Testing the protracted lexical restructuring hypothesis: The effects of position and acoustic-phonetic clarity on sensitivity to mispronunciations in children and adults

Although developmental increases in the size of the position effect within a mispronunciation detection task have been interpreted as consistent with a view of the lexical restructuring process as protracted, the position effect itself might not be reliable. The current research examined the effects of position and clarity of acoustic-phonetic information on sensitivity to mispronounced onsets in 5- and 6-year-olds and adults. Both children and adults showed a position effect only when mispronunciations also differed in the amount of relevant acoustic-phonetic information. Adults' sensitivity to mispronounced second-syllable onsets also reflected the availability of acoustic-phonetic information. The implications of these findings are discussed in relation to the lexical restructuring hypothesis. (c) 2006 Elsevier Inc. All rights reserved.

Extending the Phenotype of Monosomy 1p36 Syndrome and Mapping of a Critical Region for Obesity and Hyperphagia

Rearrangements of 1p36 are the most frequently detected abnormalities in diagnostic testing for chromosomal cryptic imbalances and include variably sized simple terminal deletions, derivative chromosomes, interstitial deletions, and complex rearrangements. These rearrangements result in the specific pattern of malformation and neurodevelopmental disabilities that characterizes monosomy 1p36 syndrome. Thus far, no individual gene within this region has been conclusively determined to be causative of any component of the phenotype. Nor is it known if the rearrangements convey phenotypes via a haploinsufficiency mechanism or through a position effect. We have used multiplex ligation-dependent probe amplification to screen for deletions of 1p36 in a group of 154 hyperphagic and overweight/obese, PWS negative individuals, and in a separate group of 83 patients initially sent to investigate a variety of other conditions. The strategy allowed the identification and delineation of rearrangements in nine subjects with a wide spectrum of clinical presentations. Our work reinforces the association of monosomy 1p36 and obesity and hyperphagia, and further suggests that these features may be associated with non-classical manifestations of this disorder in addition to a submicroscopic deletion of similar to 2-3 Mb in size. Multiplex ligation probe amplification using the monosomy 1p36 syndrome-specific kit coupled to the subtelomeric kit is an effective approach to identify and delineate rearrangements at 1p36. (C) 2009 Wiley-Liss, Inc.

A t(7;12) balanced translocation with breakpoints overlapping those of the Williams-Beuren and 12q14 microdeletion syndromes.

The molecular characterization of balanced chromosomal rearrangements have always been of advantage in identifying disease-causing genes. Here, we describe the breakpoint mapping of a de novo balanced translocation t(7;12)(q11.22;q14.2) in a patient presenting with a failure to thrive associated with moderate mental retardation, facial anomalies, and chronic constipation. The localization of the breakpoints and the co-occurrence of Williams-Beuren syndrome and 12q14 microdeletion syndrome phenotypes suggested that the expression of some of the dosage-sensitive genes of these two segmental aneuploidies were modified in cells of the proposita. However, we were unable to identify chromosomes 7 and/or 12-mapping genes that showed disturbed expression in the lymphoblastoids of the proposita. This case showed that position-effect might operate in some tissues, but not in others. It also illustrates the overlap of phenotypes presented by patients with the recently described 12q14 structural rearrangements.

Statistical evaluation of the influence of writing postures on on-line signatures. Study of the impact of time.

The aim of this study is to investigate the influence of unusual writing positions on a person's signature, in comparison to a standard writing position. Ten writers were asked to sign their signature six times, in each of four different writing positions, including the standard one. In order to take into consideration the effect of the day-to-day variation, this same process was repeated over 12 sessions, giving a total of 288 signatures per subject. The signatures were collected simultaneously in an off-line and on-line acquisition mode, using an interactive tablet and a ballpoint pen. Unidimensional variables (height to width ratio; time with or without in air displacement) and time-dependent variables (pressure; X and Y coordinates; altitude and azimuth angles) were extracted from each signature. For the unidimensional variables, the position effect was assessed through ANOVA and Dunnett contrast tests. Concerning the time-dependent variables, the signatures were compared by using dynamic time warping, and the position effect was evaluated through classification by linear discriminant analysis. Both of these variables provided similar results: no general tendency regarding the position factor could be highlighted. The influence of the position factor varies according to the subject as well as the variable studied. The impact of the session factor was shown to cover the impact that could be ascribed to the writing position factor. Indeed, the day-to-day variation has a greater effect than the position factor on the studied signature variables. The results of this study suggest guidelines for best practice in the area of signature comparisons and demonstrate the importance of a signature collection procedure covering an adequate number of sampling sessions, with a sufficient number of samples per session.

