Non-overlapping Inversions Research Articles

Mitotic exchange in female germline stem cells is the major source of Sex Ratio chromosome recombination in Drosophila pseudoobscura.

Sex Ratio chromosomes in Drosophila pseudoobscura are selfish X chromosome variants associated with 3 nonoverlapping inversions. In the male germline, Sex Ratio chromosomes distort the segregation of X and Y chromosomes (99:1), thereby skewing progeny sex ratio. In the female germline, segregation of Sex Ratio chromosomes is mendelian (50:50), but nonoverlapping inversions strongly suppress recombination establishing a 26-Mb haplotype (constituting ∼20% of the haploid genome). Rare crossover events located between nonoverlapping inversions can disrupt this haplotype, and recombinants have sometimes been found in natural populations. We recently reported on the first lab-generated Sex Ratio recombinants occurring at a rate of 0.0012 crossovers per female meiosis. An improved experimental design presented here reveals that these recombination events were at least 4 times more frequent than previously estimated. Furthermore, recombination events were strongly clustered, indicating that the majority arose from mitotic exchange in female germline stem cells and not from meiotic crossing-over in primary oocytes. Finally, asymmetric recovery of complementary recombinants was consistent with unequal exchange causing the recombination-induced viability defects. Incorporating these experimental results into population models for Sex Ratio chromosome evolution provided a substantially better fit to natural population frequencies and allowed maintenance of the highly differentiated 26-Mb Sex Ratio haplotype without invoking strong epistatic selection. This study provides the first estimate of spontaneous mitotic exchange for naturally occurring chromosomes in Drosophila female germline stem cells, reveals a much higher Sex Ratio chromosome recombination rate, and develops a mathematical model that accurately predicts the rarity of recombinant Sex Ratio chromosomes in natural populations.

Extensive Recombination Suppression and Epistatic Selection Causes Chromosome-Wide Differentiation of a Selfish Sex Chromosome in Drosophila pseudoobscura.

Sex-Ratio (SR) chromosomes are selfish X-chromosomes that distort Mendelian segregation and are commonly associated with inversions. These chromosomal rearrangements suppress recombination with Standard (ST) X-chromosomes and are hypothesized to maintain multiple alleles important for distortion in a single large haplotype. Here, we conduct a multifaceted study of the multiply inverted Drosophila pseudoobscura SR chromosome to understand the evolutionary history, genetic architecture, and present-day dynamics that shape this enigmatic selfish chromosome. The D.pseudoobscura SR chromosome has three nonoverlapping inversions of the right arm of the metacentric X-chromosome: basal, medial, and terminal. We find that 23 of 29Mb of the D.pseudoobscuraX-chromosome right arm is highly differentiated between the Standard and SR arrangements, including a 6.6Mb collinear region between the medial and terminal inversions. Although crossing-over is heavily suppressed on this chromosome arm, we discover it is not completely eliminated, with measured rates indicating recombination suppression alone cannot explain patterns of differentiation or the near-perfect association of the three SR chromosome inversions in nature. We then demonstrate the ancient basal and medial inversions of the SR chromosome contain genes sufficient to cause weak distortion. In contrast, the younger terminal inversion cannot distort by itself, but contains at least one modifier gene necessary for full manifestation of strong sex chromosome distortion. By parameterizing population genetic models for chromosome-wide linkage disequilibrium with our experimental results, we infer that strong selection acts to maintain the near-perfect association of SR chromosome inversions in present-day populations. Based on comparative genomic analyses, direct recombination experiments, segregation distortion assays, and population genetic modeling, we conclude the combined action of suppressed recombination and strong, ongoing, epistatic selection shape the D.pseudoobscura SR arrangement into a highly differentiated chromosome.

Computing Nonoverlapping Inversion Distance Between Two Strings in Linear Average Time.

