Proceedings of the National Academy of Sciences of the United States of America, Jan 30, 2015
We describe the trajectory of the human sex ratio from conception to birth by analyzing data from... more We describe the trajectory of the human sex ratio from conception to birth by analyzing data from (i) 3- to 6-d-old embryos, (ii) induced abortions, (iii) chorionic villus sampling, (iv) amniocentesis, and (v) fetal deaths and live births. Our dataset is the most comprehensive and largest ever assembled to estimate the sex ratio at conception and the sex ratio trajectory and is the first, to our knowledge, to include all of these types of data. Our estimate of the sex ratio at conception is 0.5 (proportion male), which contradicts the common claim that the sex ratio at conception is male-biased. The sex ratio among abnormal embryos is male-biased, and the sex ratio among normal embryos is female-biased. These biases are associated with the abnormal/normal state of the sex chromosomes and of chromosomes 15 and 17. The sex ratio may decrease in the first week or so after conception (due to excess male mortality); it then increases for at least 10-15 wk (due to excess female mortality)...
Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology, 1997
A method that allows the performance of double-colour chromosome painting (FISH) on previously G-... more A method that allows the performance of double-colour chromosome painting (FISH) on previously G-banded human sperm metaphases has been developed. Sperm chromosomes were obtained by using the fusion technique between zona-free hamster oocytes and human spermatozoa. Single- and double-colour chromosome painting was performed using DNA libraries specific for chromosomes X, Y and 21 on either unstained or G-banded preparations. The hybridization efficiency was very high (98%). The sequential staining technique is very useful for analyses of structural (stable) and numerical chromosome aberrations in human sperm and thus can increase the efficiency of the human sperm-hamster oocytes fusion system to assess the risk to human germ cells as a result of endogenous and exogenous factors.
The purpose of this study was to find specific rates of aneuploidy in cleavage-stage embryos comp... more The purpose of this study was to find specific rates of aneuploidy in cleavage-stage embryos compared with first trimester data and to evaluate post-zygotic selection against aneuploidy. A total of 2058 embryos were analysed by flurorescence in-situ hybridization (FISH), and specific aneuploidy rates were obtained for 14 chromosomes. Data from morphologically abnormal embryos could be pooled with data from preimplantation genetic diagnosis (PGD) cycles because it was observed that they had similar rates of aneuploidy; thus, for the purpose of studying aneuploidy they could be, and were, pooled. Specific chromosome aneuploidy rates were not related to morphology or development of the embryos. The average maternal age of patients with aneuploid embryos was significantly higher than the overall analysed population. Monosomy appeared more commonly than trisomy. The chromosomes most frequently involved in aneuploidy were (in order) 22, 16, 21 and 15. When compared with first trimester pregnancy data, aneuploidies detected at cleavage stage seem to die in excess of 90% before reaching first trimester, with the exception of chromosome 16 and gonosomes (76% and 14% respectively). Differences in chromosome-specific aneuploidy rates at first trimester conceptions are probably produced by different chromosome-specific aneuploidy rates at cleavage stage and different survival rates to first trimester.
Analysis of sperm karyotypes and two-color fluorescent in situ hybridization (FISH) on sperm nucl... more Analysis of sperm karyotypes and two-color fluorescent in situ hybridization (FISH) on sperm nuclei were carried out in a man heterozygous for the pericentric inversion inv(9)(p11q13). Sperm chromosome complements were obtained after in vitro fusion of zona-free hamster oocytes and donor sperm. A total of 314 sperm complements was analyzed: 153 (48.7%) carried the inverted chromosome 9 and 161 (51.3%) carried the normal one. None of the sperm complements contained a recombinant chromosome 9, suggesting that no chiasmata were formed in the heterochromatic region. The frequency of structural chromosome aberrations unrelated to the inversion (8.3%) and the frequency of conservative aneuploidy (3.2%) were within the limits observed in our control donors. The proportions of X-bearing (47.3%) and Y-bearing sperm (52.7%) were not significantly different from the expected 1:1 ratio. The percentage of disomy for chromosome 21 was analyzed by two-color FISH in 10336 sperm nuclei. The disomy rate for chromosome 21 (0.30%) was not significantly different from that found in our controls. These results suggest that the risk for this man of producing chromosomally abnormal offspring or spontaneous abortions was not increased, and do not support the existence of an interchromosomal effect for chromosome 21.