Analysis of a boundary protein delimiting chromatin domains in yeast

SUMMARY The expression state of a eukaryotic gene depends in part on its location in the chromosome. This position effect results from the organization of eukaryotic genomes into discrete functional domains, defined by local differences in chromatin structure. The expression of genes within each domain appears to be defined and maintained by the concerted action of regulatory elements such as promoters, enhancers, silencers and locus control regions. Individual domains may be bordered by boundary elements that separate regions of permissive and silent chromatin. When located next to chromosomal elements such as telomeres, genes can be subjected to epigenetic silencing. In yeast, this is mediated by the propagation of the SIR proteins from telomeres towards more centromeric regions. Particular transcription factors can protect downstream genes from silencing when tethered between the gene and the telomere, and they may thus act as chromatin domain boundaries. Here we have studied one of these transcription factors, CTF-1, that binds directly histone H3. A deletion mutagenesis localized the barrier activity to CTF-1 histone-binding domain. A saturating point mutagenesis of this domain identified several amino-acid substitutions that similarly inhibited the boundary and histone-binding activities. Chromatin immunoprecipitation experiments indicated that the barrier protein efficiently prevents the spreading of SIR proteins, and that it separates domains of hypoacetylated and hyperacetylated histones. Together, these results suggest a mechanism by which proteins such as CTF-1 may interact directly with histone H3 to prevent the propagation of a silent chromatin structure, thereby defining boundaries of permissive and silent chromatin domains. RESUME L'expression des gènes eucaryotes dépend en partie de leur localisation sur les chromosomes. Cet effet de position résulte de l'organisation des génomes eucaryotes en domaines fonctionnels, définis par des changements locaux au niveau de la structure de la chromatine. Dans chacun de ces domaines, l'expression des gènes est définie et maintenue par l'action concertée de différents éléments régulateurs tels que les promoteurs, les amplificateurs, les silenceurs et les locus control régions. Ces domaines peuvent être entourés par des éléments barrière, séparant les régions de chromatine répressive des régions permissive pour l'expression des gènes. Lorsqu'ils se situent à proximité d'éléments chromosomiques comme les telomères, les gènes peuvent être réprimés de manière épigénétique. Chez la levure, cette répression est établie par la propagation des protéines SIR depuis les télomères vers les régions centromériques. Certains facteurs de transcription peuvent empêcher la répression d'un gène, lorsqu'ils sont placés entre ce gène et le télomère. Nous avons étudié un de ces facteurs, CTF-1, qui a la particularité de lier directement l'histone H3. La délétion de certaines parties de CTF-1 a permis de déterminer que la région responsable de l'activité barrière correspond au domaine d'interaction avec H3. Plusieurs mutations points effectuées dans ce domaine inhibent à la fois l'activité barrière et la capacité de lier H3. Des expériences d'immuno-précipitation de la chromatine indiquent que la protéine barrière CTF-1 prévient efficacement la propagation des protéines SIR et sépare des domaines contenant des histones hypo-acétylées de ceux constitués d'histones hyper-acétylées. Ces résultats suggèrent que CTF-1 interagit directement avec l'histone H3 pour empêcher la propagation de la chromatine répressive, délimitant ainsi des domaines de chromatine permissive et des domaines de chromatine silencieuse.

