Intrauterine Selection Research Articles

Ak1 genetic polymorphism and season of conception

The season of conception affects human reproduction, intrauterine growth, neonatal parameters, sex ratio, cognitive development and, in adult life, performance in many fields. Associations between polymorphic enzymes and season of conception have been also reported. In this study we searched for a possible association between season of conception and adenylate kinase locus 1 (Ak(1)). Two samples of 381 and 248 consecutively newborn infants from two Italian cities with different geographical positions and climatic conditions were considered. Three way contingency table analysis and Student t-test analysis were performed. Ak(1)2-1 phenotype is more frequent in males conceived in the summer-autumn period than in those conceived in winter-spring and this association depends on maternal Ak(1) phenotype (p=0.001). There is also an interaction between season of conception and Ak(1) phenotype concerning their effects on sex ratio and birth weight. The present data suggest a complex interaction involving seasonal cycles, maternal and foetal Ak(1) genotype and sex of foetus concerning their effects on intrauterine selection and neonatal parameters.

Adenylate kinase genetic polymorphism and spontaneous abortion

Recent studies on healthy puerperae suggest that Adenylate kinase locus 1 (Ak(1)) genetic polymorphism could be involved in intrauterine selection. In this article, we have searched for a possible relationship between Ak(1) polymorphism and spontaneous abortion. 178 women with primary repeated spontaneous abortion (RSA), 487 healthy consecutive puerperae, 251 puerperae with diabetes, and 361 consecutive healthy female newborns from the White Caucasian population of Central Italy delivered at the Maternal Department have been studied. In these subjects, Ak(1) phenotype was determined to study the relationship between this enzyme and spontaneous abortion. The proportion of Ak(1)2-1 phenotype is higher in women with history of two or more spontaneous abortion than in puerperae with a negative history of spontaneous abortion and in female newborns infants (O.R. 1.930; 95%C.I. 1.113-3.280). Moreover, RSA women carrying the Ak(1)2-1 phenotype have a reduced probability of having live-born infants. Our findings suggest a reduced reproductive efficiency of women carrying the Ak(1)2-1 phenotype: this observation could have practical importance in predicting the probability of reproductive success in couples with RSA and in the practice of in vitro fertilization.

A Case Report of a Male Patient With Hb Hammersmith [β42(CD1)Phe→Ser, TTT>TCT

All Hb Hammersmith [β42(CD1)Phe→Ser, TTT>TCT] patients reported so far have been female, suggesting that this condition may occur as a negative, fatal intrauterine selection against males. In this case report, we describe a male case of Hb Hammersmith. A 6-month-old male patient, born from ovum donation, presented with hemolytic anemia and cyanosis. Hemoglobin (Hb) electrophoresis revealed decreased Hb A (54.0%) and Hb A2 (0.3%) and markedly increased Hb F (45.7%) levels. Direct sequencing revealed a missense mutation in the HBB gene, c.128T>C (p.Phe42Ser), which is known as Hb Hammersmith. This mutation was not identified in any of this patient’s family members. This is the first case of Hb Hammersmith in a male patient, and this study demonstrates that Hb Hammersmith is likely a non fatal condition for males during the intrauterine period.

Effect of smoking and ABO blood groups on maternal age at child bearing and on birth weight

ObjectiveThe negative effects of cigarette smoking on human reproduction and on birth weight are well documented. On the other hand ABO system, encoding for glycosyltransferases, contributes to biosynthesis of antigens and oligosaccharide structures involved in blastocyst adhesion and intrauterine selection. In this paper we have searched for possible interaction between ABO system and smoking concerning their effects on maternal age at child bearing and on birth weight. Study designWe have studied 395 consecutive healthy puerperae from the White Caucasian population of Rome. ABO blood group was determined by standard laboratory methods. Three-way contingency table analysis was performed according to Sokal and Rohlf and Chi square test of independence by SPSS programs. ResultsThe proportion of smokers is higher in A phenotype than in other ABO types among young puerperae (≤24 years) while it is lower in A phenotype than in other types among older women. The negative effects of smoke on birth weight is much more evident in women with A blood group than in women carrying other ABO phenotypes. The interaction between smoking and ABO blood groups concerning their effects on birth weight is influenced by gender of newborn and by maternal age. ConclusionABO blood groups and smoking could have a joint influence on maternal age at child bearing and on birth weight.

