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R658 Dispatch Sequence variation: Looking for effects of genetic linkage Deborah Charlesworth and Brian Charlesworth Selection at linked loci probably reduces the variability of genes in regions of infrequent recombination. Detailed sequence information is needed to test possible causes of this effect; such information is now becoming available, but its interpretation can be difficult. Address: Institute of Cell, Animal and Population Biology, University of Edinburgh, Ashworth Laboratory King’s Buildings, West Mains Road, Edinburgh EH9 3JT, UK. Current Biology 1998, 8:R658–R661 http://biomednet.com/elecref/09609822008R0658 © Current Biology Ltd ISSN 0960-9822 There is growing interest in DNA sequence variation within and between populations of the same species. Such data can give information about the action of natural selection on DNA and protein sequences, revealed as deviations from the patterns expected if the variation is selectively neutral [1]. It is increasingly clear, however, that loci cannot be treated in isolation from each other, but that selection at linked sites can significantly affect the level and structuring of the neutral variability at a given locus [2]. In Drosophila, a gene’s level of within-population variability is closely related to the frequency of recombination per nucleotide site in its neighbourhood, with genes in regions with greatly reduced rates of meiotic crossingover having lower genetic variation than those in regions with normal crossing-over rates [3]. Between-species divergence shows no such relationship, excluding the possibility of a direct causal relationship between recombination and variation [3]. Selection exerted on linked loci therefore probably causes the reduced variation. These observations were initially interpreted as evidence for adaptive evolution: as a favourable mutation sweeps through a population, linked neutral variants will ‘hitchhike’ along to high frequency, reducing the variability at linked loci [2,4] (Figure 1). It was subsequently realized, however, that linkage of neutral variants to deleterious alleles, which constantly arise through mutation, can reduce variability, a process often called ‘background selection’ [2,5] (Figure 1). Temporal fluctuations in the direction of selection on segregating alleles may also reduce variation at linked sites [6]. Selective sweeps and Figure 1 Initial population Neutral locus genotype Selected locus genotype A1 b A2 b A3 B Population after selective sweep Population undergoing deleterious mutation and background selection A3 B A1 b A1 B A2 b Current Biology Selective sweeps and background selection in a population of chromosomes. The upper part of the figure shows a genetically diverse population. A new advantageous allele, B, becomes increasingly frequent, and the frequency of the neutral allele A3 increases concomitantly by ‘hitch-hiking’. Eventually, the original allele b is eliminated, and the population is then less variable at the neutral locus (A), though recombination during the period when B is spreading will mean that chromosomes carrying B acquire some diversity of A alleles (lower left). If, on the other hand, B is a deleterious allele that is present in the population due to mutation, its elimination by natural selection also eliminates the neutral A3 allele. Unless recombination is frequent in the chromosomal region near locus A, so that the genotype A3 b is quickly produced, diversity at the neutral locus is therefore reduced as the number of segregating alleles at the A locus has been reduced by the removal of A3 (lower right). Many loci throughout the genome are constantly mutating to deleterious alleles, whose removal by selection in this way will reduce neutral variation at linked sites (background selection). Dispatch R659 Table 1 Diversity values for plant species of known breeding systems. Effect of local recombination rates in five closely related Aegilops species (from [7]). Gene diversity Mean Distal loci* Proximal loci† Breeding system Species Cross-fertilising Ae. speltoides 0.72 0.80 0.60 Some cross-fertilisation (heterozygotes common) Ae. sharonensis Ae. longissima 0.49 0.39 0.60 0.58 0.23 0.13 Self-fertilising (no heterozygotes) Ae. bicornis Ae. searsii 0.27 0.14 0.37 0.24 0.13 0.01 Effect of self-fertilisation rates on adh DNA sequence diversity. Diversity per base (π × 103)‡ Breeding system Species Cross-fertilising Zea mays Leavenworthia stylosa Penniserum glaucum Self-fertilising Arabidopsis thaliana Hordeum vulgare Intron sites Silent coding sequence sites Source of data 20.9 55.2 2.43 49.3 30.7 6.66 [15] [11] [15] 9.58 2.29 25.9 4.73 [15] [15] *Normal recombination rate; coefficient of exchange ≥ 0.5. †Suppressed recombination; coefficient of exchange ≤ 0.5. ‡π is the fraction of nucleotides that differ between a pair of randomly sampled alleles. background selection can both explain the quantitative relation between variability and recombination rates in Drosophila [2]; it is not known whether this is true for the fluctuating fitness model. These considerations raise two questions: Are such patterns general? And how can we test between different possible explanations of the patterns? Surveys of DNA sequence variation are rapidly being extended beyond Drosophila. Tests for the effect of local recombination rates on diversity require genetic and physical maps of the chromosomes, so that regions where recombination is infrequent can be compared with regions where it is common. Suppressed recombination in centromeric regions occurs over a wide taxonomic range; it has, for example, long been to