Recombination is proportional to the number of chromosome arms in mammals.
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Animals↗
Biomedical subjects
C Sapienza
Publications and source records attributed to C Sapienza.
Nonrandom segregation during meiosis: the unfairness of females.
Most geneticists assume that chromosome segregation during meiosis is Mendelian (i.e., each allele at each locus is represented equally in the gametes). The great majority of reports that discuss non-Mendelian transmission have focused on systems of gametic selection, such as the mouse t-haplotype and Segregation distorter in Drosophila, or on systems in which post-fertilization selection takes place. Because the segregation of chromosomes in such systems is Mendelian and unequal representation of alleles among offspring is achieved through gamete dysfunction or embryonic death, there is a common perception that true disturbances in the randomness of chromosome segregation are rare and of limited biological significance. In this review we summarize data on nonrandom segregation in a wide variety of genetic systems. Despite apparent differences between some systems, the basic requirements for nonrandom segregation can be deduced from their shared characteristics: i) asymmetrical meiotic division(s); ii) functional asymmetry of the meiotic spindle poles; and iii) functional heterozygosity at a locus that mediates attachment of a chromosome to the spindle. The frequency with which all three of these requirements are fulfilled in natural populations is unknown, but our analyses indicate that nonrandom segregation occurs with sufficient frequency during female meiosis, and in exceptional cases of male meiosis, that it has important biological, clinical, and evolutionary consequences.
Animals↗
Transmission ratio distortion in offspring of heterozygous female carriers of Robertsonian translocations.
Robertsonian translocations are the most common structural rearrangements of human chromosomes. Although segregation of Robertsonian chromosomes has been examined in many families, there is little consensus on whether inheritance in the balanced progeny conforms to Mendelian ratios. To address this question, we have compiled previously reported segregation data, by sex of parent, for 677 balanced offspring of Robertsonian carriers from 82 informative families and from a prenatal diagnosis study on the risk of unbalanced offspring in carriers of chromosome rearrangements. Care was taken to avoid any source of ascertainment bias. Our analysis supports the following conclusions: (1) the transmission ratio is not independent of the sex of the carrier; (2) the transmission ratio distortion is observed consistently only among the offspring of carrier females; (3) the transmission ratio distortion does not appear to be dependent on the presence of a specific acrocentric chromosome in the rearrangement. The sex-of-parent-specific origin of the non-Mendelian inheritance, the finding that the rearranged ("mutant") chromosomes are recovered at significantly higher frequency than the acrocentric ("normal") chromosomes, and the similarities between these observations and the segregation of analogous rearrangements through female meiosis in other vertebrates strongly support the hypothesis that the transmission ratio distortion in favor of Robertsonian translocations in the human results from the preferential segregation of chromosomes during the first meiotic division. This non-Mendelian inheritance will result in increased overall risk of aneuploidies in the families of Robertsonian translocation carriers, independently of the origin of the transmission ratio distortion.
Chromosome Segregation↗
Laryngostroboscopic, acoustic, and environmental characteristics of high-risk vocal performers.
Vocal performance often requires excessively high vocal demand. In particular "high-risk" performers, a group of individuals who use their voices at their maximum effort level, are often exposed to unique vocal abuse characteristics which include high environmental and performance demands and inconsistencies of cast performance. Three categories of high-risk performers were studied: musical theater, choral ensemble, and street theater. Musical theater performers produce a Broadway, West End "belting" style voice. Street theater performers use a high-energy pitch varying dialogue in order to imitate a desired character voice. Choral ensemble performance requires group cohesion and blending of four-part harmony. The melodies require sustained vocal durations within each of the respective registers. For each of these studied groups vocal tasks of sustained production of /i/ and /a/ were subjected to analysis. Acoustic measures included fundamental frequency, standard deviation of fundamental frequency, jitter percent, shimmer percent, and noise-to-harmonic ratio. Laryngostroboscopic parameters were assessed during sustained /i/. Environmental acoustic sound field measurements were made using an A weighting and linear weighting sound pressure level. These weightings were used to describe noise levels and vocal output, respectively, within the performance environments. Results of the analysis suggest that high-risk performers are a unique performance type defined by distinctive, acoustic, laryngostroboscopic, and environmental characteristics.
