Recombination between Small X Chromosome Duplications and the X Chromosome in Caenorhabditis Elegans

Twelve new X chromosome duplications were identified and characterized. Eight are translocated to autosomal sites near four different telomeres, and four are free. Ten include unc-1(+), which in wild type is near the left end of the X chromosome, and two of these, mnDp72(X;IV) and mnDp73(X;f), extend rightward past dpy-3. Both mnDp72 and mnDp73 recombined with the one X chromosome in males in the unc-1-dpy-3 interval at a frequency 15- to 30-fold higher than was observed for X-X recombination in hermaphrodites in the same interval. Recombinant duplications and recombinant X chromosomes were both recovered. Recombination with the X chromosome in the unc-1-dpy-3 interval was also detected for five other unc-1(+) duplications, even though their right breakpoints lie within the interval. In hermaphrodites, mnDp72 and mnDp73 promoted meiotic X nondisjunction and recombined with an X chromosome in the unc-1-dpy-3 interval at frequencies comparable to that found for X-X recombination; mnDp72(X;IV) also promoted trisomy for chromosome IV. A mutation in him-8 IV was identified that severely reduced recombination between the two X chromosomes in hermaphrodites and between mnDp73 and the X chromosome in males. Recombination between the X chromosome and duplications of either the right end of the X or a region near but not including the left end was rare. We suggest that the X chromosome has one or more elements near its left end that promote meiotic chromosome pairing.     

Mutant Rec-1 Eliminates the Meiotic Pattern of Crossing over in Caenorhabditis Elegans

Meiotic crossovers are not randomly distributed along the chromosome. In Caenorhabditis elegans the central portions of the autosomes have relatively few crossovers compared to the flanking regions. We have measured the frequency of crossing over for several intervals across chromosome I in strains mutant for rec-1. The chromosome is ~50 map units in both wild-type and rec-1 homozygotes, however, the distribution of exchanges is very different in rec-1. Map distances expand across the gene cluster and contract near the right end of the chromosome, resulting in a genetic map more consistent with the physical map. Mutations in two other genes, him-6 and him-14, also disrupted the distribution of exchanges. Unlike rec-1, individuals homozygous for him-6 and him-14 had an overall reduction in the amount of crossing over accompanied by a high frequency of nondisjunction and reduced egg hatching. In rec-1; him-6 and rec-1; him-14 homozygotes the frequency of crossing over was characteristic of the Him mutant phenotype, whereas the distribution of the reduced number of exchanges was characteristic of the Rec-1 pattern. It appears that these gene products play a role in establishing the meiotic pattern of exchange events.     

Crossover distribution and frequency are regulated by him-5 in Caenorhabditis elegans

Mutations in the him-5 gene in Caenorhabditis elegans strongly reduce the frequency of crossovers on the X chromosome, with lesser effects on the autosomes. him-5 mutants also show a change in crossover distribution on both the X and autosomes. These phenotypes are accompanied by a delayed entry into pachytene and premature desynapsis of the X chromosome. The nondisjunction, progression defects and desynapsis can be rescued by an exogenous source of double strand breaks (DSBs), indicating that the role of HIM-5 is to promote the formation of meiotic DSBs. Molecular cloning of the gene shows that the inferred HIM-5 product is a highly basic protein of 252 amino acids with no clear orthologs in other species, including other Caenorhabditis species. Although him-5 mutants are defective in segregation of the X chromosome, HIM-5 protein localizes preferentially to the autosomes. The mutant phenotypes and localization of him-5 are similar but not identical to the results seen with xnd-1, although unlike xnd-1, him-5 has no apparent effect on the acetylation of histone H2A on lysine 5 (H2AacK5). The localization of HIM-5 to the autosomes depends on the activities of both xnd-1 and him-17 allowing us to begin to establish pathways for the control of crossover distribution and frequency.     