Effects of epigenetic regulatory elements on telomeric gene expression

Transgene expression in eukaryotic cells strongly depends on the locus of integration in the host genome and often results in limited transcription level because of unfavorable chromatin structure at the integration site. Epigenetic regulators are DNA sequences which are believed to act on the chromatin structure and may protect transgenes from this so-called position effect. Despite being extensively used to increase transgene expression, the mechanism of action of many of these elements remains largely unknown. Here we evaluated different epigenetic regulatory DNA elements for their ability to protect transgene transcription at telomeres, a defined chromatin environment associated to low or inconsistent expression caused by the Telomere Position Effect (TPE). For the assessment of the effects of epigenetic regulators at telomeres, a novel dual reporter system had to be designed. Telomeric integration of the newly-developed dual reporter system carrying different epigenetic regulators showed that MARs (Matrix Attachment Regions), a UCOE (Ubiquitous Chromatin-Opening Element) or the chicken cHS4 insulator have strong barrier activity which prevented TPE from spreading toward the centromere, resulting in stable and in some cases increased expression of a telomeric-distal reporter gene. In addition, MARs and STAR element 40 resulted in an increase of cells expressing the telomeric-proximal reporter gene, suggesting also an anti-silencing effect. Chromatin immunoprecipitation assays revealed that at telomeres MARs actively promote the deposition of euchromatic histone marks, especially acetylation of both histone H3 and H4, which might be involved in MARs' barrier and transcriptional activator activities. Differently, the chromatin in proximity of the UCOE element was depleted of several repressive chromatin marks, such as trimethylated lysine 9 and lysine 27 on histone H3 and trimethylated lysine 20 of histone H4, possibly favoring the preservation of an open chromatin structure at the integration site. We conclude that epigenetic regulatory elements that may be used to enhance and sustain transgene expression have all a specific epigenetic signature which might be at the basis of their mechanism of action, and that a combination of different classes of epigenetic regulators might be advantageous when high levels of protein expression are required. - L'expression des transgènes dans les cellules eucaryotes est fortement influencée par leur site d'intégration dans le génome. En effet, une structure chromatinienne défavorable au niveau du site d'intégration peut fortement limiter le degré d'expression d'un transgène. Il existe toutefois des séquences d'ADN qui, en agissant sur la structure de la chromatine, permettent de limiter cet effet de position et, par conséquent, de promouvoir l'expression soutenue d'un transgène. Ces éléments génomiques, connus comme régulateurs épigénétiques, sont largement utilisés dans plusieurs domaines où une expression élevée et soutenue est requise, malgré un mode de fonctionnement parfois méconnu. Dans cette étude, j'ai évalué la capacité de différents régulateurs épigénétiques à protéger la transcription de transgènes au niveau des télomères, régions chromatiniennes bien définies qui ont été associées à un fort effet de silençage, connu comme «effet de position télomérique». Pour cela, un nouveau système à deux gènes rapporteurs a été développé. Lorsque des MARs (Matrix Attachment Regions, séquences d'ADN pouvant s'associer à la matrice nucléaire), un UCOE (Ubiquitous Chromatin-Opening Element, élément pouvant ouvrir la chromatine) ou l'isolateur génétique cHS4 (dérivé du locus de la β-globine de poulet) sont placés entre les deux gènes rapporteurs, une forte activité barrière bloquant la propagation de la chromatine répressive télomérique est observée, résultant en un plus grand nombre de cellules exprimant le gène télomérique-distal. D'autre part, une augmentation du nombre de cellules exprimant le gène télomérique-proximal, observée en présence des éléments MAR et STAR 40 (Stabilizing Anti-Repressor element 40, un élément pouvant prévenir la répression génique), suggère aussi un faible effet anti-silençage pour ces éléments. Des expériences d'immunoprécipitation de la chromatine démontrent qu'au télomère, les MARs favorisent l'assemblage de marqueurs de la chromatine active, surtout l'acétylation des histones H3 et H4, qui pourraient être à la base de l'activité barrière et de celle d'activateur transcriptionel. Différemment, la chromatine à proximité de l'élément UCOE est particulièrement pauvre en marqueurs de la chromatine silencieuse, comme la trimethylation des lysines 9 et 27 de l'histone H3, ainsi que la trimethylation de la lysine 20 de l'histone H4. Cela suggère que UCOE pourrait préserver une structure chromatinienne ouverte au site d'intégration, favorisant l'expression des gènes à sa proximité. En conclusion, les régulateurs épigénétiques analysés lors de cette étude ont tous montré une signature épigénétique spécifique qui pourrait être à la base de leurs mécanismes de fonctionnement, suggérant aussi qu'une utilisation d'éléments épigénétiques de classe différente dans un même vecteur d'expression pourrait être avantageuse lorsque de hauts et soutenus niveaux d'expression sont nécessaires.