Biological events like inversions are not automatically detected by the usual alignment algorithms. Alignment with inversions does not have a known polynomial time algorithm and Schöniger and Waterman introduced a simplification of the alignment problem with nonoverlapping inversions, where all regions will not be allowed to overlap. They presented an \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\usepackage{upgreek}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} $${ \cal O} ( {n^6} )$$ \end{document} algorithm to compute nonoverlapping inversion distance between two strings of length n. The time and space complexities were improved to \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\usepackage{upgreek}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} $${ \cal O} ( {n^3} )$$ \end{document} and \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\usepackage{upgreek}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} $${ \cal O} ( {n^2} )$$ \end{document} later by Cho, Vellozo, and Ta. In this article, a linear space and linear average time algorithm to compute the inversion distance between two strings of the same length is presented. The recursive formula for this purpose is new to the best of our knowledge. The space costs of the algorithms to solve the same problem are quadratic in the literature, and thus our original algorithm is the first linear space and linear average time algorithm to solve the inversion distance problem.

A Simple Linear Space Algorithm for Computing Nonoverlapping Inversion and Transposition Distance in Quadratic Average Time.

In the sequence alignment problem, it is important to compare DNA sequences to retrieve relevant information and align these sequences. An inversion and a translocation are important operations in comparing DNA sequences in biosequence analysis. The alignment problem with nonoverlapping inversions and translocations is to find an alignment with nonoverlapping inversions and translocations for the given two strings X and Y. This problem has interesting application for finding a common sequence from two mutated sequences. A linear space and quadratic average time algorithm to compute the mutation distance between two strings of the same length under nonoverlapping inversions and transpositions is presented in this article. The recursive formula for this purpose is novel to the best of our knowledge. The space costs of the algorithms to solve the same problem are typically quadratic, and thus, our original algorithm is the first linear space algorithm to solve the mutation distance problem.

Non-overlapping inversion on strings and languages

Given a string, a non-overlapping inversion is to reverse some non-overlapping fragments of the string simultaneously. We define a non-overlapping inversion operation to be the computation of all possible non-overlapping inversions. We apply the operation on a string, which gives rise to a set of strings, and construct an NFA recognizing the set. Then, we design an efficient DFA reduction algorithm from the resulting NFA. We also consider the non-overlapping inversion operation on a language and show the closure properties for regular, context-free and context-sensitive languages. We furthermore examine iterative non-overlapping inversions and establish the closure properties. Finally, we introduce non-overlapping inversion-free languages and present the decidability results for regular and context-free languages.

Alignment with non-overlapping inversions and translocations on two strings

An inversion and a translocation are important in bio sequence analysis and motivate researchers to consider the sequence alignment problem using these operations. Based on inversion and translocation, we introduce a new alignment problem with non-overlapping inversions and translocations—given two strings x and y, find an alignment with non-overlapping inversions and translocations for x and y. This problem has interesting application for finding a common sequence from two mutated sequences. We, in particular, consider the alignment problem when non-overlapping inversions and translocations are allowed for both x and y. We design an efficient algorithm that determines the existence of such an alignment and retrieves an alignment, if exists.

Efficient string-matching allowing for non-overlapping inversions

Inversions are a class of chromosomal mutations, widely regarded as one of the major mechanisms for reorganizing the genome.In this paper we present a new algorithm for the approximate string matching problem allowing for non-overlapping inversions which runs in O(nm) worst-case time and O(m2) space, for a character sequence of size n and pattern of size m. This improves upon a previous O(nm2)-time algorithm.In addition we present a variant of our algorithm with the same complexity in the worst case, but with a O(n) time complexity in the average case.

Alignments with non-overlapping moves, inversions and tandem duplications in O(n 4) time

Sequence alignment is a central problem in bioinformatics. The classical dynamic programming algorithm aligns two sequences by optimizing over possible insertions, deletions and substitutions. However, other evolutionary events can be observed, such as inversions, tandem duplications or moves (transpositions). It has been established that the extension of the problem to move operations is NP-complete. Previous work has shown that an extension restricted to non-overlapping inversions can be solved in O(n 3) with a restricted scoring scheme. In this paper, we show that the alignment problem extended to non-overlapping moves can be solved in O(n 5) for general scoring schemes, O(n 4log n) for concave scoring schemes and O(n 4) for restricted scoring schemes. Furthermore, we show that the alignment problem extended to non-overlapping moves, inversions and tandem duplications can be solved with the same time complexities. Finally, an example of an alignment with non-overlapping moves is provided.