A Cis-Acting Locus That Promotes Crossing over between X Chromosomes in Caenorhabditis Elegans

This study reports the characterization of a cis-acting locus on the Caenorhabditis elegans X chromosome that is crucial for promoting normal levels of crossing over specifically between the X homologs and for ensuring their proper disjunction at meiosis I. The function of this locus is disrupted by the mutation me8, which maps to the extreme left end of the X chromosome within the region previously implicated by studies of X;A translocations and X duplications to contain a meiotic pairing site. Hermaphrodites homozygous for a deletion of the locus (Df/Df) or heterozygous for a deletion and the me8 mutation (me8/Df) exhibit extremely high levels of X chromosome nondisjunction at the reductional division; this is correlated with a sharp decrease in crossing over between the X homologs as evidenced both by reductions in genetic map distances and by the presence of achiasmate chromosomes in cytological preparations of oocyte nuclei. Duplications of the wild-type region that are unlinked to the X chromosome cannot complement the recombination and disjunction defects in trans, indicating that this region must be present in cis to the X chromosome to ensure normal levels of crossing over and proper homolog disjunction. me8 homozygotes exhibit an altered distribution of crossovers along the X chromosome that suggests a defect in processivity along the X chromosome of an event that initiates at the chromosome end. Models are discussed in which the cis-acting locus deleted by the Dfs functions as a meiotic pairing center that recruits trans-acting factors onto the chromosomes to nucleate assembly of a crossover-competent complex between the X homologs. This pairing center might function in the process of homolog recognition, or in the initiation of homologous synapsis.     

Dominant X-Chromosome Nondisjunction Mutants of CAENORHABDITIS ELEGANS

Eight dominant X-chromosome nondisjunction mutants have been identified and characterized. Hermaphrodites (XX) heterozygous for any one of the mutations produce 20–35% male (XO) self-progeny compared with the wild-type frequency of 0.2%. Seven of the eight mutants carry X-autosome translocations. Three of these, represented by mnT2, involve linkage group (LG) II and show severe crossover suppression for X-linked markers. The two half-translocations comprising mnT2 are separable and of very unequal size. The smaller one includes the left tip of X and the right end of LGII and can exist as a free duplication, being present in addition to the normal chromosome complement, in either hermaphrodites or males; it has no effect on X nondisjunction. The reciprocal half-translocation of mnT2 includes the bulk of both LGII and X chromosomes; it disjoins regularly from a normal LGII and confers the property of X-chromosome nondisjunction. A fourth translocation, mnT10(V;X), is also reciprocal and consists of half-translocations that recombine with V and X, respectively. Either half-translocation of mnT10 can exist in heterozygous form in the absence of the other to give heterozygous duplication-deficiency animals; the property of X-chromosome nondisjunction is conferred, in homozygotes as well as heterozygotes, solely by one of the half-translocations, which is deficient for the left tip of the X. The final three translocations have X breakpoints near the right end of X and autosomal breakpoints near the right end of LGIV, the left end of LGV and the right end of LGI, respectively. All three are homozygous inviable. Males hemizygous for the X portion of any of the seven translocations are viable and fertile. The final mutant, mn164, maps as a point at or near the left tip of the X and causes X-chromosome nondisjunction in both heterozygotes and homozygotes. In heterozygotes, mn164 promotes equational nondisjunction of itself but not its wild-type allele. The mutants are discussed in light of the holocentric nature of the C. elegans chromosomes. It is proposed that the left end of the X chromosome plays a critical structural role in the segregation of X chromosomes during meiosis in XX animals.     

