of source of gene-associated polymorphisms representing human populations as well as directions of migration genetic signatures of divergent selection. For example, and timing of post-glacial human expansion in Europe analysis of 95 EST-microsatellites, isolated during a (Rootsi et al., 2004). In salmonids, SSRs have been salmonid EST screening project (Rise et al., 2004), in successfully used for defining temporal intervals and Salmo salar populations inhabiting contrasting natural explaining mechanisms of severe decline of populations environments and geographically distinct regions, of brown trout in Denmark (Hansen et al., 2002) and resulted in the selection of nine loci linked to candidate lake trout in the North American Great Lakes (Guinand genes associated with adaptive divergence (Vasemägi et and Scribner, 2003; Guinand et al., 2003). However, al., 2005). D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 15

Conservation and fisheries genetics focus on the since mitochondrial DNA has maternal inheritance. effects of inbreeding, demography, contemporary genet- Conservation strategies depend on neither paternal nor ic structuring and adaptation on the long-term survival maternal variation, but focus on using biparental poly- of a species. Stock identification is a big issue (Fergu- morphism of nuclear DNA to reflect characteristics son et al., 1995), helping wildlife managers to protect needed to cope with environmental conditions (Zhang biodiversity by identifying series of conservation units and Hewitt, 2003). A high mutation rate of SSR loci such as evolutionarily significant units (ESUs), man- also supports use of these markers in the genetic anal- agement units (MUs) and action units (AUs) (Wan et ysis of very recent events in the dynamics of popula- al., 2004). tions, e.g., to MUs and AUs. If populations within species show significant adaptive differentiation to different habitats (ecological 6.4. Molecular epidemiology and pathology niches) or significant genetic diffrentiation, they may justify management as separate evolutionary lineages Genomic instability of microsatellites has been ex- termed ESUs (Moritz, 1994). The ESU concept was tensively evaluated in the field of carcinogenesis, where developed to assign units for protection below the tax- chromosomal rearrangements (e.g., translocations, onomical level. The identification of an ESU preferably insertions and deletions of genomic regions) occur depends on significantly differentiated genetic structure (Charames and Bapat, 2003). Carcinogenic events detected by presumably neutral markers. In that case, often happen within a genomic region harbouring a SSRs represent markers of choice for identifying ESUs. tumour suppressor gene and hence inactivate the gene However, to find a true ESU, multiple, prefererably (Grady, 2004). Carcinogenic rearrangements are associ- different kinds of markers should be exploited, since ated with loss of heterozygosity (LOH) in microsatel- size homoplasy and null (e.g., non-amplifiable) alleles lites located within the affected chromosome region. could affect PCR-based microsatellite analysis (Brown Thus, detecting microsatellite LOH in tumour tissues et al., 2005). For example, mitochondrial and microsa- contributes not only to molecular diagnosis of cancer, tellite DNA markers revealed four genetically differen- but also points the possible location of a tumour sup- tiated lineages of European grayling (Thymallus pressor gene (Presneau et al., 2003). thymallus) in central and nothern Europe, which Zebrafish is a relevant vertebrate system for model- evolved in geographical isolation during the Pleistocene ing human cancer, displaying many similarities in tu- and could be recognized as the ESUs (Gum et al., morigenic pathways, despite the evolutionary 2005). The genotype data should be complemented divergence of tetrapods and fishes more than 300 mil- with ecological and biological (e.g., life-history and lion years ago. The zebrafish (whose cell-cycle genes, behavioural) evidence (Crandall et al., 2000; Fraser tumor suppressor genes and oncogenes are homologous and Bernatchez, 2001). to those found in humans and other mammals) has Genetic analyses often reveal differences between enormous potential as a vertebrate system in which to sampled populations with substantial but noncomplete identify novel molecular pathways of oncogenesis, es- phylogenetic separation, which have minor but statisti- pecially because they are prone to develop tumors cally significant differences in allele frequency of nu- (Amatruda et al., 2002; Rubinstein, 2003). Zebrafish clear or mitochondrial loci. These populations are also have played an important role as a vertebrate