Alignment with non-overlapping inversions in -time

Alignment with non-overlapping inversions in -time

A sparse dynamic programming algorithm for alignment with non-overlapping inversions

Alignment of sequences is widely used for biological sequence comparisons, and only biological events like mutations, insertions and deletions are considered. Other biological events like inversions are not automatically detected by the usual alignment algorithms, thus some alternative approaches have been tried in order to include inversions or other kind of rearrangements. Despite many important results in the last decade, the complexity of the problem of alignment with inversions is still unknown. In 1992, | | || || | | | | | || ||****|

Molecular population genetics of X-linked genes in Drosophila pseudoobscura.

This article presents a nucleotide sequence analysis of 500 bp determined in each of five X-linked genes, runt, sisterlessA, period, esterase 5, and Heat-shock protein 83, in 40 Drosophila pseudoobscura strains collected from two populations. Estimates of the neutral migration parameter for the five loci show that gene flow among D. pseudoobscura populations is sufficient to homogenize inversion frequencies across the range of the species. Nucleotide diversity at each locus fails to reject a neutral model of molecular evolution. The sample of 40 chromosomes included six Sex-ratio inversions, a series of three nonoverlapping inversions that are associated with a strong meiotic drive phenotype. The selection driven by the Sex-ratio meiotic drive element has not fixed variation across the X chromosome of D. pseudoobscura because, while significant linkage disequilibrium was observed within the sisterlessA, period, and esterase 5 genes, we did not find evidence for nonrandom association among loci. The Sex-ratio chromosome was estimated to be 25,000 years old based on the decomposition of linkage disequilibrium between esterase 5 and Heat-shock protein 83 or 1 million years old based on the net divergence of esterase 5 between Standard and Sex-ratio chromosomes. Genetic diversity was depressed within esterase 5 within Sex-ratio chromosomes, while the four other genes failed to show a reduction in heterozygosity in the Sex-ratio background. The reduced heterogeneity in esterase 5 is due either to its location near one of the Sex-ratio inversion breakpoints or that it is closely linked to a gene or genes responsible for the Sex-ratio meiotic drive system.

Genetic mapping of 10 microsatellites in the t complex region of mouse chromosome 17.

A complete t haplotype consists of four large non-overlapping inversions of mouse Chromosome (Chr) 17 with respect to the wild-type homolog and is naturally occurring in wild mouse populations by recombination suppression and transmission ratio distortion (Silver et al. 1992). This t complex includes the major histocompatibility complex (H2), the loci of Brachyury (T) and tufted (tf), as well as several lethal mutations like tclw5 and tcl12 (Hamvas et al. 1997). The tclw5 mutation is an early acting embryonic lethal, recombinationally inseparable from H2-K (Shin et al. 1984). In an attempt to positionally clone tclw5, contigs of cosmids have been made, 18 genes have been identified, and a detailed description of the region is now available (Abe et al. 1988; Yeom et al. 1992; Lai et al. 1994). Unfortunately, the restricted polymorphism of probes and the size of the region to explore have made the approach particularly tedious. When the first microsatellites (Mits) became available (Dietrich et al. 1994), they proved to be extremely useful for our linkage analysis project: we refined the mapping of 12 Mits, using our panel of 140 t/t recombinants and narrowed down the genetic region containing tclw5 (Vernet and Artzt 1995). In the present report, using the same panel, we have refined the location of 10 new satellites from the second release of microsatellites and define now a new genetic limit to tclw5. Mit primer pairs for the polymerase chain reaction (PCR) were purchased from Research Genetics (Huntsville, Ala.); isolated DNA from recombinant mice was amplified under conditions described by Dietrich and co-workers (1994). Amplified bands were resolved on 6% denaturating polyacrylamide electrophoresis gels. Figure 1 shows a summary of the Mit map and the number of recombinants between each locus. The t recombinant crosses were able to separate several markers that previously were considered to be in the same bin. Additionally, D17Mit147 is the new telomeric limit for the region where tclw5 is located.