Genetic Analysis of Sex Chromosomal Meiotic Mutants in DROSOPHILA MELANOGASTER

A total of 209 ethyl methanesulfonate-treated X chromosomes were screened for meiotic mutants that either (1) increased sex or fourth chromosome nondisjunction at either meiotic division in males; (2) allowed recombination in such males; (3) increased nondisjunction of the X chromosome at either meiotic division in females; or (4) caused such females, when mated to males heterozygous for Segregation-Distorter (SD) and a sensitive homolog to alter the strength of meiotic drive in males.-Twenty male-specific meiotic mutants were found. Though the rates of nondisjunction differed, all twenty mutants were qualitatively similar in that (1) they alter the disjunction of the X chromosome from the Y chromosome; (2) among the recovered sex-chromosome exceptional progeny, there is a large excess of those derived from nullo-XY as compared to XY gametes; (3) there is a negative correlation between the frequency of sex-chromosome exceptional progeny and the frequency of males among the regular progeny. In their effects on meiosis these mutants are similar to In(1)sc(4L)sc(8R), which is deleted for the basal heterochromatin. These mutants, however, have normal phenotypes and viabilities when examined as X/0 males, and furthermore, a mapping of two of the mutants places them in the euchromatin of the X chromosome. It is suggested that these mutants are in genes whose products are involved in insuring the proper functioning of the basal pairing sites which are deleted in In(1)sc(4L)sc(8R), and in addition that there is a close connection, perhaps causal, between the disruption of normal X-Y pairing (and, therefore, disjunction) and the occurrence of meiotic drive in the male.-Eleven mutants were found which increased nondisjunction in females. These mutants were characterized as to (1) the division at which they acted; (2) their effect on recombination; (3) their dominance; (4) their effects on disjunction of all four chromosome pairs. Five female mutants caused a nonuniform decrease in recombination, being most pronounced in distal regions, and an increase in first division nondisjunction of all chromosome pairs. Their behavior is consistent with the hypothesis that these mutants are defective in a process which is a precondition for exchange. Two female mutants were allelic and caused a uniform reduction in recombination for all intervals (though to different extents for the two alleles) and an increase in first-division nondisjunction of all chromosomes. Limited recombination data suggest that these mutants do not alter coincidence, and thus, following the arguments of Sandler et al. (1968), are defective in exchange rather than a precondiiton for exchange. A single female mutant behaves in a manner that is consistent with it being a defect in a gene whose functioning is essential for distributive pairing. Three of the female meiotic mutants cause abnormal chromosome behavior at a number of times in meiosis. Thus, nondisjunction at both meiotic divisions is increased, recombinant chromosomes nondisjoin, and there is a polarized alteration in recombination.-The striking differences between the types of control of meiosis in the two sexes is discussed and attention is drawn to the possible similarities between (1) the disjunction functions of exchange and the process specified by the chromosome-specific male mutants; and (2) the prevention of functional aneuploid gamete formation by distributive disjunction and meiotic drive.     

C. elegans HIM-8 functions outside of meiosis to antagonize EGL-13 Sox protein function

egl-13 encodes a Sox domain protein that is required for proper uterine seam cell development in Caenorhabditis elegans. We demonstrate that mutations of the C2H2 zinc fingers encoded by the him-8 (high incidence of males) gene partially suppress the egg-laying and connection-of-gonad morphology defects caused by incompletely penetrant alleles of egl-13. him-8 alleles have previously characterized recessive effects on recombination and segregation of the X chromosome during meiosis due to failure of X chromosome homolog pairing and subsequent synapsis. However, we show that him-8 alleles are semi-dominant suppressors of egl-13, and the semi-dominant effect is due to haplo-insufficiency of the him-8 locus. Thus, we conclude that the wild-type him-8 gene product acts antagonistically to EGL-13. Null alleles of egl-13 cannot be suppressed, suggesting that this antagonistic interaction most likely occurs either upstream of or in parallel with EGL-13. Moreover, we conclude that suppression of egl-13 is due to a meiosis-independent function of him-8 because suppression is observed in mutants that have severely reduced meiotic germ cell populations and suppression does not depend on the function of him-8 in the maternal germ line. We also show that the chromosomal context of egl-13 seems important in the him-8 suppression mechanism. Interactions between these genes can give insight into function of Sox family members, which are important in many aspects of metazoan development, and into functions of him-8 outside of meiosis.     