ABH secretor genetic polymorphism: evidence of intrauterine selection

Objective Fucosyltransferase locus 2 (FUT2) controls the presence or absence of blood group substances (A, B, H) in the saliva and other body secretions. Secretor/non-secretor phenotypes are associated with some metabolic and infectious diseases. ABO and FUT2 contribute to build up oligosaccharide structures of the cell surface that are important for blastocyst adhesion and resistance to microbial invasion. We investigated a possible selection on ABH secretor phenotypes during intrauterine life. Study design Three hundred and fifty-six consecutive healthy puerperae and their newborn infants from the caucasian population of Rome were studied. Informed consent for study participation was obtained from the mothers to participate and the study was approved by the Institutional Review Board. ABH secretor Se phenotype was determined on saliva by standard laboratory procedure. Results Symmetry analysis of mother infant Se phenotype revealed a deficit of mother Se+/newborn Se− with respect to expected values. The asymmetry is present only in infants carrying the A blood group antigen. The asymmetry was dependent on several maternal and neonatal parameters including maternal age, smoke, parity and gestational duration. Conclusions The data suggest intrauterine selection against Se− of the embryo carried by a Se+ mother. Such selection is dependent on factors influencing the maternal environment. The study could have practical importance in assessing the risk of infertility and success of artificial insemination.

Smoking and Human Reproduction: The Effect of Adenylate Kinase Genetic Polymorphism

We investigated the possible influence of adenylate kinase genetic variability on the effect of maternal smoking on intrauterine selection and development. Adenylate kinase locus 1 belongs to a family of monophosphate kinases that plays an important role in the synthesis of nucleotides involved in several metabolic functions. Three hundred forty-five newborn consecutive infants from the Caucasian population of Rome and 360 consecutive infants from the Caucasian population of Penne were studied. The proportion of newborns carrying AK1*2 allele was analyzed in relation to smoking and maternal age. The effect of smoking on birth weight was also analyzed in relation to AK1 phenotype and maternal age. Statistical analyses have been performed according to SPSS programs. In offspring of women aged 28 years or less, the proportion of newborns carrying the AK1*2 allele is much higher in smoking than in nonsmoking mothers (13.2% versus 2.6%). Such association is lacking in mothers aged more than 28 years (6.5% versus 9.2%). The negative effects of smoke on birth weight is more marked in AK11 mothers than in AK1*2 carriers. The data suggest that zygotes carrying AK1*2 allele are relatively protected from the damaging effects of smoking, resulting in a relatively higher proportion of newborns carrying this allele among smoking mothers.

Evidence of an association between the adenylate kinase genetic polymorphism and primary repeated spontaneous abortion

A recent study of healthy pueperae suggests that the adenylate kinase locus 1 (Ak1) genetic polymorphism may be involved in intrauterine selection. This prompted us to search for a possible relationship between this polymorphism and primary repeated spontaneous abortion. Ak1 catalizes the reaction ATP+AMP <—>2ADP, and has an important role in the synthesis of nucleotides involved in several metabolic functions as well as in DNA and RNA synthesis.

Nonmosaic balanced homologous translocations of major clinical significance: Some may be mosaic

The main mechanism proposed for formation of homologous translocations/isochromosomes is mitotic and if this occurs in a chromosomally normal conceptus, mosaicism would be expected to be seen. The lack of mosaicism in published cases of rearrangement (REA) of mitotic origin might be explained by under-detection due to the low level mosaicism for a normal line. Recently it was reported that sex-specific centromere instability in early embryogenesis leads to a female prevalence among individuals with mosaicism for pericentromeric rearrangements. To determine whether carriers of apparent non-mosaic homologous REA could be mosaics for a normal cell line, the sex ratio (male to female ratio) among carriers of balanced and unbalanced homologous translocations/isochromosomes was studied. This ratio was determined to establish if there is a female predominance similar to that seen in carriers of REA with mosaicism. In reviewing the literature, a female prevalence among fetuses with balanced homologous REA and among carriers of unbalanced homologous REA detected prenatally, postnatally and in miscarriages was found. Overall, there were 48 males and 72 females in the collected sample, and this ratio differed significantly from the expected sex ratio of 1.06 (P = 0.0075). There is not a male prevalence among miscarried fetuses, there is no evidence of selection against males in the collected material of this study. The analysis of sex ratios in different variants of trisomy 13 with respect to ascertainment (prenatal diagnosis, miscarriages, liveborn) also does not support an intrauterine selection against males as a cause of a female prevalence among carriers of homologous REA. Thus the data presented in this paper suggests that a proportion of the carriers of balanced homologous REA may have mosaicism for a normal line. Since low level mosaicism for a normal line in a translocation carrier would alter his/her reproductive options, it can be recommended that molecular polymorphic analysis be applied to these cases. This would allow those resulting from meiotic formation to be distinguished from those resulting from postzygotic formation. This latter mechanism may indicate the presence of a mosaicism for a normal line, making further intensive karyotypic analysis advisable. However, additional studies of healthy carriers of homologous REA of chromosome 14 or 15 should not be done. (c) 2007 Wiley-Liss, Inc.

