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Spontaneous dizygotic DZ twinning in humans is under genetic control. In sheep, heterozygous loss pu function mutations in bone morphogenetic protein 15 Ccg increase ovulation and hence twinning rates. There was some evidence for association between DZ 197 and a ccagg intronic BMP15 variant rsbut this was not significant after correction for multiple testing.

Three of the four novel variants p. We conclude that neither rare nor common BMP15 variants play a significant role in the variation in human DZ twinning.

The transforming growth factor signalling pathway within the ovary is critical for the regulation of ovarian function, ovulation rate and fertility Moore et al. Two genes in this pathway are growth differentiation factor 9 GDF9 on chromosome 5 and bone morphogenetic protein 15 BMP15 on the X chromosome.

Loss of function of Gdf9 in female mice blocks folliculogenesis during early follicle development and leads to infertility McGrath et al. Heterozygous mutations in both genes increase the frequency of twins and higher order multiples, whereas homozygous loss of function mutations results in ovarian dysgenesis and infertility Galloway et al. This pathway is also essential for human fertility Di Pasquale et al. Two sisters with hypergonadotrophic ovarian failure due to ovarian dysgenesis were found to carry a non-conservative amino acid substitution in the pro region of BMP15 p.

Additionally, we found that some mothers of spontaneous dizygotic DZ twins MODZT carry rare deletions and missense mutations in the coding region of GDF9 that are significantly associated with twinning Montgomery et al. BMP15 is expressed in oocytes in several mammalian species Laitinen ;i al. BMP15 stimulates granulosa cell proliferation Otsuka et al. Five different heterozygous mutations in the coding region of BMP15 in different lines of sheep increase pu rate and litter size McNatty et al.

It is unknown if variants in BMP15 contribute to variation in human twinning.

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The human BMP15 sequence has a number of variants that alter the predicted protein sequence, including rs c. We hypothesized that variation in BMP15 may contribute to the variation in human twinning and genotyped common variants identified from the literature and public databases in families of MODZT and controls.

We also searched for rare variants by conducting a mutation cccag of the coding region of the BMP15 gene in a subset of MODZT and typed these novel variants in additional families to determine whether these are associated with DZ twinning.

Study subjects were Caucasians recruited from families with a history of DZ twinning families from Australia and New 197 and families from the Netherlands with individuals available for genotyping, including MODZT.

We recruited families with two or more sisters who had given birth to spontaneous DZ twins Duffy et al. MODZT and their families were identified through records from our genetic epidemiology studies using twins and their families in Australia Lewis et al.

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In the Netherlands, ascertainment was population-based through community records as part of a systematic recruitment to the Netherlands Twin Register Meulemans et al. Mothers were explicitly asked about fertility treatments and all such cases were excluded. Genetic investigation was extended to a population-based control group of Caucasian females and males unselected for twinning historyselected at random from the electoral roll in Australia.

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Participation was voluntary and each participant gave written informed consent. Genomic DNA was extracted Miller et al. PCR fragments covering the entire coding sequence and intron—exon junctions of the BMP15 gene were analysed in MODZT, where one sister was drawn from each of affected sister pair families.

Analyses were performed using the Star Workstation version 5 Varian. The appearance of additional peaks was interpreted as indicative of a mismatch in the PCR fragment.

The completed PCR reactions were then incubated with 0. A two-step short-cycles program was used for the iPLEX extension reaction: Products were spotted on a SpectroChip Sequenom Inc. The program Sib-pair http: Since variants were genotyped in families, the case—control comparisons of allele frequencies to test association allowing for the family nature of the data were carried out using the program MENDEL 7.

To make the comparison as clear as possible, a case was defined as an MODZT, whereas a control was a member male or female of our population-based sample; other relatives of cases were treated as having unknown phenotypes. We fitted allelic association models i.

For association analysis of rare variants discovered via sequencing where only cases were sequencedwe carried out ascertainment correction conditioning the family likelihood on that of the sequenced proband. The program uses an extension of the Grantham difference and compares the amino acid substitutions taking into account composition, polarity and volume of amino acid substitutions within the context of a multiple sequence alignment for the protein.

Amino acid changes are classified as to their likelihood of interfering with protein function on a scale from class C65 most likely to C0 least likely. Two SNPs rs and rs were monomorphic in our samples and were omitted from all analyses. Genotype data for the remaining 12 common SNPs were in Hardy—Weinberg equilibrium, and overall minor allele frequencies ranged from 0.