termed MUs (Wan et al., 2004). The MU is considered model system for carcinogenesis regarding environmen- to be a conservation unit level below that of the ESU, tal effects, genetic susceptibility, and environmental– which is based on multiple evidence such as molecular genomic interactions (Amatruda et al., 2002). markers, habitat use and adaptive characters. Using an The instability of triplet motifs was found in lower MU is focused on the monitoring of the contemporary vertebrates, including fishes (Schartl et al., 1998; Liu et population structure and requires defining genetic struc- al., 2001). A variable number of trinucleotide repeats ture of currently fragmented populations compared to occurred within the coding region of functionally im- the ESU, which is derived from historical genetic dif- portant genes expressed in the brain of adult fishes such ferentiation (Moritz, 1994). Using an MU designation as the channel catfish orthologue of the RAD23B gene does not imply detailed genetic structure of populations, (Liu et al., 2001) and the zebrafish Clock gene (Saleem but indicates the populations to be treated as a unit. AUs et al., 2001). A RAD23B gene product functions in the display genetic patterns of living populations. Microsa- nucleotide exclusion repair (NER) pathway. NER tellites could be more successfully applied for identify- defects are associated with higher incidence of muta- ing MUs and AUs than mitochondrial DNA markers, genesis and carcinogenesis and cause Xeroderma 16 D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 pigmentosum, an autosomal recessive disease in es, they have been mostly performed on Salmonidae.In humans (Sancar and Hearst, 1993). The Clock locus rainbow trout, genomic DNA was screened for loci regulating circadian rhythms is highly conserved in controlling natural killer cell-like activity (Zimmerman various organisms. Alterations of circadian rhythms et al., 2004) and linked to resistance to infectous hema- could be related to a large number of diseases, including topoietic necrosis virus (Palti et al., 1999; Khoo et al., psychiatric disorders in humans (King and Takahashi, 2004), ceratomyxosis (Nichols et al., 2003b) and pan- 2000). The polyglutamine (CAG)n tract at the Clock creatic necrosis virus (Ozaki et al., 2001; Gibson, gene is highly polymorphic in Drosophila, ranging 2002). In Atlantic salmon, polymorphic loci associated from 25 to 33 pure glutamine repeats. In zebrafish, the with resistance to infectious salmon anemia have been (CAG)n stretch includes up to 51 repeat units (Saleem et identified (Grimholt et al., 2003; Moen et al., 2004b). al., 2001). However, it is shortest and non-polymorphic For an interspecific tilapia hybrid (Oreochromis mos- in human. The lack of polymorphism may indicate that sambicus×O. aureus), a genome scan using microsatel- variation at this locus is deleterious to the individual and lite markers found five loci in different linkage groups hence not tolerated. The above examples suggest that linked to innate immunity (Cnaani et al., 2004). Identi- expansion of trimeric repeats within exons is tightly fication of six microsatellite loci linked to resistance to regulated during molecular evolution and that regulato- red sea bream iridovirus, which causes high mortalities ry mechanisms preserve coding sequences from the in cultured red sea bream in Japan, have also been uncontrolled extension of triplet motifs. reported (Inami et al., 2005). Since microsatellite markers are usually selectively Transmission of diseases is a major problem in aqua- neutral and often represent non-functional sequences, culture production, and determining the genetic archi- they cannot be defined as loci directly responsible for tecture of disease resistance traits is of great interest to disease phenotype. However, SSR markers, showing geneticists working on aquaculture species. Due to the linkage and association with disease, can be in strong rapid accumulation of genetic and genomic data and linkage disequilibrium with other functional genetic availability of high-density microsatellite maps for cer- variations which truly cause the pathological pheno- tain farmed fishes, the number of studies searching for type. These disease-associated markers typically are marker loci and genes associated with resistance to represented by single nucleotide polymorphisms, or pathogens is expected to increase dramatically. SNPs. They are often functionally relevant and, therefore, could be responsible for determination of the path- 6.5. Quantitative trait loci mapping ogenic phenotypes (Schork et al., 2000). Genome-wide scans using SSRs often reveal linkage A quantitative trait is one that has measurable