To assess correlation between blastocyst morphology and chromosomal status. Observational researc... more To assess correlation between blastocyst morphology and chromosomal status. Observational research study. An IVF clinic and a specialist preimplanation genetic diagnosis (PGD) laboratory. Ninety-three couples undergoing IVF treatment in combination with chromosome screening of embryos. Five hundred blastocysts underwent trophectoderm biopsy and comprehensive chromosome screening using comparative genomic hybridization (CGH). The morphology of the embryos was evaluated using standard methods. Association of aneuploidy and morphologic score. A total of 56.7% of blastocysts were aneuploid. One-half of the grade 5/6 blastocysts were euploid, compared with only 37.5% of embryos graded 1/2, suggesting an effect of aneuploidy on blastocyst development. Aneuploidy also had a negative effect on inner cell mass and trophectoderm grades. Morphologically poor blastocysts had a higher incidence of monosomy and abnormalities affecting several chromosomes. The gender ratio was significantly skewed in relation to morphology. A total of 72% of blastocysts attaining the highest morphologic scores (5AA and 6AA) were found to be male, compared with only 40% of grade 3 embryos. Morphology and aneuploidy are linked at the blastocyst stage. However, the association is weak, and consequently, morphologic analysis cannot be relied on to ensure transfer of chromosomally normal embryos. A significant proportion of aneuploid embryos are capable of achieving the highest morphologic scores, and some euploid embryos are of poor morphology. Gender was associated with blastocyst grading, male embryos developing at a significantly faster rate than females.
To determine if preimplantation genetic diagnosis (PGD) for translocation carriers with three or ... more To determine if preimplantation genetic diagnosis (PGD) for translocation carriers with three or more pregnancy losses reduces loss rates. Retrospective review of data. Preimplantation genetic diagnosis laboratory servicing IVF groups. Patients (n = 192) undergoing PGD for either a reciprocal translocation or Robertsonian translocation who had three or more previous pregnancy losses. Preimplantation genetic diagnosis for translocations. Pregnancy loss rate, pregnancy success rate defined as delivery of at least one child or an ongoing pregnancy in the third trimester, and length of time to success. Pregnancy loss rate was significantly reduced to 13% post-PGD compared with 88.5% in previous non-PGD pregnancies and to 35% to 64% from naturally conceived pregnancies as reported in the literature. Pregnancy success rate was 87%. Conception occurred after an average of 1.4 cycles or <4 months. Individuals with translocations who have experienced three or more losses benefit from PGD by realizing a significant reduction in loss rate and improvement in rate of success of pregnancy. Length of time to conceive is also dramatically reduced compared with data in the literature for similar populations not undergoing PGD.
Proceedings of the National Academy of Sciences of the United States of America, Jan 30, 2015
We describe the trajectory of the human sex ratio from conception to birth by analyzing data from... more We describe the trajectory of the human sex ratio from conception to birth by analyzing data from (i) 3- to 6-d-old embryos, (ii) induced abortions, (iii) chorionic villus sampling, (iv) amniocentesis, and (v) fetal deaths and live births. Our dataset is the most comprehensive and largest ever assembled to estimate the sex ratio at conception and the sex ratio trajectory and is the first, to our knowledge, to include all of these types of data. Our estimate of the sex ratio at conception is 0.5 (proportion male), which contradicts the common claim that the sex ratio at conception is male-biased. The sex ratio among abnormal embryos is male-biased, and the sex ratio among normal embryos is female-biased. These biases are associated with the abnormal/normal state of the sex chromosomes and of chromosomes 15 and 17. The sex ratio may decrease in the first week or so after conception (due to excess male mortality); it then increases for at least 10-15 wk (due to excess female mortality)...
Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology, 1997
A method that allows the performance of double-colour chromosome painting (FISH) on previously G-... more A method that allows the performance of double-colour chromosome painting (FISH) on previously G-banded human sperm metaphases has been developed. Sperm chromosomes were obtained by using the fusion technique between zona-free hamster oocytes and human spermatozoa. Single- and double-colour chromosome painting was performed using DNA libraries specific for chromosomes X, Y and 21 on either unstained or G-banded preparations. The hybridization efficiency was very high (98%). The sequential staining technique is very useful for analyses of structural (stable) and numerical chromosome aberrations in human sperm and thus can increase the efficiency of the human sperm-hamster oocytes fusion system to assess the risk to human germ cells as a result of endogenous and exogenous factors.