A SNP in the promoter region rs; c. However, the differences in allele frequencies between MODZT and controls were small and the effects were not significant after correcting for multiple testing of all SNPs.

Common SNPs that were not polymorphic in our samples are not shown, 197 only the exons are drawn to scale. A search for rare variants in the BMP15 gene in MODZT identified four rare missense alterations resulting in cccag changes in the amino acid sequence. PheSer were located in the pro-region of BMP15 and two variants c. ArgThr in the mature protein region.

AlaThr as slightly less likely to affect protein function class C55, one class below C65whereas p. ProSer is predicted to have no effect class C0. The other three variants were seen in twinning families ccg not controls; the p. ProSer variant in additional members of ccay family in which it was first found, the p.

AlaThr variant in members of the original and one additional family and the p. ArgThr variant only in the sample in which it was first detected. The P -values were calculated for the likelihood ratio test MENDEL binomial link measured genotype model testing for effect of the variant on the likelihood of having twins under a multiplicative model.

BMP15 is a strong candidate gene likely to contribute to pk variation in human twinning. The gene is specifically expressed in the oocytes of developing follicles Laitinen et al. The frequency of the C allele of one intronic SNP rs was higher in MODZT than in controls, although this oi not significant after accounting for multiple testing.

There were no significant associations between haplotype frequencies and the DZ twinning phenotype. We carried out a similar screen of BMP15 in probands from our most twin dense families. One of these p. The other three variants were seen only in twinning families.

However, the variant most likely to affect protein function, p. It is possible that these variants are twinning associated alleles with reduced penetrance; but although both are predicted to interfere to some degree with protein function, whether or not they actually have an effect is unknown. AlaThr variant within one of the two families in which it was detected cannot be determined due to the incomplete sampling of this very large extended pedigree.

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Taken together, our results suggest that the contribution of rare variants in BMP15 to the variability in human twinning would be small. There are species differences in the actions of BMP Loss of function mutations in humans and sheep has dramatic consequences on follicle development. A mutation at codon in the preproregion of human BMP15 associated with hypergonadotrophic ovarian failure in two sisters with streak ovaries Di Pasquale et al. In contrast, the targeted deletion of the second exon of the Bmp15 gene in mice has limited effects on folliculogenesis Yan et al.

Female Bmp15 knockout mice are subfertile due to defects in the ovulation process and the ability of oocytes to develop into normal embryos Liao et al. The differences between these species may reflect differences in the relative importance of BMP15 and GDF9 in regulating events of folliculogenesis Liao et al.

Studies with a recombinant human BMP15 p. Ile31Asp substitution Liao et al. Val31Asp variant in the Inverdale strain of sheep Galloway et al.

This contrasts with evidence for sheep where at least five different BMP15 mutations are associated with high ovulation rates and litter sizes in different flocks, where they have attained high frequencies due to artificial selection or genetic drift McNatty et al.

These variants have been identified in prolific breeds of sheep, and to date there has been no systematic screen for variants in either BMP15 or GDF9 in the wider sheep population to estimate the frequency of rare variants or the relative importance of variation in these two growth factors influencing ovulation rate.

Taken together, our results suggest GDF9 plays a more important role than BMP15 in the regulation of twinning in humans Montgomery et al. Four of the common BMP15 variants analysed here have recently been associated with high response to treatment with recombinant follicle-stimulating hormone FSH during assisted reproduction Moron et al.

Minor alleles for variants c. Although the numbers of women involved were small We have earlier shown that the GDF9 variant p.

Arg68Trp Di Pasquale et al. AlaThr Di Pasquale et al. Ser70Ser Dixit et al. In previous reports, the p. This and the other variants we detected may be rare polymorphisms rather than mutations, and further studies are now required to confirm whether these variants are in fact associated with POF.

The association of the GDF9 p. ProSer variant with both twinning Palmer et al. We found no globally significant association between twinning and any BMP15 variant or haplotype, but the possibility that multiple variants might affect either POF or twinning is intriguing. Further studies will be required to determine if such differences reflect the rare frequencies of these variants in each condition or whether variants can influence POF and twinning independently. In conclusion, we found no evidence that either rare or common variants in BMP15 play any significant role in the variation in human DZ twinning.

We cannot entirely rule out weak effects or epistatic interactions with other variants, but very large studies will be required to examine these effects.

ProSer variant associated with twinning Palmer et al. Further studies should examine the relationships between twinning and POF. National Center cxag Biotechnology InformationU.

Published online Jul 9. Zhen Zhen Zhao1 Jodie N. Painter2 James S.

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