New genes in the left arm of the bacteriophage phi 80 chromosome.

We describe the isolation and partial genetic characterization of 247 amber (suppressor-sensitive) mutants of temperate bacteriophage phi 80 of Escherichia coli. Of these 247 mutants, the mutations of 201 mapped to the left arm of the phi 809 chromosome and the mutations of 39 mapped to the right arm of the genome. Complementation tests among these and previously described left arm mutants defined five additional genes in the left arm of the chromosome. The positions of these genes are consistent with the hypothesis that four of them represent functions essential for phi 80 tail assembly and one represents a capsid assembly function, probably the major coat protein. The identification of these genes brings the phi 80 genome into closer correspondence with the organization of the phage lambda genome. Two- and three-factor crosses performed between mutants with defects in each of the previously identified genes and mutants with defects in the five new genes allowed us to construct a consistent, roughly additive recombination map of the left arm of the bacteriophage phi 80 genome.     

Meiotic Recombination, Noncoding DNA and Genomic Organization in Caenorhabditis Elegans

The genetic map of each Caenorhabditis elegans chromosome has a central gene cluster (less pronounced on the X chromosome) that contains most of the mutationally defined genes. Many linkage group termini also have clusters, though involving fewer loci. We examine the factors shaping the genetic map by analyzing the rate of recombination and gene density across the genome using the positions of cloned genes and random cDNA clones from the physical map. Each chromosome has a central gene-dense region (more diffuse on the X) with discrete boundaries, flanked by gene-poor regions. Only autosomes have reduced rates of recombination in these gene-dense regions. Cluster boundaries appear discrete also by recombination rate, and the boundaries defined by recombination rate and gene density mostly, but not always, coincide. Terminal clusters have greater gene densities than the adjoining arm but similar recombination rates. Thus, unlike in other species, most exchange in C. elegans occurs in gene-poor regions. The recombination rate across each cluster is constant and similar; and cluster size and gene number per chromosome are independent of the physical size of chromosomes. We propose a model of how this genome organization arose.     

Comparison of the physical and recombination maps of the mouse X chromosome

The locations of five random mouse genomic DNA markers and five cloned genes, including the genes for clotting factors VIII and IX (Cf-8 and Cf-9), Duchenne muscular dystrophy (Dmd), phosphoglycerate kinase-1 (Pgk-1), and alpha-galactosidase (Ags), on the mouse X chromosome were determined by in situ hybridization. The five random DNA markers provide new genetic loci with useful restriction fragment length polymorphisms between mouse strains and species, including one locus close to the centromeric region of the mouse X chromosome. The physical map and the recombination map of these loci on the X chromosome were compared. There was good agreement in the order of loci. Relative distances between loci were consistent along the X chromosome, with the exception of the telomeric end of the long arm, where the recombination fraction observed between loci closely associated on the physical map was higher than that between similarly spaced markers located in the proximal region of the X chromosome. These results are discussed in comparison to the human X-chromosome map.     

The teflon gene is required for maintenance of autosomal homolog pairing at meiosis I in male Drosophila melanogaster

In recombination-proficient organisms, chiasmata appear to mediate associations between homologs at metaphase of meiosis I. It is less clear how homolog associations are maintained in organisms that lack recombination, such as male Drosophila. In lieu of chiasmata and synaptonemal complexes, there must be molecules that balance poleward forces exerted across homologous centromeres. Here we describe the genetic and cytological characterization of four EMS-induced mutations in teflon (tef), a gene involved in this process in Drosophila melanogaster. All four alleles are male specific and cause meiosis I-specific nondisjunction of the autosomes. They do not measurably perturb sex chromosome segregation, suggesting that there are differences in the genetic control of autosome and sex chromosome segregation in males. Meiotic transmission of univalent chromosomes is unaffected in tef mutants, implicating the tef product in a pairing-dependent process. The segregation of translocations between sex chromosomes and autosomes is altered in tef mutants in a manner that supports this hypothesis. Consistent with these genetic observations, cytological examination of meiotic chromosomes suggests a role of tef in regulating or mediating pairing of autosomal bivalents at meiosis I. We discuss implications of this finding in regard to the evolution of heteromorphic sex chromosomes and the mechanisms that ensure chromosome disjunction in the absence of recombination.     