The purpose of this study was to find specific rates of aneuploidy in cleavage-stage embryos comp... more The purpose of this study was to find specific rates of aneuploidy in cleavage-stage embryos compared with first trimester data and to evaluate post-zygotic selection against aneuploidy. A total of 2058 embryos were analysed by flurorescence in-situ hybridization (FISH), and specific aneuploidy rates were obtained for 14 chromosomes. Data from morphologically abnormal embryos could be pooled with data from preimplantation genetic diagnosis (PGD) cycles because it was observed that they had similar rates of aneuploidy; thus, for the purpose of studying aneuploidy they could be, and were, pooled. Specific chromosome aneuploidy rates were not related to morphology or development of the embryos. The average maternal age of patients with aneuploid embryos was significantly higher than the overall analysed population. Monosomy appeared more commonly than trisomy. The chromosomes most frequently involved in aneuploidy were (in order) 22, 16, 21 and 15. When compared with first trimester pregnancy data, aneuploidies detected at cleavage stage seem to die in excess of 90% before reaching first trimester, with the exception of chromosome 16 and gonosomes (76% and 14% respectively). Differences in chromosome-specific aneuploidy rates at first trimester conceptions are probably produced by different chromosome-specific aneuploidy rates at cleavage stage and different survival rates to first trimester.
Analysis of sperm karyotypes and two-color fluorescent in situ hybridization (FISH) on sperm nucl... more Analysis of sperm karyotypes and two-color fluorescent in situ hybridization (FISH) on sperm nuclei were carried out in a man heterozygous for the pericentric inversion inv(9)(p11q13). Sperm chromosome complements were obtained after in vitro fusion of zona-free hamster oocytes and donor sperm. A total of 314 sperm complements was analyzed: 153 (48.7%) carried the inverted chromosome 9 and 161 (51.3%) carried the normal one. None of the sperm complements contained a recombinant chromosome 9, suggesting that no chiasmata were formed in the heterochromatic region. The frequency of structural chromosome aberrations unrelated to the inversion (8.3%) and the frequency of conservative aneuploidy (3.2%) were within the limits observed in our control donors. The proportions of X-bearing (47.3%) and Y-bearing sperm (52.7%) were not significantly different from the expected 1:1 ratio. The percentage of disomy for chromosome 21 was analyzed by two-color FISH in 10336 sperm nuclei. The disomy rate for chromosome 21 (0.30%) was not significantly different from that found in our controls. These results suggest that the risk for this man of producing chromosomally abnormal offspring or spontaneous abortions was not increased, and do not support the existence of an interchromosomal effect for chromosome 21.
To assess correlation between blastocyst morphology and chromosomal status. Observational researc... more To assess correlation between blastocyst morphology and chromosomal status. Observational research study. An IVF clinic and a specialist preimplanation genetic diagnosis (PGD) laboratory. Ninety-three couples undergoing IVF treatment in combination with chromosome screening of embryos. Five hundred blastocysts underwent trophectoderm biopsy and comprehensive chromosome screening using comparative genomic hybridization (CGH). The morphology of the embryos was evaluated using standard methods. Association of aneuploidy and morphologic score. A total of 56.7% of blastocysts were aneuploid. One-half of the grade 5/6 blastocysts were euploid, compared with only 37.5% of embryos graded 1/2, suggesting an effect of aneuploidy on blastocyst development. Aneuploidy also had a negative effect on inner cell mass and trophectoderm grades. Morphologically poor blastocysts had a higher incidence of monosomy and abnormalities affecting several chromosomes. The gender ratio was significantly skewed in relation to morphology. A total of 72% of blastocysts attaining the highest morphologic scores (5AA and 6AA) were found to be male, compared with only 40% of grade 3 embryos. Morphology and aneuploidy are linked at the blastocyst stage. However, the association is weak, and consequently, morphologic analysis cannot be relied on to ensure transfer of chromosomally normal embryos. A significant proportion of aneuploid embryos are capable of achieving the highest morphologic scores, and some euploid embryos are of poor morphology. Gender was associated with blastocyst grading, male embryos developing at a significantly faster rate than females.
To determine if preimplantation genetic diagnosis (PGD) for translocation carriers with three or ... more To determine if preimplantation genetic diagnosis (PGD) for translocation carriers with three or more pregnancy losses reduces loss rates. Retrospective review of data. Preimplantation genetic diagnosis laboratory servicing IVF groups. Patients (n = 192) undergoing PGD for either a reciprocal translocation or Robertsonian translocation who had three or more previous pregnancy losses. Preimplantation genetic diagnosis for translocations. Pregnancy loss rate, pregnancy success rate defined as delivery of at least one child or an ongoing pregnancy in the third trimester, and length of time to success. Pregnancy loss rate was significantly reduced to 13% post-PGD compared with 88.5% in previous non-PGD pregnancies and to 35% to 64% from naturally conceived pregnancies as reported in the literature. Pregnancy success rate was 87%. Conception occurred after an average of 1.4 cycles or <4 months. Individuals with translocations who have experienced three or more losses benefit from PGD by realizing a significant reduction in loss rate and improvement in rate of success of pregnancy. Length of time to conceive is also dramatically reduced compared with data in the literature for similar populations not undergoing PGD.
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