phe- to susceptibility loci on chromosomes that harbour notypic variation owing to genetic and/or environmen- genes contributing to genetic predisposition/resistance tal influences. The variation can be measured to pathology. Further fine mapping with microsatellite numerically (for example, height, size or blood pres- markers located within the region of linkage often sure) and quantified. Generally, quantitative traits are results in identifying the susceptibility gene, but not in complex (multifactorial) and influenced by several the detection of the genetic variation, which directly polymorphic genes and by environmental conditions. causes clinical outcomes of the disease. In some cases, A QTL is a genetic locus (gene), the alleles of which only when a microsatellite marker has direct functional affect phenotypic variation. One or many QTLs can significance, can it represent a genetic marker for dis- contribute to a trait or a phenotype. When more than ease (Fornoni et al., 2002; Wang et al., 2002). one QTL influences a particular trait, each might have a Microsatellite-based screening strategies can be used different effect size, and the effects of individual QTLs in the fields of veterinary and medical parasitology and can vary from strong to weak. The size and nature of for molecular studies of infectious diseases. This these effects also can be affected by the genetic back- includes mapping and further identification of genes ground (the total genotype of the individual), and inter- responsible for resistance to parasites and pathogens actions between QTLs are common (Mackay, 2001). and the identification of genes controlling drug resis- To date, microsatellite-based strategies (scans across tance in pathogenic organisms (Gasser, 1999; Naidoo individual chromosomes and a whole genome) repre- and Chetty, 1998; Behnke et al., 2003; Anderson, sent appropriate techniques to identify QTLs, particu- 2004). Such approaches have been applied in a variety larly those that are associated with medically, of domesticated and farmed animals and plants (Naidoo economically and evolutionarily important complex and Chetty, 1998; Yencho et al., 2000). In farmed fish- traits. Due to the genome-wide distribution and high D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 17 levels of allelic polymorphism, SSR loci are very help- discovery of a suitable candidate gene (Nadeau et al., ful in coarse and fine linkage mapping approaches. 2000). However, it is difficult to find a candidate gene Coarse mapping resolves detection of a putative QTL even when the crucial region was 0.5 cM if no signif- in a chromosomal region, usually within a range of 10– icant sequence information on that region is available. 30 cM. For a given QTL, the likelihood of success and Generation and analysis of knock-out and knock-in mapping resolution depends on the number of loci (for a given gene) animals (Hentschel and Bonventre, screened and the magnitude of their effect on the trait 2005), transgenesis with bacterial artificial chromo- of interest. Also important are recombination events in somes carrying the target gene (Yang and Seed, 2003), the mapping population, the mode of expression of the detection and evaluation of polymorphic markers within trait (dominant, recessive or additive), size of the map- the candidate gene (Fanara et al., 2002), in vitro func- ping population, and number of genes that define the tional studies (Ponsuksili et al., 2005), examination of quantitative trait (Glazier et al., 2002). gene function (Salvi and Tuberosa, 2005) and other Characteristics and types of experimental crosses techniques can be used for further identification and used to breed a mapping population are also crucial in confirmation of the gene responsible for the quantitative precise QTL mapping. Typically, approaches that in- trait. However, identification of genes controlling com- crease the number of breakpoints in a mapping popula- plex traits often is complicated by the action of non- tion provide higher mapping resolution, but also require coding regulatory variants that are problematic for sim- a larger number of animals to achieve significance for a ple functional characterization. Until 2002, a total of given size of a QTL effect. Lander and Kruglyak (1995) 1700 genes responsible for a variety of genetic traits defined threshold values to assign significance of link- have been detected in various species, and only 31 of age of a marker to a given trait in a genome-wide them (including 7 human genes) have been defined for screen: ‘highly significant’ refers to Pb4.9×10− 6, ‘sig- complex traits (Peltonen and McKusick, 2001; Glazier nificant’ refers to 1.7×10− 3 ×P×4.9×10− 6 and ‘sug- et al., 2002). Five complex QTLs have been defined in gestive’ refers to P×1.7×10− 3 after correction for agricultural plants and only one QTL in farmed animals multiple testing. Permutation tests represent a proven (Glazier et al., 2002). The latter involves the DGAT1 technique to calculate threshold values adjusted for gene encoding an enzyme which catalyzes the final step multiple testing (Doerge and Churchill, 1996). in tryglyceride synthesis. Three polymorphisms within All QTLs detected, including those only with sug- the gene are found to cosegregate with milk production, gestive significance, should be designated as proposed and one of them represents lysine-to-alanine amino acid by Lander and Kruglyak (1995); it facilitates further substitution in codon 232, which underlies variation in confirmation of such loci. It is wise to reconfirm any milk yield and composition (Coppieters et al., 1998). significant linkages before proceeding to finer mapping, For farmed fishes, the first mapping of an econom- to avoid unexpected effects. The reconfirmation can be ically important QTL was reported in 1998 (Jackson et done with independent crosses but requires a simple test al., 1998). To date, no QTL gene has been defined, but of the proposed chromosome interval for linkage to the several microsatellite-based QTL screenings have been quantitative trait. Another way includes analysis of a performed. Most of these mapping experiments have congenic strain produced by repeated backcrosses to an targeted three salmonid species (Atlantic salmon, rain- inbred strain with selection for a particular marker or bow trout and Arctic charr). These sceenings include chromosomal region, which shows a maximum strength searches for QTLs related to temperature tolerance of linkage. This approach was widely applied in QTL (Jackson et al., 1998; Danzmann et al., 1999; Perry et mapping in rat and mouse, providing rapid confirmation al., 2001; Cnaani et al., 2003; Somorjai et al., 2003), of loci with modest genetic effect using a limited num- body weight (Cnaani et al., 2003; O'Malley et al., 2003; ber of animals (Nadeau et al., 2000). Borrell et al., 2004; Reid et al., 2005), body length Fine mapping narrows the putative location of a QTL (Borrell et al., 2004), spawning date (Sakamoto et al., within the chromosome to the interval of less than 1–5 1999; O'Malley et al., 2003), embryonic development cM but requires more recombination events to separate rate (Nichols et al., 2000; Robison et al., 2001) and the genes that drive expression of the quantitative trait condition factor (Nakamura et al., 2001; Perry et al., from closely linked markers. If there are several linked 2003; Reid et al., 2005). In rainbow trout, the sex-linked QTLs, it is nessessary to perform more sensitive phe- microsatellite marker OmyFGT19TUF showed signifi- notyping procedures. Creation of subcongenic strains, cant association with fork length (FL) and upper ther- subdividing the crucial interval of linkage into several mal tolerance (UTT), explaining dependence of male segments, greatly facilitates fine mapping and further advantages in FL and UTT compared to their female 18 D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 sibs with the origin of the Y chromosome (Perry et al., genotyped to find QTLs linked to several gill raker and 2005). A body weight QTL search has been reported for body armour traits. A major QTL was mapped for every all three salmonids mentioned above (Reid et al., 2005). trait, each explaining between 17% and 37% of the Several markers linked to feed conversion efficiency phenotypic variance. A new and relatively large (360 have been found in channel catfish (Karsi et al., 2000). F2 progeny) stickleback mapping population was re- An interspecific hybrid tilapia stock (four-way cross cently produced using a marine female (from Japan) between Oreochromis mossambicus, O. aureus, O. mos- and benthic male (from Lake Paxton, British Columbia) sambicus and Sarotherodon galilaeus) has been suc- to study the genetics of armour plate reduction (Colo- cessfully developed for linkage mapping and QTL simo et al., 2004). QTLs were discovered for lateral analysis (Agresti et al., 2000; Cnaani et al., 2003). A plate number, with a major locus in linkage group 4 search for association with deleterious alleles and sex- accounting for 75% of the phenotypic variance. A sec- ratio distortions revealed three microsatellite loci linked ond cross was generated from benthic and limnetic fish to sex distortion genes in tilapia, and one of the markers (Lake Frient, California). Three of the QTLs (including was likely to be related to a modifier of these genes the major one) segregated in the second