Is Delayed Childbearing Changing Gene Frequencies in Western Populations?

Experimental data and clinical observations suggest that delaying childbearing influences the biology of the mother-fetus relationship, with a negative effect on fetal development and predisposition to severe diseases such as type 1 diabetes. We reason that advanced maternal age may influence intrauterine selection, favoring genotypes that are more adapted to the intrauterine environment of less young women. In the present study we have investigated the relationship of maternal age to HP genotype and PGM1-Rh area (chromosome 1) that have been previously found to be associated with fertility and developmental parameters. HP phenotype was determined in 679 consecutive puerperae from the population of central Italy. PGM1 phenotype and Rh C phenotype were determined in 222 puerperae and 200 newborns. The HP 1,1 phenotype decreases and the HP 2,2 phenotype increases with maternal age. The proportion of phenotypes carrying both the Rh C and PGM1*1 alleles is much higher in puerperae older than 36 years than in puerperae of age 22 years. The frequency of the PGM1*1-Rh C haplotype increases and the frequency of the PGM1*2-Rh C haplotype decreases with maternal age. The changes in these genetic systems with advancing maternal age are similar in mothers and newborns. The delay of childbearing age, associated in Western countries with the fertility transition in addition to detrimental effects on intrauterine development and increased susceptibility to severe disorders, could bring about changes in the genetic composition of a population.

Epidemiology of double aneuploidies involving chromosome 21 and the sex chromosomes

The chance of two chromosome abnormalities occurring in one conceptus is very small. However, some authors have suggested that double aneuplodies (DAs) might be more common than the product of their individual frequencies. The nonrandomness of such DA events was considered to be evidence that nondisjunction (NDJ) may be genetically determined. Data collected from the National Down syndrome Cytogenetic Register (NDSCR) in England and Wales and from the literature indicate that the frequencies of all nonmosaic DAs, except for 48,XXY,+21, are lower than expected, probably because of strong intrauterine selection against such pregnancies. Collectively, we identified 52 cases of nonmosaic 48,XXY,+21; 28 cases of 48,XYY,+21; and 14 cases of 48,XXX,+21 in liveborns and 13 cases of 48,XXY,+21; four cases of 48,XYY,+21; and two cases of 48,XXX,+21 after prenatal diagnoses. Among these cases, analysis of the published unbiased cytogenetic surveys of liveborn DS revealed 24 cases of 48,XXY,+21; nine cases of 48,XYY,+21; and seven cases of 48,XXX,+21. These figures are different from the expected proportion of 1:1:1 (P < 0.001), with carriers of XXY overrepresented in the group of carriers of DA. Mechanisms put forth to account for the higher occurrence of 48,XXY,+21 may include greater accessibility of disomic ovum to Y-carrying sperm, and promotion of NDJ in ovum by Y-bearing sperm. 48,XXY,+21 DA was found to be age-dependent, as the proportion of mothers over age 35 (x = 33.0) was increased over the general population. This is in contrast to the apparently age-independent 48,XYY,+21 DA, with a mean maternal age of 24.7 (P < 0.001). Paternal ages were also remarkably different between the groups, with a mean age of 37.9 in 48,XXY,+21 cases and a mean age of 27.9 in 48,XYY,+21 cases (P < 0.01). Maternal age-related factors, rather than genetic predisposition, may play a more important role in the etiology of the most common DA, 48,XXY,+21.