Adolescent↗
Female meiosis drives karyotypic evolution in mammals.
Speciation is often accompanied by changes in chromosomal number or form even though such changes significantly reduce the fertility of hybrid intermediates. We have addressed this evolutionary paradox by expanding the principle that nonrandom segregation of chromosomes takes place whenever human or mouse females are heterozygous carriers of Robertsonian translocations, a common form of chromosome rearrangement in mammals. Our analysis of 1170 mammalian karyotypes provides strong evidence that karyotypic evolution is driven by nonrandom segregation during female meiosis. The pertinent variable in this form of meiotic drive is the presence of differing numbers of centromeres on paired homologous chromosomes. This situation is encountered in all heterozygous carriers of Robertsonian translocations. Whenever paired chromosomes have different numbers of centromeres, the inherent asymmetry of female meiosis and the polarity of the meiotic spindle dictate that the partner with the greater number of centromeres will attach preferentially to the pole that is most efficient at capturing centromeres. This mechanism explains how chromosomal variants become fixed in populations, as well as why closely related species often appear to have evolved by directional adjustment of the karyotype toward or away from a particular chromosome form. If differences in the ability of particular DNA sequences or chromosomal regions to function as centromeres are also considered, nonrandom segregation is likely to affect karyotype evolution across a very broad phylogenetic range.
Animals↗
Transmission of Robertsonian chromosomes through human female meiosis.
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Chromosome Segregation↗
Natural selection and the function of genome imprinting: beyond the silenced minority.
Most hypotheses of the evolutionary origin of genome imprinting assume that the biochemical character on which natural selection has operated is the expression of the allele from only one parent at an affected locus. We propose an alternative - that natural selection has operated on differences in the chromatin structure of maternal and paternal chromosomes to facilitate pairing during meiosis and to maintain the distinction between homologues during DNA repair and recombination in both meiotic and mitotic cells. Maintenance of differences in chromatin structure in somatic cells can sometimes result in the transcription of only one allele at a locus. This pattern of transcription might be selected, in some instances, for reasons that are unrelated to the original establishment of the imprint. Differences in the chromatin structure of homologous chromosomes might facilitate pairing and recombination during meiosis, but some such differences could also result in non-random segregation of chromosomes, leading to parental-origin-dependent transmission ratio distortion. This hypothesis unites two broad classes of parental origin effects under a single selective force and identifies a single substrate through which Mendel's first and second laws might be violated.
Animals↗
A genetic test to determine the origin of maternal transmission ratio distortion. Meiotic drive at the mouse Om locus.
We have shown previously that the progeny of crosses between heterozygous females and C57BL/6 males show transmission ratio distortion at the Om locus on mouse chromosome 11. This result has been replicated in several independent experiments. Here we show that the distortion maps to a single locus on chromosome 11, closely linked to Om, and that gene conversion is not implicated in the origin of this phenomenon. To further investigate the origin of the transmission ratio distortion we generated a test using the well-known effect of recombination on maternal meiotic drive. The genetic test presented here discriminates between unequal segregation of alleles during meiosis and lethality, based on the analysis of genotype at both the distorted locus and the centromere of the same chromosome. We used this test to determine the cause of the transmission ratio distortion observed at the Om locus. Our results indicate that transmission ratio distortion at Om is due to unequal segregation of alleles to the polar body at the second meiotic division. Because the presence of segregation distortion at Om also depends on the genotype of the sire, our results confirm that the sperm can influence segregation of maternal chromosomes to the second polar body.
Animals↗
Sex-of-offspring-specific transmission ratio distortion on mouse chromosome X.