population (Shirak et al., 2002). A recent complex search for ge- (Colosimo et al., 2004). The authors also performed a netic linkage between DNA markers and QTLs for ‘complementation” cross between Paxton and Frient innate immunity, response to stress, biochemical para- populations and found that the same gene within the meters of blood, and fish size in the tilapia hybrid major QTL was responsible for the high plate number in revealed 35 significant marker-trait associations involv- these populations. This indicates that a single gene ing 26 microsatellite markers in 16 linkage groups causing a major shift in phenotype can explain cases (Cnaani et al., 2004). A different hybrid line was used of parallel evolution (Colosimo et al., 2004). for the detection of QTLs controlling body color (Howe The cross between Japanese marine and Paxton ben- and Kocher, 2003) and sex determination (Lee et al., thic sticklebacks was used to investigate the genetic 2003, 2004). background of reduction or complete loss of pelvic QTL mapping in natural populations represents a spines in benthic stickleback populations (Shapiro et powerful tool to study the genetic architecture of fitness al., 2004). A major QTL was mapped to linkage group traits and reproductive isolation. This approach has not 7. Within this QTL, a likely candidate gene (Pitx1), been extensively exploited yet since there are no well- which causes a similar phenotype (asymmetry in pelvic developed genetic and genomic tools for most free- limb reduction) in mice, was localized. However, no living species. The search for QTLs in wild populations amino acid-changing mutation was found in the coding requires the design or observation of appropriate crosses portion of Pitx1. Functional studies showed that Pitx1 is to create a suitable mapping population, which contains not expressed in pelvic tissues of benthic fish, whereas individuals of measured phenotype and which can be marine fish showed normal expression in pelvic tissue. pedigreed. The availability of a genetic map of variable Complementation tests showed that the same locus is markers is also crucial (Slate, 2005). responsible for loss of pelvic structures in a stickleback Marine three-spined stickleback represents a good population from Iceland (Shapiro et al., 2004). This example of an organism that successfully colonized suggests that a functional polymorphism, affecting new freshwater lakes approximately 15,000 years ago gene expression, is located in the noncoding region of and rapidly adapted to a diverse array of new environ- Pitx1. Hence, a second gene, contributing to the parallel ments. Within these lakes, sympatric forms adapted to a evolution in stickleback, was found, providing an ex- different ecological niche-benthic forms have reduced ample of the successful application of the candidate body armour, increased body length and decreased gene analysis to identify loci responsible for quantita- number of gill rakers, while limnetic forms more closely tive variation. In addition, QTL mapping experiments in resemble marine forms with a streamlined body, exten- stickleback showed that replicate populations offered sive armour and a large number of gill rakers. To dissect considerable power for understanding evolutionary the genetic architecture of the traits that cause reproduc- changes. tive isolation, a mapping population was derived from a benthic female and limnetic male from Priest Lake 6.6. Marker-assisted selection (British Columbia), followed by backcrossing an F1 male to a benthic female (Peichel et al., 2001). A Marker-assisted selection is based on the concept medium-density linkage map containing 227 microsa- that it is possible to infer the presence of a gene from tellites was constructed. The F2 progeny (n=92) was the presence of a marker tightly linked to the gene. For D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 19 this purpose, it is important to have high-density and have been implemented in agricultural plants, for high-resolution genetic maps, which are saturated by which significant genetic and genomic knowledge is markers in the vicinity of a target locus (gene) that available (Koebner and Summers, 2002; Dale and Brad- will be selected. The degree of saturation is the propor- shaw, 2003). For example, wheat lines resistant to leaf tion of the genome that will be covered by markers at rust, a world-wide disease caused by Puccinia recondita the density such that the maximum separation between f.sp. tritici, have been selected using molecular markers markers is no greater than a few centimorgans (usually linked to resistant alleles of genes Lr9, Lr10, Lr19, Lr21, 1–2 cM), within which linkage of markers and QTLs