Offspring sex and pregnancy outcome by length of gestation

Background: It takes a higher number of male than female embryos to produce a live born infant. The unbalanced pregnancy survival by offspring sex may also be reflected in higher proportion of preterm male births, and in unbalanced sex distribution in certain pregnancy conditions, such as preeclampsia. Methods: We used data from the Medical Birth Registry of Norway, a population-based registry that has recorded births since 1967. For this study, we used information on offspring sex and length of gestation that was available for 1,691,053 (92.8%) singleton births among a total of 1,822,982 births from 1967 to 1998. We estimated sex ratios and perinatal mortality by length of gestation, and assessed whether the ratio of offspring sex in preeclampsia varied by length of gestation. Results: For preterm births, there was a strong male dominance. Within five categories of gestational age between 16 and 36 weeks, the male/female ratios were 2.48, 1.26, 1.28, 1.32, and 1.28. At weeks 37–39, the sex ratio was 1.17, but at weeks 40–42 the number of male and female births was practically identical (sex ratio 1.00). Over all, the male/female ratio was 1.06. Perinatal mortality was consistently higher in males across the whole range of gestational age; in total it was 21% (95% CI, 18–25%) higher in male offspring. In preeclampsia with preterm delivery (<37 weeks), the sex ratio was reversed: female offspring was substantially more common than males (sex ratio 0.87), but in preeclampsia with delivery at term (37–42 weeks), the proportion of males was higher (sex ratio 1.06) than for females. Conclusion: The sex differences by length of gestation and in preeclampsia may reflect that male embryos are subject to stronger intrauterine selection forces than females. Possibly, implantation may be the critical event, where offspring sex may be one of the factors that determine success.

Distribution of abnormal karyotypes among malformed fetuses detected by ultrasound throughout gestation.

A karyotype was obtained from 755 fetuses with structural anomalies detected by sonography between 13 and 40 weeks' gestation. Gestational age was found to have no influence on the prevalence of chromosomal aberrations. The incidence in the second and third trimesters of pregnancy was 15.7 and 17.5 per cent, respectively. The contribution of the different malformations to such proportions did, however, change throughout gestation. Cystic hygroma was by far predominant in the early second trimester, cardiac defects in the late second trimester, and duodenal atresia in late pregnancy. Our findings confirm that karyotyping of malformed fetuses is highly advisable; the importance of chromosomal investigation is not dependent on the gestational age at detection of the structural defect as the likelihood of finding a chromosomal anomaly during the second and third trimesters is quite similar. Spontaneous intrauterine selection of chromosomally abnormal fetuses is most likely counterbalanced by the limited accuracy of prenatal ultrasound in recognizing many fetal anomalies early in pregnancy.

Is p53 polymorphism maintained by natural selection?

We present here a new interesting feature of the human tumor suppressor gene p53: a very pronounced ethnic and clinal variation of polymorphic codon 72 alleles. The frequency of the A1 (Pro) allele showed a north-south cline from 17% in Swedish Saamis to 63% in African Blacks (Nigerians), and there was a significant (p < 0.001) correlation (r = 0.95) between the A2 frequency and latitude. In the Finnish and Swedish populations no significant differences were found with respect to the genotype and allele distributions in spontaneously aborted fetuses and liveborn children, which makes differential intrauterine selection unlikely. However, the ethnic and clinal variations suggest that the codon 72 polymorphism is balanced and maintained by natural selection.

The distorted α2-adrenoceptor genotype distribution in F 2 populations of dahl salt sensitive and resistant rats cross

To examine the role of the α 2-adrenoceptor gene in the development of genetic hypertensive rats, we tested Dahl salt sensitive (S) and resistant rats (R) for the presence of a restriction fragment length polymorphism (RFLP) in that gene. An RFLP was found between the S and R rats with a human kidney cDNA α 2-adrenoceptor probe ( α 2-C4) and Msp I restriction endonuclease. The α 2-C4 probe detected two alleles, S and R, of 3.0 and 2.8 kb in size. The two strains of rats were each homozygous for their corresponding allele. The inheritance of the alleles was investigated by crossbreeding S and R rats and subsequent brother/sister mating of F 1 rats. Two hundred and fifteen F 2 rats were produced by breeding 14 pairs of F 1 rats. An atypical distribution of α 2-adrenoceptor genotypes was observed. We found a reduced number of the SS genotype in both males and females of the F 2 generation. To investigate the mechanism of this distorted α 2-adnenoceptor genotype distribution in the F 2 rats of S and R cross, we backrossed the F 1 rats to their S and R parents. The litter size and gender distribution were counted for each breeding colony. Analysis by chi-square test showed that there was no sex difference among the backcrosses. Also, there was no significant decrease in litter size. This excludes the possibilities of fetal demise of S homozygotes and intrauterine selection. Therefore the deficiency of SS genotype may be due to gene recombination or may not be due to the α 2-adrenoceptor gene itself, but to the effect of other genes closely linked to the α 2-adrenoceptor.