occur known in plants, including the grass species maize and wheat [7] and tomato species [8]. The intensive research presently being carried out on genetic markers, primarily aimed at constructing detailed genetic maps, is generating information that, as a spin-off, is providing opportunities to compare related species and to test for effects of recombination on diversity. A recent study [7] has compared DNA sequence variation of genes in different locations in the genome of Aegilops species — grasses closely related to wheat — that were either available as multiple accessions of independent genotypes in germplasm collections or collected from wild populations. In these species, centromeric suppression is dramatic: recombination is almost entirely restricted to the distal third of the chromosomes. Gene diversities were estimated using restriction fragment length polymorphisms (RFLPs), the genetic map locations of which were estimated; fifty-one loci were selected so as to minimise the danger of treating bands from different loci as allelic variants. Errors would presumably obscure any systematic patterns in diversity. High average diversity was found, especially in the outbreeding species Ae. speltoides, which had more than fivefold higher diversity than the most inbred species (Table 1). In all species except Ae. speltoides, diversity estimates for the loci correlated significantly with a measure of the local recombination rate, the coefficient of exchange. Proximal loci, in regions of suppressed recombination, had lower diversity than distal loci in all species. Low recombination also correlates with low diversity in Lycopersicon species (W. Stephan, personal communication) and in mice [9]. All the models outlined above predict that organisms with low genome-wide levels of recombination should show particularly low levels of within-population genetic diversity, as neutral variants in genes will experience the effects of selection at loci throughout the genome [5]. Highly self-fertilising species provide opportunities to test this prediction, as they have little or no effective genetic R660 Current Biology, Vol 8 No 18 recombination. In both the RFLP studies of Aegilops [7] and Lycopersicon [10] species, and sequencing studies of Leavenworthia species [11], comparisons of closely related taxa found that inbreeding is indeed associated with greatly lowered diversity. The pattern seen in Drosophila thus does appear to be general, extending both to genomic regions with low recombination rates in other species, and to inbred plants. The second question above — how to distinguish different possible explanations for this pattern — is harder. One approach is to compare observed differences in levels of variation between taxa with different breeding systems with theoretical predictions. A high level of selffertilisation is expected to reduce the effective population size by a factor of two, compared with a random mating population of the same absolute size, in the absence of other forces [5]. Further reductions are expected from selective sweeps or background selection. If great reductions in variability were found not to be consistently associated with inbreeding, background selection and selective sweeps could be ruled out as important factors. More discriminating tests examine patterns of variation at individual loci that may have been affected by selective sweeps or background selection. Selective sweeps affect the frequency distribution of variants in a sample of alleles from a population. As diversity recovers by mutation after a recent selective sweep, there will for a long time be an excess of low-frequency variants compared with the equilibrium expectation under neutrality; statistical tests can detect this distortion in frequencies [12,13]. Although background selection and fluctuating selection alter the frequencies in a similar manner, their effects are slight and unlikely to be detectable by these tests [6,14]. This kind of test cannot be applied in the case of Aegilops, because RFLP data do not give the required resolution. As variability is very low at the loci in question, it will often require considerable effort to obtain sufficient sequence data to have the needed variants; the limited data that are available tend to suggest, however, that distorted patterns of variation are uncommon [13,14]. A recent analysis of sequences of the alcohol dehydrogenase (adh) gene in the inbreeding plant species Hordeum vulgare var. spontaneum has revealed enough diversity for the tests to be informative [15]. Overall, adh diversity appears low in H. vulgare, even though the 23 alleles sequenced came from throughout the species’ range and thus estimate the diversity in the species as a whole. The variable sites were divided into two classes: (i) ‘synonymous’ changes in the coding region (nucleotide changes that fail to alter the protein sequence) and changes in introns; and (ii) ‘nonsynonymous’ changes in the coding region, which result in variant protein sequences. Class (i) changes are likely to be under no, or very weak, selective constraints [1], and hence the frequency distribution of these variants should not depart from neutral expectation in the absence of disturbances such as selective sweeps. In contrast, departures from neutrality for class (ii) variants could be produced by selection acting on the amino-acid changes themselves [1]. Statistical tests for departures from neutrality for the adh sequence were non-significant for class (i) variants, but significant for class (ii) variants. This suggests that the low diversity at the adh locus is unlikely to have been caused by