Analyse des modifications de la chromatine impliquées dans l'effet barrière de CTF1 aux télomères humains

Eukaryotic genomes are compartmentalized in different structural domains that can affect positively or negatively gene expression. These regions of euchromatin and heterochromatin are characterized by distinct histones marks which can facilitate or repress gene transcription. The chromatin environment represents thus one of the main problems to control gene expression in biotechnological applications or gene therapy, since its expression is affected by the chromatin neighboring its locus of insertion. Some chromatin regions like telomeres are composed of constitutive heterochromatin which leads to the telomeric position effect (TPE) that silences genes adjacent to the telomere. TPE is known to spread by the selfrecruitment of the SIR histone deacetylase complex from the telomere in S.cerevisiae, but the histone marks that are associated to telomeric chromatin in mammalian cells remain mostly unknown. The transcription factor CTF1 has shown antisilencing properties in mammalian cells and also a boundary activity against TPE in yeast cells when fused to the yeast Gal4 DNA binding domain. In the work presented here, we describe a dual-reporter system to assess the boundary activity of proteins such as CTF1 at human telomeres. When located between the two reporter genes, CTF1 shields the telomere distal gene from TPE, while the telomereproximal gene remains silenced by telomeric heterochromatin. The boundary activity of CTF1 is shown to act regardless its function of transcriptional activator, by opposition to the transcriptional activator VP16 which activates indifferently both transgenes. Moreover, this study shows that CTF1 boundary activity is linked to its H3 binding function, as expected from a chromatin remodeler. ChIP experiments showed that histone deacetylation is the main histone modification involved in gene silencing at mammalian cell telomeres. Distinctly to yeast cells, the histone deacetylation signal in human cells extented over a short range along the chromosome. CTF1 may help to block this propagation and therefore to restore histones acetylation level on telomere protected locus. Surprisingly, other histone marks such as trimethyl-H3K9 or trimethyl-H4K20 were found on telomere protected locus, while in another clone, unsilencing of telomere distal transgene was associated with recruitment of the histone variant H2A.Z. Thus, I conclude that CTF1 displays a chromatin boundary function which is independent of its transcriptional activity and therefore exhibit features required for use as chromatin insulator in biotechnological applications. RESUME Les génomes eucaryotes sont compartementalisés en domaines structurels qui peuvent affecter positivement ou négativement l'expression des gènes avoisinants. Ces régions dites d'euchromatine ou d'hétérochromatine sont caractérisées par des modifications posttraductionnelles des histones qui peuvent faciliter ou au contraire inhiber la transcription des gènes qui s'y trouvent. Ainsi, isoler un gène de son environnement chromatinien est problème fréquent lorsqu'il s'agit de contrôler son expression dans le cadre d'applications en biotechnologie ou encore en thérapie génique. Certaines régions de chromatine telles que les télomères sont composées d'hétérochromatine constitutive qui mène au silençage des gènes avoisinants. Cet effet de position télomérique (TPE) est connu dans la levure S.cerevisiae comme se propageant par auto-recrutement du complexe de déacétylation d'histone SIR, alors que peu de modifications de chromatine ont pu être associées à ce phénomène dans les cellules de mammifères. Le facteur de transcription CTF1 a montré des propriétés d'anti-silençage dans les cellules de mammifères, ainsi qu'une activité barrière contre le silençage télomérique dans les cellules de levures lorsqu'il est fusionné au domaine de liaison à l'ADN de la protéine de levure Gal4. Dans le travail présenté ci-après est décrit un système à deux gènes rapporteurs permettant de mesurer l'activité barrière de protéines telles que CTF1 aux télomères humains, et les modifications de chromatine qui y sont associées. Lorsque CTF1 est placé entre les deux gènes rapporteurs, le gène distant du télomère est protégé du silençage qui lui est associé, alors que le gène proche du télomère reste soumis à ce silençage induit par l'hétérochromatine télomérique. L'activité barrière de CTF1 est montrée ici comme agissant indépendamment de son activité transcriptionnelle, par opposition à l'activateur transcriptionnel VP16 qui active indifféremment les deux transgènes. En outre, cette étude appuie l'hypothèse stipulant que CTF1 agisse comme remodeleur chromatinien puisqu'elle démontre que son activité barrière est directement dépendante de son activité de liaison avec l'histone H3. De plus, des expériences d'immuno-précipitation de la chromatine démontrent que la déacétylation des histones est le majeur phénomène intervenant dans le silençage télomérique. Par opposition à la levure, ce signal de déacétylation ne se propage dans les cellules humaines que sur une courte distance le long du chromosome. CTF1 agit ainsi en bloquant cette propagation et en restaurant le niveau d'acétylation des histones sur le locus protégé du télomère. De manière surprenante et inattendue, d'autres modifications d'histones telles que 4 les H3K9 et H4K20 triméthylées sont aussi observées à ce locus, tandis le recrutement du variant H2A.Z peut aussi être suffisant à restaurer l'expression du gène distant du télomère. En terme de cette analyse, CTF1 exhibe ainsi une fonction de barrière chromatinienne qui exclue une activité transcriptionnelle non désirée - propriété qui est requise dans l'établissement des isolateurs visant à permettre le contrôle d'un transgène dans le cadre d'applications en biotechnologies.