Heterosis and the lack of coadaptation in Drosophila nasuta

Natural populations of Drosophila nasuta are polymorphic for several paracentric inversions. Two non-overlapping inversions on the third chromosome (III-2 and III-35) are heterotic in both laboratory and natural populations and display an extreme case of linkage disequilibrium. Intra- and interpopulation crosses involving standard and inverted gene orders of the III-2 and III-35 inversions were made to test if the polygenic complexes within these inversions are coadapted. The inversion heterozygotes formed by the two chromosomes derived from different localities exhibited heterosis since the viability of the heterozygotes was greater than that of either of the two homozygotes. In intrapopulation crosses, the heterozygotes were also heterotic. The present results thus indicated a lack of coadaptation among polygenic complexes within the inversions of D. nasuta. The data suggest that the heterosis produced by these linked inversions is the result of natural selection and epistasis.

Inversion Polymorphism in Drosophila obscura

The inversion polymorphism of Drosophila obscura Fallen, a European species of the obscura group of the subgenus Sophophora, is described. A total of 21 inversions have been recorded; they are located in the five large chromosomes of the species (a dot chromosome is also present) and form 25 gene arrangements present in the species' natural populations. Strains from five different countries were studied. Two of these inversions were found to be pericentric, and the remaining were paracentric. The presence of "hot" points (multibreaks) was noticed. The distribution of the relative lengths of inversions conformed to the Van Valen-Levins distribution, contrary to what happens in D. subobscura. Observations also showed that there is no crossover inhibition between nonoverlapping inversions. The phylogeny of chromosome C was reconstructed; the existence of several arrangements not found was postulated; and the primitive gene arrangement, linking D. obscura to its closely related species was identified, as well as the primitive gene arrangements of the other chromosomes. Photographic maps of the chromosomes of D. obscura are provided here.

Genetic and molecular analysis of the proximal region of the mouse t-complex using new molecular probes and partial t-haplotypes.

The t-complex is located on the proximal third of chromosome 17 in the house mouse. Naturally occurring variant forms of the t-complex, known as complete t-haplotypes, are found in wild mouse populations. The t-haplotypes contain at least four nonoverlapping inversions that suppress recombination with the wild-type chromosome, and lock into strong linkage disequilibrium loci affecting normal transmission of the chromosome, male gametogenesis and embryonic development. Partial t-haplotypes derived through rare recombination between t-haplotypes and wild-type homologs have been critical in the analysis of these properties. Utilizing two new DNA probes. Au3 and Au9, and several previously described probes, we have analyzed the genetic structure of several partial t-haplotypes that have arisen in our laboratory, as well as several wild-type chromosomes deleted for loci in this region. With this approach we have been able to further our understanding of the structural and dynamic characteristics of the proximal region of the t-complex. Specifically, we have localized the D17Tul locus as most proximal known in t-haplotypes, achieved a better structural analysis of the partial t-haplotype t6, and defined the structure and lethal gene content of partial t-haplotypes derived from the lethal tw73 haplotype.

Molecular characterization of four intra-t mouse recombinants

Recombination in the proximal region of mouse chromosome 17 is greatly reduced in heterozygotes carrying the wild-type and the t complex-type chromosomes. The reason for this is the presence of two non-overlapping inversions in the t complex. Rare crossing-over does, however, occur within the t complex of the t/+ heterozygotes. Here we characterize four such exceptional intra-t recombinants, tTu1 through tTu4. To map the positions of the genetic exchange in these four recombinants, we analyzed them with DNA probes specific for 16 loci distributed over the t complex. The analysis revealed that in three of the four recombinants, an equal crossing-over occurred in the short region between the two inversions, producing chromosomes carrying either the proximal inversion only (tTu1 and tTu4) or the distal inversion only (tTu2). In the fourth recombinant (tTu3), unequal crossing-over occurred within the proximal inversion between loci D17Leh119 and D17Leh66, producing a chromosome in which the region containing loci Tcp-1, T, and D17Tu5 has been duplicated. The duplication of the Brachyury locus leads to the suppression of the tail-shortening effect normally produced by the interaction of the dominant (T) and recessive (tct) alleles at this locus so that the T/tTu3 mice have normal tails.

Evolution of mouse chromosome 17 and the origin of inversions associated with t haplotypes.