selective sweeps [12,13], but could be due to background selection or fluctuating selection [6,14]. The departures from neutrality for class (ii) variants are likely to be due to selection against amino-acid replacements, as the frequencies of these are lower than expected under neutrality. An apparent inconsistency with background selection having a strong effect emerges when different species are compared, as there is no clear relationship between adh diversity and inbreeding [15]. Diversity is certainly lower in H. vulgare than in the outcrossing grass Zea mays or the self-incompatible Leavenworthia stylosa [11], and lower than in the highly inbreeding Arabidopsis thaliana — in which high diversity in a part of the adh locus may be maintained by some form of balancing selection — but cultivated and wild strains of the outbreeding grass Penniserum glaucum have very low diversity, lower even than in A. thaliana (Table 1). There is, of course, no guarantee that the only difference affecting diversity in the species included in such a comparison will be their breeding system. It is possible that adh lies in a low recombination region in P. glaucum. Isozyme diversity is not generally low for this species [15], so it is unlikely that an event such as a bottleneck in population size has caused reduced diversity throughout its genome. Before any general conclusion can be reached, surveys of other loci and further species are needed. These should help show whether a clear relationship between inbreeding and low diversity really exists and, if so, whether low diversity is accompanied by distorted allele frequencies. References 1. Kreitman M, Akashi H: Molecular evidence for natural selection. Annu Rev Ecol Syst 1995, 26:403-422. 2. Charlesworth B, Guttman DS: Reductions in genetic variation in Drosophila and Escherichia coli caused by selection at linked sites. J Genet 1996, 75:49-61. 3. Aquadro CF, Begun DJ, Kindahl EC: Selection, recombination, and DNA polymorphism in Drosophila. In Non-neutral Evolution: Theories and Molecular Data. Edited by Golding B. London: Chapman and Hall; 1994:46-56. 4. Maynard Smith J, Haigh J: The hitch-hiking effect of a favourable gene. Genet Res Camb 1974, 23:23-35. 5. Charlesworth B, Morgan MT, Charlesworth D: The effect of deleterious mutations on neutral molecular variation. Genetics 1993, 134:1289-1303. 6. Gillespie JH: Alternatives to the neutral theory. In Non-neutral Evolution: Theories and Molecular Data. Edited by Golding B. London: Chapman and Hall; 1994:1-17. Dispatch 7. Dvorak J, Luo MC, Yang ZL: Restriction fragment length polymorphism and divergence in the genomic regions of high and low recombination in self-fertilizing and cross-fertilizing Aegilops species. Genetics 1998, 148:423-434. 8. Sherman JD, Stack SM: Two-dimensional spreads of synaptonemal complexes from solanaceous plants. VI. Highresolution recombination map for tomato (Lycopersicon esculentum). Genetics 1995, 141:683-708. 9. Nachman NW: Patterns of DNA variability at X-linked loci in Mus domesticus. Genetics 1997, 147:1303-1316. 10. Miller JC, Tanksley SD: RFLP analysis of phylogenetic relationships and genetic variation in the genus Lycopersicon. Theoret Appl Genet 1990, 80:437-448. 11. Liu F, Zhang L, Charlesworth D: Genetic diversity in Leavenworthia populations with different inbreeding levels. Proc R Soc Lond [B] 1998, 265:293-301. 12. Simonsen KL, Churchill GA, Aquadro CF: Properties of statistical tests of neutrality for DNA polymorphism data. Genetics 1995, 141:413-429. 13. Braverman JM, Hudson RN, Kaplan NL, Langley CH, Stephan W: The hitchhiking effect on the site frequency spectrum of DNA polymorphisms. Genetics 1995, 140:783-796. 14. Charlesworth D, Charlesworth B, Morgan MT: The pattern of neutral molecular variation under the background selection model. Genetics 1995, 141:1619-1632. 15. Cummings MP, Clegg MT: Nucleotide sequence diversity at the alcohol dehydrogenase 1 locus in wild barley (Hordeum vulgare ssp. spontaneum): an evaluation of the background selection hypothesis. Proc Natl Acad Sci USA 1998, 95:5637-5642. If you found this dispatch interesting, you might also want to read the June 1998 issue of Current Opinion in Genetics & Development which included the following reviews, edited by Huntington F Willard and Kay E Davies, on Genetics of disease: Haemochromatosis: an inherited metal and toxicity syndrome Timothy M Cox and Alison L Kelly The genetics of alcoholism Alison M Goate and Howard J Edenberg Mapping genes for psychiatric disorders and behavioral traits L Alison McInnes, Victor I Reus and Nelson B Freimer Animal models for dysmorphology Robin M Winter The genetics of hereditary common cancers Albert de la Chapelle and Päivi Peltomäki Tumor suppressor mutations in mice: the next generation Andrea I McClatchey and Tyler Jacks Genomic strategies for defining and dissecting developmental and physiological pathways Joseph H Nadeau and Patrick J Dunn Down syndrome and mouse models Ismail Kola and Paul J Hertzog Turner syndrome and haploinsufficiency Andrew R Zinn and Judith L Ross The role of Xist in X-inactivation Neil Brockdorff Imprinting in Angelman and Prader–Willi syndrome Yong-hui Jiang, Ting-Fen Tsai, Jan Bressier and Arthur L Beaudet Mobile elements and disease Haig H Kazazian Jr Mammalian artificial chromosomes as tools for gene therapy Jean-Michel H Vos Recent advances in skeletal-muscle-based gene therapy Deborah J Marshall and Jeffrey M Leiden Fetal gene reactivation Richard A Swank and George Stamatoyannopoulos The full text of Current Opinion in Genetics & Development is in the BioMedNet library at http://BioMedNet.com/cbiology/gen R661