During our study of the DDK syndrome, we observed sex ratio distortion in favor of males among the offspring of F(1) backcrosses between the C57BL/6 and DDK strains. We also observed significant and reproducible transmission ratio distortion in favor of the inheritance of DDK alleles at loci on chromosome X among female offspring but not among male offspring in (C57BL/6 x DDK)F(1) x C57BL/6 and (C57BL/6-Pgk1(a) x DDK)F(1) x C57BL/6 backcrosses. The observed transmission ratio distortion is maximum at DXMit210 in the central region of chromosome X and decreases progressively at proximal and distal loci, in a manner consistent with the predictions of a single distorted locus model. DXMit210 is closely linked to two distortion-controlling loci (Dcsx1 and Dcsx2) described previously in interspecific backcrosses. Our analysis suggests that the female-offspring-specific transmission ratio distortion we observe is likely to be the result of the death of embryos of particular genotypic combinations. In addition, we confirm the previous suggestion that the transmission ratio distortion observed on chromosome X in interspecific backcrosses is also the result of loss of embryos.
Animals↗
Male-offspring-specific, haplotype-dependent, nonrandom cosegregation of alleles at loci on two mouse chromosomes.
F(1) backcrosses involving the DDK and C57BL/6 inbred mouse strains show transmission ratio distortion at loci on two different chromosomes, 11 and X. Transmission ratio distortion on chromosome X is restricted to female offspring while that on chromosome 11 is present in offspring of both sexes. In this article we investigate whether the inheritance of alleles at loci on one chromosome is independent of inheritance of alleles on the other. A strong nonrandom association between the inheritance of alleles at loci on both chromosomes is found among male offspring, while independent assortment occurs among female offspring. We also provide evidence that the mechanism by which this phenomenon occurs involves preferential cosegregation of nonparental chromatids of both chromosomes at the second meiotic division, after the ova has been fertilized by a C57BL/6 sperm bearing a Y chromosome. These observations confirm the influence of the sperm in the segregation of chromatids during female meiosis, and indicate that a locus or loci on the Y chromosome are involved in this instance of meiotic drive.
Alleles↗
Heritability of the maternal meiotic drive system linked to Om and high-resolution mapping of the Responder locus in mouse.
Matings between (C57BL/6 x DDK)F(1) females and C57BL/6 males result in a significant excess of offspring inheriting maternal DDK alleles in the central region of mouse chromosome 11 due to meiotic drive at the second meiotic division. We have shown previously that the locus subject to selection is in the vicinity of D11Mit66, a marker closely linked to the Om locus that controls the preimplantation embryo-lethal phenotype known as the "DDK syndrome." We have also shown that observation of meiotic drive in this system depends upon the genotype of the sire. Here we show that females that are heterozygous at Om retain the meiotic drive phenotype and define a 0.32-cM candidate interval for the Responder locus in this drive system. In addition, analysis of the inheritance of alleles at Om among the offspring of F(1) intercrosses indicates that the effect of the sire is determined by the sperm genotype at Om or a locus linked to Om.
Animals↗
A role for modifier genes in genome imprinting.
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Animals↗
The maternal DDK syndrome phenotype is determined by modifier genes that are not linked to Om.
The DDK syndrome is a polar, early embryonic lethal phenotype caused by incompatibility between a maternal factor of DDK origin and a paternal gene of non-DDK origin. Both maternal factor and paternal gene have been mapped to the Om locus on mouse Chromosome (Chr) 11. The paternal contribution to the syndrome has been shown to segregate as a single locus. Although the inheritance of the maternal contribution has not been characterized in depth, it as been assumed to segregate as a single locus. We have now characterized the segregation of the DDK fertility phenotype in over 240 females. Our results demonstrate that females require at least one DDK allele at Om to manifest the syndrome. However, the DDK syndrome inter-strain cross-fertility phenotype of heterozygous females is highly variable and spans the gamut from completely infertile to completely fertile. Our results indicate that this phenotypic variability has a genetic basis and that the modifiers of the DDK syndrome segregate independently of Om.
Animals↗
Respiratory-related evoked potential elicited by expiratory occlusion.
