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947.Full.Pdf (:opyright 0 1986 by the Genetics Society of America THE EVOLUTION OF RESTRICTED RECOMBINATION AND THE ACCUMULATION OF REPEATED DNA SEQUENCES BRIAN CHARLESWORTH,' CHARLES H. LANGLEY* AND WOLFGANG STEPHAN' School of Biological Sciences, University of Sussex, Brighton BNI 9QG, England Manuscript received April 9, 1985 Revised copy accepted December 13, 1985 ABSTRACT We suggest hypotheses to account for two major features of chromosomal organization in higher eukaryotes. The first of these is the general restriction of crossing over in the neighborhood of centromeres and telomeres. We propose that this is a consequence of selection for reduced rates of unequal exchange between repeated DNA sequences for which the copy number is subject to stabilizing selection: microtubule binding sites, in the case of centromeres, and the short repeated sequences needed for terminal replication of a linear DNA molecule, in the case of telomeres. An association between proximal crossing over and nondisjunction would also favor the restriction of crossing over near the centromere. The second feature is the association between highly repeated DNA sequences of no obvious functional significance and regions of restricted crossing over. We show that highly repeated sequences are likely to persist longest (over evolutionary time) when crossing over is infrequent. This is because unequal exchange among repeated sequences generates single copy sequences, and a population that becomes fixed for a single copy sequence by drift remains in this state indefinitely (in the absence of gene amplification processes). In- creased rates of exchange thus speed up the process of stochastic loss of repeated sequences. N this paper, we propose some evolutionary hypotheses to account for two I major features of the genetic and molecular evolution of the chromosomes of eukaryotes. The first such feature is the reduced frequency of genetic recombination in the neighborhood of centromeres and telomeres. A lowered probability of genetic exchange in meiosis in these regions has been most clearly documented in Drosophila melanogaster (LINDSLEYand SANDLER1977; YAMAMOTOand MIKLOS1978; SZAUTER1984), but a relative contraction of the genetic map near centromeres and/or telomeres is observable in several Present address: Department of Biology, The University of Chicago, I103 Fast 57th Street, Chicago, Illinois 60637. ' Present address: Laboratory of Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709. Present address: Physikalische Chemie 1, Technische Hochschule Darmstadt, 6100 Darmstadt, West Cer- many. (;enetics 112: 947-962 April, 1986. 948 B. CHARLESWORTH, C. H. LANGLEY AND W. STEPHAN other well-studied species, such as maize (NEUFFER and COE 1974), tomato (KHUSH and RICK 1968) and barley (RICK 1971). We suggest here that this reduction in crossover frequencies is the consequence of natural selection for a lower frequency of unequal exchange between repeated sequences of DNA of functional significance that are located in these chromosomal regions. This suggestion is based on a simple population genetics model, and we show that it is consistent with a range of facts about the cytogenetics and molecular organization of centromeres and telomeres. The other phenomenon that we shall discuss is the tendency for highly repeated DNA (HRDNA) sequences, of no apparent functional significance, to be concentrated in regions of restricted crossing over (JOHN and MIKLOS 1979; SIMSet al. 1984). Many inconclusive attempts (reviewed by JOHN and MIKLOS 1979) have been made to interpret this association. We shall show here that the rate of loss from a population of a family of HRDNA, due to natural selection and genetic drift, increases with the rate of unequal exchange be- tween members of the family. It follows that regions of restricted crossing over will tend to contain a higher-than-average abundance of HRDNA, if there is some long-term evolutionary steady state between the generation of new re- peated sequences by amplification processes (SCHIMKE1984) and the forces leading to loss. Similarly, HRDNA sequences that rarely undergo exchange will persist longest. RESTRICTED CROSSING OVER NEAR CENTROMERES AND TELOMERES Centromeres: We start with the observation that the structure of the cen- tromeres of eukaryotes with very small chromosomes, such as yeast, is appar- ently very simple (BLACKBURNand SZOSTAK1984). According to PETERSON and RIS (1976), the yeast centromere lacks an identifiable structure, such as kinetochore, and each chromosome is attached to a single microtubule. In contrast, the chromosomes of mammals and most other higher organisms pos- sess a highly differentiated kinetochore, through which many microtubules attach to a large