Mouse t haplotypes are variant forms of chromosome 17 that exist at high frequencies in worldwide populations of several species of house mouse. They are known to differ from wild-type chromosomes with respect to two relative inversions referred to as proximal and distal. An untested assumption has been that these two inversions originated in the chromosomal lineage leading to present-day t haplotypes. To investigate the evolutionary origins of these inversions and the possibility of additional inversions, interspecific crosses were performed between Mus spretus or Mus abbotti and laboratory strains of Mus domesticus that carried wild-type and t haplotypes forms of chromosome 17. The results provide evidence for the existence of two additional nonoverlapping inversions--one between the proximal and distal inversions and one between the centromere and the proximal inversion. These four inversions span nearly the entire region of t haplotype recombination suppression. Considering the distribution of these inversions among the species studied as well as the organization of the D17Leh66 family of DNA elements, we infer that the proximal inversion occurred on the lineage leading to the common ancestor of M. domesticus and M. abbotti, and that the other three inversions occurred on the separate lineage leading to present-day t haplotypes. Alternative models for the evolution of t haplotypes are discussed in light of these findings.

Linkage disequilibrium in laboratory populations of Drosophila nasuta

Natural populations of Drosophila nasuta are polymorphic for many gene arrangements. Two non-overlapping inversions of the third chromosome, III-2 and III-35, are most common and display extreme linkage disequilibrium. Six randomly mating laboratory stocks, each founded by one gravid female heterozygous in coupling for both III-2 and III-35, were observed after 32 generations. Significant linkage disequilibrium was observed in all stocks. Recombinants were found in only two stocks. The absence of effective recombination in some stocks and its presence in others might be due to different genotypic backgrounds. We suggest that natural selection, influencing recombination rates in several ways, and intrachromosomal epistasis between the two inversions were the main factors for the maintenance of linkage disequilibrium in D. nasuta.

"SEX-RATIO" TRAIT, SEX COMPOSITION, AND RELATIVE ABUNDANCE IN DROSOPHILA PSEUDOOBSCURA.

A considerable number of theoretical and laboratory studies of segregation distortion systems have provided insight into their biological consequences (see Zimmering et al. [1970], or Crow [1979] for a review). Yet these studies have provided few clues into the behavior of such systems in natural populations. Sex-ratio trait (SR) is particularly interesting, not only as a naturally occurring segregation distortion system, but also for its effects on the proportion of females in the offspring of SR males and the consequent effects on the sex composition of the population and on population growth. The trait in Drosophila pseudoobscura is associated with three non-overlapping inversions of the X-chromosome. Males carrying SR produce progenies consisting almost entirely of females. The presence of SR in a female, whether heterozygous or homozygous, has no effect on the sex composition of her progeny. The system is a widely occurring polymorphism in natural populations of D. pseudoobscura, reaching gene frequencies as high as 0.3 near the boundary of Arizona and Mexico. Its frequency declines both with increasing altitude and latitude, and it disappears at about the latitude of northern California (Sturtevant and Dobzhansky, 1936). The frequency of SR exhibits wide seasonal fluctuations in some localities (Dobzhansky, 1943), but aside from this seasonal cycle, it was found to be stable over a period of 20 years (Dobzhansky, 1958). Although SR is apparently held in equilibrium in many natural populations, in population cages it rapidly declines in frequency (Wallace, 1948; Anderson, 1974). In Wallace's experimental populations, SR was rapidly eliminated from the 25 C cages and dropped below a frequency of 0.1 in the cages maintained at 16.5 C. These results appear to conflict with the observations on natural populations: SR is present at higher temperatures (low altitudes and latitudes) and absent in regions characterized by lower temperatures. In this study, we analyze the relationships among temperature, the frequency of the SR trait, the frequency of females, and the frequency of Drosophila pseudoobscura in a mixed species Drosophila population studied for several years in Southern California.

Crossing-over in Drosophila willistoni.

IN the course of analysing the frequency of chromosomal inversions in 292 adult females of Drosophila willistoni, we have recorded for the first time evidence of crossing-over between two non-overlapping inversions in the same chromosome arm of this species. These findings are of some general interest since, as Dobzhansky and Epling1 have said: “The biological function of inversions in natural populations of Drosophila and their principal role in the evolution of these insects might be conceived to be the suppression of crossing over between gene complexes which have reached an adaptive equilibrium. Crossing over would destroy these complexes and would result in gene combinations of different adaptive values, but would be prevented by the binding effect of the inversions”.