Lr24, Lr28, Lr29 and Lr35 through construction and can be detected. Strategies to find markers tightly linked analysis of near-isogenic and single-gene lines. These to the target gene are similar to those that are used for lines differ in the presence or absence of the target gene fine QTL mapping. Strategies, such as flanking marker and a small region flanking the target gene (Kolmer, analysis (Dixon et al., 1995) and pooled sample map- 2005). SSR markers located in the vicinity of these ping (Churchill et al., 1993), are used to order these genes were converted into sequence-tagged sites, or markers. When implementing flanking marker analysis, STS, representing short DNA sequences, which have a a large segregating population is screened with markers single occurrence in the genome and whose location and flanking the target interval (usually 5–10 cM) in order base sequence are known. The STS tightly linked to to identify individuals with a crossover within that each of the leaf rust protective genes are clearly associ- interval. In pooled sample mapping, DNA from indivi- ated with the preferable phenotype and can be rapidly duals from a large segregating population that share a detected by PCR (Singh et al., 2004; Blaszczyk et al., given phenotype is pooled. DNA from each pool is 2004). The Lr10 and Lr21 genes have been cloned and analysed with markers flanking the target gene. The sequenced (Feuillet et al., 2003; Huang et al., 2003). order of markers then is determined from the proportion Both genes have sequences encoding nucleotide-bind- of pools that show a crossover with respect to the ing site-leucine-rich regions, which are characteristic of markers used for analysis. disease resistance genes in plants. Leaf rust infections Once a tight linkage is found between a molecular occur when the resistance gene interacts with a specific marker and a gene of interest, the inheritance of the gene antivirulence gene in the rust, while compatible infec- can be traced in breeding programs. The availability of a tions occur in the absence of an antivirulence gene. phenotype, which can be clearly identified and quanti- New races of rust develop by mutation and selection fied, plays an important role in successful MAS pro- of virulence against rust resistance genes in wheat grammes. MAS should be performed with strong control (Kolmer, 2005). of the correlation and matching ratio between the phe- MAS was successfully implemented in farmed ani- notype of interest and genotype information. Breeders mals, such as cattle (Maillard et al., 2003), pig (Roths- select animals or plants carrying beneficial genotypes child, 2003), sheep (Notter and Cockett, 2005) and and alleles of markers that associate with or contribute to chicken (Malek and Lamont, 2003), for which many a trait of interest. Successful implementation of MAS QTLs have been completed. It can be combined with requires well-developed genomic tools, including op- candidate gene analyses that have identified important tional information on genetic variations relevant to the chromosomal regions and individual genes associated QTL phenotype, mode of inheritance, interactions with with traits of economic interest (Rothschild, 2003). other contributing QTLs and economical magnitude of To date, most of genetic improvements in aquaculture the QTL studied (Poompuang and Hallerman, 1997). To have been performed following the use of traditional plan MAS, breeders also should take into account pos- breeding approaches. For example, the Norwegian se- sible interactions between QTLs, which could relate to lective breeding programme for Atlantic salmon has each other and have overlapping genetic backgrounds. focused on growth rate, age at sexual maturity and In that case, MAS should preferably represent a complex later, disease resistance and carcass quality traits. The selection index and take into consideration all econom- selection response for growth rate in salmon is generally ically significant traits that interact. much higher than that obtained for traditional livestock Production (such as growth rate, stress response and animals. Gjerde and Korsvoll (1999) reported the aver- disease resistance) and reproductive (such as sex deter- age genetic gain for growth rate of 14% per generation mination and development rate) traits are extremely through six generations per selection. These authors also important to breeders. Discovery of genes that control reported that four rounds of selection for delayed sexual these features could greatly benefit MAS in breeding maturation have reduced the incidence of salmon be- programs. Some marker-assisted breeding approaches coming sexually mature before they reach market size. 20 D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29