Meiotic Nondisjunction and Recombination of Chromosome III and Homologous Fragments in Saccharomyces Cerevisiae

A yeast strain, in which nondisjunction of chromosome III at the first-meiotic division could be assayed, was constructed. Using chromosome fragmentation plasmids, chromosomal fragments (CFs) were derived in isogenic strains from six sites along chromosome III and one site on chromosome VII. Whereas the presence of the CFs derived from chromosome III increased considerably the meiosis I nondisjunction of that chromosome, the CF derived from chromosome VII had no effect on chromosome III segregation. The effects of the chromosome III-derived fragments were not linearly related to fragment length. Two regions, one of 12 kb in size located at the left end of the chromosome, and the other of 5 kb, located at the center of the right arm, were found to have profound effects on chromosome III nondisjunction. Most disomics arising from meioses in strains containing chromosome III CFs did not contain the CF; thus it appears that the two chromosome III homologs had segregated away from the CF. Among the disomics, recombination between the homologous chromosomes III was lower than expected from the genetic distance, while recombination between one of the chromosomes III and the fragment was frequent. We suggest that there are sites along the chromosome that are more involved than others in the pairing of homologous chromosomes and that the pairing between fragment and homologs involves recombination among these latter elements.     

A deficiency screen of the major autosomes identifies a gene (matrimony) that is haplo-insufficient for achiasmate segregation in Drosophila oocytes

In Drosophila oocytes, euchromatic homolog-homolog associations are released at the end of pachytene, while heterochromatic pairings persist until metaphase I. A screen of 123 autosomal deficiencies for dominant effects on achiasmate chromosome segregation has identified a single gene that is haplo-insufficient for homologous achiasmate segregation and whose product may be required for the maintenance of such heterochromatic pairings. Of the deficiencies tested, only one exhibited a strong dominant effect on achiasmate segregation, inducing both X and fourth chromosome nondisjunction in FM7/X females. Five overlapping deficiencies showed a similar dominant effect on achiasmate chromosome disjunction and mapped the haplo-insufficient meiotic gene to a small interval within 66C7-12. A P-element insertion mutation in this interval exhibits a similar dominant effect on achiasmate segregation, inducing both high levels of X and fourth chromosome nondisjunction in FM7/X females and high levels of fourth chromosome nondisjunction in X/X females. The insertion site for this P element lies immediately upstream of CG18543, and germline expression of a UAS-CG18543 cDNA construct driven by nanos-GAL4 fully rescues the dominant meiotic defect. We conclude that CG18543 is the haplo-insufficient gene and have renamed this gene matrimony (mtrm). Cytological studies of prometaphase and metaphase I in mtrm hemizygotes demonstrate that achiasmate chromosomes are not properly positioned with respect to their homolog on the meiotic spindle. One possible, albeit speculative, interpretation of these data is that the presence of only a single copy of mtrm disrupts the function of whatever "glue" holds heterochromatically paired homologs together from the end of pachytene until metaphase I.     