Epigenetic regulatory elements associate with specific histone modifications to prevent silencing of telomeric genes.

In eukaryotic cells, transgene expression levels may be limited by an unfavourable chromatin structure at the integration site. Epigenetic regulators are DNA sequences which may protect transgenes from such position effect. We evaluated different epigenetic regulators for their ability to protect transgene expression at telomeres, which are commonly associated to low or inconsistent expression because of their repressive chromatin environment. Although to variable extents, matrix attachment regions (MARs), ubiquitous chromatin opening element (UCOE) and the chicken cHS4 insulator acted as barrier elements, protecting a telomeric-distal transgene from silencing. MARs also increased the probability of silent gene reactivation in time-course experiments. Additionally, all MARs improved the level of expression in non-silenced cells, unlike other elements. MARs were associated to histone marks usually linked to actively expressed genes, especially acetylation of histone H3 and H4, suggesting that they may prevent the spread of silencing chromatin by imposing acetylation marks on nearby nucleosomes. Alternatively, an UCOE was found to act by preventing deposition of repressive chromatin marks. We conclude that epigenetic DNA elements used to enhance and stabilize transgene expression all have specific epigenetic signature that might be at the basis of their mode of action.

The roles of olfaction and vision in host-plant finding by the diamondback moth, Plutella xylostella

The relative roles of olfaction and vision in the crepuscular host-finding process of a major lepidopteran pest of cruciferous crops, the diamondback moth Plutella xylostella are investigated in a series of laboratory and semi-field experiments. Flying female moths use volatile plant chemical cues to locate and to promote landing on their host, even in complex mixed-crop environments in large cages. Multiple regression analysis shows that both the plant position (front, middle or back rows) and the type of plant (host plant, nonhost plant) are needed to explain the distribution of insects in such a mixed-crop situation. This strong plant position effect indicates that, when host plants are present in a mixture, foraging P. xylostella are more likely to alight on the first row of the plants. The findings are discussed with regard to current theories of host-plant location by phytophagous insects and the possible implications for integrated pest management.

In vitro conservation and low cost micropropagation of Cochlospermum regium (Mart. Ex. Scharank)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Autism spectrum disorder in a girl with a de novo x;19 balanced translocation

Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with a de novo X;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed a de novo balanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated with de novo balanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.

Experimental analysis of a separation control device based on plasma technology

In this thesis effects of plasma actuators based on Dielectric Barrier Discharge (DBD) technology over a NACA 0015 bidimensional airfoil have been analyzed in an experimental way, at low Reynolds number. Work developed on thesis has been carried on in partnership with the Department of Electrical Engineering of Università di Bologna, inside Wind Tunnel of the Applied Aerodynamic Laboratory of Aerospace Engineering faculty. In order to verify the effectiveness of these active control devices, the analysis has shown how actuators succeed in prevent boundary layer separation only in certain conditions af angle of attack and Reynolds numbers. Moreover, in this thesis actuators’ chordwise position effect has been also analyzed, together with the influence of steady and unsteady operations.