stretch of specialized chromatin (RIS and WITT 1981; RIEDER 1982). It seems reasonable to suppose that this complex kinetochore may have a basic unit of organization similar to that of the yeast centromere. Recent genetic and molecular analyses of the yeast centromere and its associated chro- matin indicate that a specific DNA sequence is recognized by a protein, perhaps a microtubule-associated protein (BLOOM,FITZGERALD-HAYES and CARBON 1983; BLACKBURNand SZOSTAK1984; CARBON1984), which is presumably involved in attachment of the microtubule to the chromosome. Although very small chromosomes often do show differentiated kineto- chores, it is usually the case that chromosomes without differentiated kineto- chores are small (e.g., the chromosomes of Physarum, various yeasts, Neuro- spora and the microchromosomes of birds; see KUBAI 1975; PETERSONand RIS 1976; RIS and WITT 1981). It is likely that the disjunction of large chromo- somes requires a greater force than is necessary for small chromosomes; hence, more microtubules per chromosome are needed. The evolution of larger chro- RECOMBINATION AND REPEATED DNA 949 mosomes presumably led to the multitubule spindle fiber and to multiple cen- tromeric microtubule binding sites. Unequal exchange between these repeated sites would lead to variation in the number of binding sites per chromosome (KRUEGER and VOGEL 1975; PERELSONand BELL 1977; OHTA198 1; OHTA and KIMURA198 1; TAKAHATA 1981). Chromosomes with a number that deviates from the optimum may suffer an imbalance of spindle forces at disjunction, leading to nondisjunction events and aneuploidy, with a consequent reduction in fitness. Natural selection will therefore favor a reduction in crossing over in the centromeric region. In APPENDIX 1, we present an explicit model of this selection process and show that a population with zero recombination around the centromere is stable to invasion by mutants which cause recombination and associated unequal ex- change. If the kinetochore found at the centromere of most animal chromosomes is organized around an optimal number of microtubule binding sites, then it is not surprising from the above considerations that crossing over is restricted in these regions, as mentioned in the Introduction. The only optimum number of binding sites that would not favor the evolution of restricted recombination would be one. It is interesting to note that yeast has only one binding site and does not exhibit a centromeric reduction in crossing over comparable in mag- nitude to that of Drosophila (MORTIMERand SCHILD1980; CLARKEand CAR- BON 1980). There is a similar lack of evidence for a centromere effect in filamentous fungi, such as Neurospora and Aspergillus (FINCHAM,DAY and RADFORD1979), but the structure of the centromere is at present unknown in these species. Our hypothesis leads to the expectation of a single binding site. It should be noted that there is little or no HRDNA in Aspergillus (TIMBER- LAKE 1978). Telomeres: WALMSLEYet al. (1984) have proposed a model of the terminal replication of linear chromosomes that requires the existence of a terminal block of repetitive DNA sequences. There is now clear molecular evidence from yeast and Tetrahymena for the presence of such specialized telomeric repeated sequences (BLACKBURNand SZOSTAK1984). If there were an optimum number of repeats for efficient telomeric replication, the argument used above for centromeres applies, and reduced recombination in telomeric regions would be favored by natural selection. There is, however, evidence that the size of the block of telomeric sequences in yeast and Tetrahymena is under some degree of control by replicative mechanisms (BLACKBURNand SZOSTAK 1984; WALMSLEYand PETES 1985). This might reduce any effect of unequal exchange on the number of copies of the repeats, although WALMSLEYand PETES (1985) have demonstrated the existence of stable genetic variants of telomere length in yeast. Recombination can take place in the yeast telomere under some experimental circumstances (DUNNet al. 1984), so that any selec- tion for restricted crossing over has not been completely successful. Relative contraction of the genetic map near telomeres has been well doc- umented in Drosophila species (STURTEVANTand TAN1937; MATHER 1939; MORIWAKIand TOBARI1975; LINDSLEYand SANDLER1977). Evidence from 950 B. CHARLESWORTH, C. H. LANGLEY AND W. STEPHAN other species is less clear, although observations on grasshopper species have demonstrated an effect of telomeric chromatin in repressing chiasma formation in its neighborhood (MIKLOS and NANKIVELL1976; NAVAS-CASTILLO,CABRERO and CAMACHO1985). AMOUNT OF HRDNA IN RELATION TO RECOMBINATION RATE In this section, we shall develop some population genetics
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