Respiratory-related evoked potentials (RREPs) have been elicited by inspiratory loads in adults and children. The RREP was recorded over the somatosensory region of the cerebral cortex. It was hypothesized that a RREP could be recorded by using expiratory occlusion. Electroencephalographic activity was recorded in adults from 14 scalp locations, referenced to the linked earlobes. The occlusion was presented as an interruption of expiration. Epochs of electroencephalographic activity and mouth pressure were recorded for each expiratory occlusion presentation. There were two occlusion trials and a control trial of 100 presentations each. The epochs in each trial were averaged and examined for the presence of short-latency, occlusion-related peaks. RREP peaks were observed bilaterally with expiratory occlusion and were absent in control unoccluded averages. A positive peak, P(34), was observed at central and postcentral sites. A negative peak, N(53), was observed at frontal and central sites. A second positive peak, P(95), was observed at frontal and central sites. These results demonstrate that expiratory occlusion elicits a RREP. This suggests that expiratory occlusion-related sensory information activates the cerebral cortex similar to that for inspiratory loads.
Adult↗
The M31 gene has a complex developmentally regulated expression profile and may encode alternative protein products that possess diverse subcellular localisation patterns.
HP1-like chromobox genes comprise an evolutionarily conserved family of genes that encode components of centromeric heterochromatin. In order to investigate the role of the murine HP1-like gene, M31, in heterochromatin formation we have isolated its gene and characterised its transcripts and protein products. PCR products that represent M31 transcripts were detected at the one-cell stage and were maternal in origin. Maternal provision of M31 transcripts may reflect a need for M31 in the formation of a functional centromere in order that there is proper segregation of chromosomes during the early cleavage divisions; studies in fission yeast and Drosophila have suggested a crucial role for HP1-like genes in centromere function. There are three protein products encoded by the M31 gene. Surprisingly, the two smaller products are found almost exclusively in the cytoplasm.
Alternative Splicing↗
Monoallelic expression: 'there can only be one'.
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Alleles↗
Parental origin-dependent, male offspring-specific transmission-ratio distortion at loci on the human X chromosome.
We have analyzed the transmission of maternal alleles at loci spanning the length of the X chromosome in 47 normal, genetic disease-free families. We found a significant deviation from the expected Mendelian 1:1 ratio of grandpaternal:grandmaternal alleles at loci in Xp11.4-p21.1. The distortion in inheritance ratio was found only among male offspring and was manifested as a strong bias in favor of the inheritance of the alleles of the maternal grandfather. We found no evidence for significant heterogeneity among the families, which implies that the major determinant involved in the generation of the non-Mendelian ratio is epigenetic. Our analysis of recombinant chromosomes inherited by male offspring indicates that an 11.6-cM interval on the short arm of the X chromosome, bounded by DXS538 and DXS7, contains an imprinted gene that affects the survival of male embryos.
Animals↗
Localization of genes encoding egg modifiers of paternal genome function to mouse chromosomes one and two.
It is now well established that genomic imprinting effects in mammals require a combination of epigenetic modifications imposed during gametogenesis and additional modifications imposed after fertilization. The earliest post-fertilization modifications to be imposed on the genome are those thought to be mediated by factors in the egg cytoplasm. Strain-dependent differences in the actions of these egg modifiers in mice reveal an important potential for genetic variability in the imprinting process, and also provide valuable genetic systems with which to identify some of the factors that participate in imprinting. Previous studies documented a strain-dependent difference in the modification of paternal genome function between the C57BL/6 and DBA/2 mouse strains. This difference is revealed as a difference in developmental potential of androgenetic embryos produced with eggs from females of the two strains by nuclear transplantation. The specificity of the effect for the paternal genome is consistent with an effect on imprinted genes. The egg phenotype is largely independent of the genotype of the fertilizing sperm, and the C57BL/6 phenotype is dominant in reciprocal F1 hybrids. Genetic studies demonstrated that the difference in egg phenotypes between the two strains is most likely controlled by two independently segregating loci. We now report the results of experiments in which the egg phenotypes of the available BxD recombinant inbred mouse strains have been determined. The results of the analysis are consistent with the two locus model, and we have identified candidate chromosomal locations for the two loci. These data demonstrate clearly that differences in how the egg cytoplasm modifies the incoming paternal genome are indeed genetically determined, and vary accordingly.
Animals↗