Etoposide exposure during male mouse pachytene has complex effects on crossing-over and causes nondisjunction

In experiments involving different germ-cell stages, we had previously found meiotic prophase of the male mouse to be vulnerable to the induction of several types of genetic damage by the topoisomerase-II inhibitor etoposide. The present study of etoposide effects involved two end points of meiotic events known to occur in primary spermatocytes--chromosomal crossing-over and segregation. By following assortment of 13 microsatellite markers in two chromosomes (Ch 7 and Ch 15) it was shown that etoposide significantly affected crossing-over, but did not do so in a uniform fashion. Treatment generally changed the pattern for each chromosome, leading to local decreases in recombination, a distal shift in locations of crossing-over, and an overall decrease in double crossovers; at least some of these results might be interpreted as evidence for increased interference. Two methods were used to explore etoposide effects on chromosome segregation: a genetic experiment capable of detecting sex-chromosome nondisjunction in living progeny; and the use of FISH (fluorescence in situ hybridization) technology to score numbers of Chromosomes X, Y, and 8 in spermatozoa. Taken together these two approaches indicated that etoposide exposure of pachytene spermatocytes induces malsegregation, and that the findings of the genetic experiment probably yielded a marked underestimate of nondisjunction. As indicated by certain segregants, at least part of the etoposide effect could be due to disrupted pairing of achiasmatic homologs, followed by precocious sister-centromere separation. It has been shown for several organisms that absent or reduced levels of recombination, as well as suboptimally positioned recombination events, may be associated with abnormal segregation. Etoposide is the only chemical tested to date for which living progeny indicates an effect on both male meiotic crossing-over and chromosome segregation. Whether, however, etoposide-induced changes in recombination patterns are direct causes of the observed malsegregation requires additional investigation.     

Multiple genetic pathways involving the Caenorhabditis elegans Bloom's syndrome genes him-6, rad-51, and top-3 are needed to maintain genome stability in the germ line

Bloom's syndrome (BS) is an autosomal-recessive human disorder caused by mutations in the BS RecQ helicase and is associated with loss of genomic integrity and an increased incidence of cancer. We analyzed the mitotic and the meiotic roles of Caenorhabditis elegans him-6, which we show to encode the ortholog of the human BS gene. Mutations in him-6 result in an enhanced irradiation sensitivity, a partially defective S-phase checkpoint, and in reduced levels of DNA-damage induced apoptosis. Furthermore, him-6 mutants exhibit a decreased frequency of meiotic recombination that is probably due to a defect in the progression of crossover recombination. In mitotically proliferating germ cells, our genetic interaction studies, as well as the assessment of the number of double-strand breaks via RAD-51 foci, reveal a complex regulatory network that is different from the situation in yeast. Although the number of double-strand breaks in him-6 and top-3 single mutants is elevated, the combined depletion of him-6 and top-3 leads to mitotic catastrophe concomitant with a massive increase in the level of double-strand breaks, a phenotype that is completely suppressed by rad-51. him-6 and top-3 are thus needed to maintain low levels of double-strand breaks in normally proliferating germ cells, and both act in partial redundant pathways downstream of rad-51 to prevent mitotic catastrophy. Finally, we show that topoisomerase IIIalpha acts independently during a late stage of meiotic recombination.     

Trisomy 21: Association between reduced recombination and nondisjunction

To assess the association between recombination and nondisjunction of chromosome 21, we analyzed cytogenetic and DNA markers in 104 trisomy 21 individuals and their parents. Our DNA marker studies of parental origin were informative in 100 cases, with the overwhelming majority (94) being maternal in origin. This value is significantly higher than the 75%-80% maternal nondisjunction rate typically observed in cytogenetic studies of trisomy 21 and illustrates the increased accuracy of the molecular approach. Using the maternally derived cases and probing at 19 polymorphic sites on chromosome 21, we created a genetic map that spans most of the long arm of chromosome 21. The map was significantly shorter than the normal female linkage map, indicating that absence of pairing and/or recombination contributes to nondisjunction in a substantial proportion of cases of trisomy 21.     