However, traits difficult to measure, such as disease lead to the replacement of SSRs by other types of resistance, low-heritability traits, sex-limited traits and genetic markers (ESTs and SNPs) in later stages of traits expressed late in life would benefit from the use of marker-assisted breeding programmes. This would gene technology (Poompuang and Hallerman, 1997). lead to even more precise selection by gene-assisted In fish culture, DNA marker-based techniques have selection (GAS), based on the use of favorable haplo- been applied in several cases, for example, in breeding types and genotypes derived from genes directly con- programmes for Atlantic halibut Hippoglossus hippo- tributing to the target trait (Hulata, 2001). glossus (Jackson et al., 2003), channel catfish (Waldbie- ser and Wolters, 1999), European sea bass (García de 7. Prospects León et al., 1995), Japanese flounder (Hara and Sekino, 2003; Sekino et al., 2003) and salmonids (Herbinger et In this review, with special emphasis on fishes, we al., 1995; Fjalestad et al., 2003; Wilson et al., 2003). considered microsatellites as structural genomic compo- Apart from facilitating survival under variable environ- nents and as genetic markers which have specific evo- mental conditions, a higher genetic diversity within a lutionary mechanisms, functions and applications. progeny array stemming from multiple matings by Microsatellite loci have a high utility for constructing a females might also serve to reduce the potential cost of genetic framework onto which other markers and genes inbreeding and reduce the deleterious effects of genetic are incorporated using various mapping strategies (link- incompatibility between two partners (Jennions and Pet- age mapping, physical mapping and comparative genet- rie, 2000). ic and genomic tools). Using microsatellite markers will There are not yet large-scale fish breeding pro- greatly benefit the genetic dissection of complex and grammes using MAS. However, the current status of quantitative traits in order to map, identify and eventu- genetic information and advanced genomic tools avail- ally clone and characterize the candidate genes control- able for rainbow trout, Atlantic salmon and channel ling economically important traits. In aquaculture, SSRs catfish provide an opportunity for the successful appli- represent the markers of choice for genetic monitoring of cation of the DNA marker-based technology to selective farmed stocks in view of breeding programs through the breeding in these species. Predictions of the benefits of analysis of genetic variablity and pedigree structure to MAS in beef production are that genetic progress may design beneficial crosses, select genetically improved increase by about 11% under specific circumstances stocks, minimise inbreeding and increase selection re- (Gomez-Raya and Klemensdal, 1999). Estimates of sponse (Davis and DeNise, 1998; Knibb, 2000). benefits to aquaculture breeding are yet undefined. Large-scale DNA marker-based approaches derived Microsatellite markers are useful in early stages of from population and conservation genetics will greatly MAS for the primary selection of parents for further assist the management of wild fish stocks, such as trout crossing and subsequent genetic characterization of and salmon. As advanced genomic resources become progeny. For this, SSRs linked to the target QTL more and more available in model and economically would be used. Further improvements, such as enrich- important organisms, the possibility of applying them ment of linkage maps with type I markers, construction in related nonmodel species increases. For example, of high-resolution linkage maps, development of phys- mapping studies in red deer have benefited from ical maps and their integration with linkage maps, fine resources created for cattle (Slate et al., 2002). Genetic QTL mapping using the candidate gene approach, will and genomic information from rainbow trout and

Fig. 3. Results of STRUCTURE clustering and assignment analysis (Pritchard et al., 2000). Bar plot of individual assignment scores for eight populations of four morphologically defined eel species (represented by four colours). Each bar represents a single eel. Green: European eel Anguilla anguilla; yellow: American eel A. rostrata; blue: Japanese eel A. japonica; red: giant mottled eel A. marmorata. A colour different from the baseline may point to introgression (e.g., between A. anguilla and A. rostrata) (courtesy of G. Maes). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) D.A. Chistiakov et al. / Aquaculture 255 (2006) 1–29 21

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