Evidence of selective interaction between adenosine deaminase and acid phosphatase polymorphisms in fetuses carried by diabetic women

Possible selective interaction between genetic polymorphisms of acid phosphatase locus 1 (ACP1) and adenosine deaminase (ADA) has been investigated in a sample of 211 infants from diabetic women, and in 350 consecutive infants from normal women. Newborns from diabetic pregnancies carrying the ADA2 allele show a lower proportion of BA and CB phenotypes (heterozygotes for the main allele of ACP1 system), compared with both their mothers and normal infants. The observation suggests that, in a diabetic environment, intrauterine selection may act against double heterozygotes for the ACP1 and ADA systems.

Sex ratios in otosclerotic families.

The sex ratio (proportion of males) of offspring of otosclerotics is significantly and substantially below expectation. To account for this and other features of the condition, it has been suggested elsewhere that otosclerosis is subject to autosomal dominant transmission with intrauterine selection against male heterozygotes. To test this hypothesis, a search was made for published data on the sexes of sibs of otosclerotics. These sibs do not have an unusual sex ratio, thus casting doubt on the hypothesis. Accordingly it is suggested here that both the condition and the sex ratios are causally related to levels of steroid hormones.

Intrauterine death: an approach to the analysis of genetic heterogeneity.

A study of survival time of zygotes in utero and the relationship with parental phenotype of a series of genetic polymorphisms was carried out in 41 couples with habitual abortion. Variability of intrauterine survival time was found to be much higher between families than within families suggesting that several genetic entities contribute to the condition clinically defined as habitual abortion. Significant differences of survival time were found in relation to the length of the paternal Y chromosome and to the maternal phenotypes of PGM1 and Ss. These observations are in line with previous data suggesting intrauterine selection in these polymorphisms. Further studies of the timing of intrauterine death in relation to 'normal' genetic polymorphisms may help to clarify the aetiology of spontaneous fetal loss.

Transferrin C subtypes and spontaneous abortion.

The transferrin C subtypes were studied in relation to spontaneous abortion and a number of different genetic markers and traits. Among mothers with a history of spontaneous abortion an increased frequency of the C2 gene and especially of the C2 type was found. A correlation was found between the maternal C2 type and the placental alkaline phosphatase variant F, which previously has been shown to be associated with spontaneous abortion. The mechanism behind the intrauterine selection implied is unlikely to be immunological incompatibility between mother and fetus. No association was found with ABO and Rh blood groups, Hp and Gc serum groups, the pregnancy zone protein (PZ), red cell acid phosphatase types and birth weight.

Cytogenetics of the South American akodont rodents (Cricetidae). IV. Interspecific crosses between Akodon dolores × Akodon molinae

AbstractInterspecific hybridization of Akodon molinae × Akodon dolores was obtained by crossing animals from our laboratory breeding colony. Sixteen pregnant females which produced a total of 86 Akodon hybrids were obtained from a total of 40 matings. The sex ratio in the hybrids was 2.58 males for each female. No clear explanation for this abnormal ratio can at the present time be given; however it cannot be ascribed to a phenomenon of intrauterine selection between sexes. The presence of natural hybrids has not been detected; therefore, the appearance of Akodon molinae × Akodon dolores hybrids is up to this moment a laboratory phenomenon.

ABO blood groups and fertility--with special reference to intrauterine selection due to materno-fetal incompatibility.

The purpose of the present investigation was to study whether there is differential fertility between different mating types of ABO blood group system. Selective force which is operating through maternal-fetal incompatibility has been observed in the differential fertility between compatible and incompatible mating groups in the present sample of 183 families of Visakhapatnam town of Andhra Pradesh,India. The differences in the mean numbers of pregnancies as well as living children between the two major mating groups, compatible and incompatible are significant. The fertility rates of O fathers and O mothers were significantly higher than those in matings in which neither parents belongs to O. The selection is operating to reduce the gene ratio of A and to increase the gene ratios of O and B in this sample.