Dis1: A Yeast Gene Required for Proper Meiotic Chromosome Disjunction

Mutants at a newly identified locus, DIS1 (disjunction), were detected by screening for mutants that generate aneuploid spores (chromosome VIII disomes) at an increased frequency. Strains carrying the partially dominant alleles, DIS1-1 or DIS1-2, generate disomes at rates up to 100 times the background level. Mitotic nondisjunction is also increased 10- to 50-fold over background. Half-tetrad analysis of disomes for a marked interval on chromosome VIII yields wild-type map distances, indicating that a general recombination deficiency is not the cause of nondisjunction. Meiotic nondisjunction in DIS1 mutants is not chromosome specific; 5% of the spores disomic for chromosome VIII are also disomic for chromosome III. Although only one disomic spore is found per exceptional ascus most of the disomes appear to be generated in the first meiotic division because recovered chromosome VIII disomes contain mostly nonsister chromosomes. We propose that disome generation in the DIS1 mutants results from precocious separation of sister centromeres.     

Centromere mapping functions for aneuploid meiotic products: Analysis of rec8, rec10 and rec11 mutants of the fission yeast Schizosaccharomyces pombe.

Recent evidence suggests that the position of reciprocal recombination events (crossovers) is important for the segregation of homologous chromosomes during meiosis I and sister chromatids during meiosis II. We developed genetic mapping functions that permit the simultaneous analysis of centromere-proximal crossover recombination and the type of segregation error leading to aneuploidy. The mapping functions were tested in a study of the rec8, rec10, and rec11 mutants of fission yeast. In each mutant we monitored each of the three chromosome pairs. Between 38 and 100% of the chromosome segregation errors in the rec8 mutants were due to meiosis I nondisjunction of homologous chromosomes. The remaining segregation errors were likely the result of precocious separation of sister chromatids, a previously described defect in the rec8 mutants. Between 47 and 100% of segregation errors in the rec10 and rec11 mutants were due to nondisjunction of sister chromatids during meiosis II. In addition, centromere-proximal recombination was reduced as much as 14-fold or more on chromosomes that had experienced nondisjunction. These results demonstrate the utility of the new mapping functions and support models in which sister chromatid cohesion and crossover position are important determinants for proper chromosome segregation in each meiotic division.     

XY chromosome nondisjunction in man is associated with diminished recombination in the pseudoautosomal region.

To assess the possible association between aberrant recombination and XY chromosome nondisjunction, we compared pseudoautosomal region recombination rates in male meiosis resulting in 47,XXY offspring with those resulting in 46,XY and 46,XX offspring. Forty-one paternally derived 47,XXYs and their parents were tested at six polymorphic loci spanning the pseudoautosomal region. We were able to detect crossing-over in only six of 39 cases informative for the telomeric DXYS14/DXYS20 locus. Subsequently, we used the data to generate a genetic linkage map of the pseudoautosomal region and found it to be significantly shorter than the normal male map of the region. From these analyses we conclude that most paternally derived 47,XXYs result from meiosis in which the X and Y chromosomes did not recombine.     

Genetic linkage map of human chromosome 21

Two of the most common disorders affecting the human nervous system, Down syndrome and Alzheimer's disease, involve genes residing on human chromosome 21. A genetic linkage map of human chromosome 21 has been constructed using 13 anonymous DNA markers and cDNAs encoding the genes for superoxide dismutase 1 (SOD1) and the precursor of Alzheimer's amyloid beta peptide (APP). Segregation of restriction fragment length polymorphisms (RFLPs) for these genes and DNA markers was traced in a large Venezuelan kindred established as a "reference" pedigree for human linkage analysis. The 15 loci form a single linkage group spanning 81 cM on the long arm of chromosome 21, with a markedly increased frequency of recombination occurring toward the telomere. Consequently, 40% of the genetic length of the long arm corresponds to less than 10% of its cytogenetic length, represented by the terminal half of 21q22.3. Females displayed greater recombination than males throughout the linkage group, with the difference being most striking for markers just below the centromere. Definition of the linkage relationships for these chromosome 21 markers will help refine the map position of the familial Alzheimer's disease gene and facilitate investigation of the role of recombination in nondisjunction associated with Down syndrome.