Conserved characteristics of heterochromatin-forming DNA at the 15q11-q13 imprinting center

Nuclear matrix binding assays (NMBAs) define certain DNA sequences as matrix attachment regions (MARs), which often have cis-acting epigenetic regulatory functions. We used NMBAs to analyze the functionally important 15q11-q13 imprinting center (IC). We find that the IC is composed of an unusually high density of MARs, located in close proximity to the germ line elements that are proposed to direct imprint switching in this region. Moreover, we find that the organization of MARs is the same at the homologous mouse locus, despite extensive divergence of DNA sequence. MARs of this size are not usually associated with genes but rather with heterochromatin-forming areas of the genome. In contrast, the 15q11-q13 region contains multiple transcribed genes and is unusual for being subject to genomic imprinting, causing the maternal chromosome to be more transcriptionally silent, methylated, and late replicating than the paternal chromosome. We suggest that the extensive MAR sequences at the IC are organized as heterochromatin during oogenesis, an organization disrupted during spermatogenesis. Consistent with this model, multicolor fluorescence in situ hybridization to halo nuclei demonstrates a strong matrix association of the maternal IC, whereas the paternal IC is more decondensed, extending into the nuclear halo. This model also provides a mechanism for spreading of the imprinting signal, because heterochromatin at the IC on the maternal chromosome may exert a suppressive position effect in cis. We propose that the germ line elements at the 15q11-q13 IC mediate their effects through the candidate heterochromatin-forming DNA identified in this study.

Loss of sequences 3' to the testis-determining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination.

The condition termed 46,XY complete gonadal dysgenesis is characterized by a completely female phenotype and streak gonads. In contrast, subjects with 46,XY partial gonadal dysgenesis and those with embryonic testicular regression sequence usually present ambiguous genitalia and a mix of Müllerian and Wolffian structures. In 46,XY partial gonadal dysgenesis gonadal histology shows evidence of incomplete testis determination. In 46,XY embryonic testicular regression sequence there is lack of gonadal tissue on both sides. Various lines of evidence suggest that embryonic testicular regression sequence is a variant form of 46,XY gonadal dysgenesis. The sex-determining region Y chromosome gene (SRY) encodes sequences for the testis-determining factor. To date germ-line mutations in SRY have been reported in approximately 20% of subjects with 46,XY complete gonadal dysgenesis. However, no germ-line mutations of SRY have been reported in subjects with the partial forms. We studied 20 subjects who presented either 46,XY partial gonadal dysgenesis or 46,XY embryonic testicular regression sequence. We examined the SRY gene and the minimum region of Y-specific DNA known to confer a male phenotype. The SRY-open reading frame (ORF) was normal in all subjects. However a de novo interstitial deletion 3' to the SRY-ORF was found in one subject. Although it is possible that the deletion was unrelated to the subject's phenotype, we propose that the deletion was responsible for the abnormal gonadal development by diminishing expression of SRY. We suggest that the deletion resulted either in the loss of sequences necessary for normal SRY expression or in a position effect that altered SRY expression. This case provides further evidence that deletions of the Y chromosome outside the SRY-ORF can result in either complete or incomplete sex reversal.

Y chromosome short arm-Sxr recombination in XSxr/Y males causes deletion of Rbm and XY female sex reversal.

We earlier described three lines of sex-reversed XY female mice deleted for sequences believed close to the testes-determining gene (Sry) on the Y chromosome short arm (Yp). The original sex-reversed females appeared among the offspring of XY males that carried the Yp duplication Sxr on their X chromosome. Earlier cytogenetic observations had suggested that the deletions resulted from asymmetrical meiotic recombination between the Y and the homologous Sxr region, but no direct evidence for this hypothesis was available. We have now analyzed the offspring of XSxr/Y males carrying an evolutionarily divergent Mus musculus domesticus Y chromosome, which permits detection and characterization of such recombination events. This analysis has enabled the derivation of a recombination map of Yp and Sxr, also demonstrating the orientation of Yp with respect to the Y centromere. The mapping data have established that Rbm, the murine homologue of a gene family cloned from the human Y chromosome, lies between Sry and the centromere. Analysis of two additional XY female lines shows that asymmetrical Yp-Sxr recombination leading to XY female sex reversal results in deletion of Rbm sequences. The deletions bring Sry closer to Y centromere, consistent with the hypothesis that position-effect inactivation of Sry is the basis for the sex reversal.