Association of ACE I/D polymorphism and recurrent miscarriages in an Italian population with a pre-modern reproductive pattern.

Angiotensin I-converting enzyme (ACE), in addition to its role in the renin angiotensin system, has a physiological function in the fibrinolysis pathway, the accurate control of which is critical for the normal development of pregnancy. Recently, the ACE I/D polymorphism was found to be associated with recurrent spontaneous miscarriages (RM). The present study analysed the relationship between ACE I/D polymorphism and the number of spontaneous miscarriages, the number of pregnancies and the number of children in a sample of 88 Italian women born before 1930, with a pre-modern reproductive behaviour. The ACE DD genotype was more prevalent among women with RM (p = 0.02). However, the women carrying the DD genotype not only had the highest number of miscarriages (p = 0.03), but also the highest number of pregnancies with an eventual complete fertility (children no = 4.4), similar to that of women carrying the other ACE genotypes. In contrast, published data on contemporary women with RM seem to indicate that the DD genotype could now be associated with a reduced reproductive success compared to the other ACE genotypes. It is suggested that this phenomenon may be the effect of the interaction between ACE genotypes and contemporary reproductive behaviours (delay in childbearing, below-replacement fertility).

Estrogen receptor alpha polymorphisms and fertility in populations with different reproductive patterns.

The estrogen receptor (ER) plays an important role in mediating estrogen action on target tissues. ER-alpha, the most abundant, is found in all human reproductive tissues and studies on alpha-ER knockout mice have highlighted its role in reproduction. ER-alpha gene (ESR1) polymorphisms have been associated with a variety of disorders including human infertility. In this study, we examined the association of ESR1 PvuII and XbaI polymorphisms with fertility in two populations with different reproductive patterns and precisely in a sample of healthy Italian men and women (n=178) and in a sample of healthy African-Ecuadorian women (n=57). ESR1 xx and ppxx genotypes among the Italian men were found to be associated with an above-median number of children (P=0.01 and P=0.004, respectively). ESR1 pp genotype among the Italian women showed a tendency to be associated with a lower number of abortions (P=0.04), whereas ESR1 pp and ppxx genotypes among African-Ecuadorian women were associated with a higher number of children (P=0.02 and P=0.03, respectively). These results are consistent with previous observations indicating a role of ESR1 genotypes in human infertility and give insight into the complex interactions between genotypes and reproductive behaviours in human populations.

Absence of selection on birth weight in modern Italy.

The effect of stabilizing and directional selection on birth weight has been analyzed for Italian births from 1954 to 1994, a period of rapid improvement in environmental conditions. The population of newborns was subdivided according to gestational age, one of the main covariates of birth weight. In the last cohort of births, no selection at all (neither stabilizing nor directional) was found in full-term babies, which represent more than 95% of total deliveries. Preterm babies are still selected against, even if at lower rates than in the past. It can therefore be claimed that improved and widely available prenatal and neonatal care has dramatically changed the selection patterns previously associated with birth weight in the majority of the Italian population. The mortality rates associated with birth-weight variations lying in a wide interval (2.5 kg-4.5 kg) are nowadays very similar, and both stabilizing and directional selection have practically disappeared.

Effects of environmental changes on natural selection active on human polygenic traits.

During the last century, industrialized countries experienced such an improvement in socioeconomic conditions and in sanitation that it is likely that the selective forces active on human metric traits have been modified. Perinatal mortality as a function of birth weight is one of the clearest examples of natural selection in humans. Here, trends over time of stabilizing and directional selection associated with birth weight have been analyzed in Japan from 1969 to 1989. The population of newborns has been subdivided according to gestational age, which is one of the main covariates of birth weight. The results show that in full-term babies both stabilizing and directional selection are coming to an end, whereas in babies born after 8 months of gestation these selective forces are still active, even if at much lower levels than in the past. The peculiar results found in the 7-month-gestation population are probably due to grossly abnormal cases of immaturity.

Relationships between early mortality and sex ratio: changes over the last century in Italy.

Italy, like other industrialized countries, experienced during the last century a dramatic change in socio-economic conditions and in sanitation. In order to ascertain whether the improvement in living conditions has modified the relationships between the sex ratio at birth and selection by early mortality (stillbirth, mortality up to 1 month, mortality up to 1 year of life), the secular trends of the sex ratio in total births, in survivors up to 1 month and up to 1 year of age have been calculated for the Italian population over the last century. The results can be summarized as follows: (i) the sex ratio in total births progressively decreases; (ii) the sex ratio in survivors up to 1 year progressively increases. As a result of these two opposite trends, the difference between sex ratio at birth and after the incidence of early mortality is progressively getting smaller.

Birth weight and natural selection: an example of selection relaxation in man.

Differential mortality as a function of birth weight was studied in Japan in the years 1969, 1974 and 1984. During the 15-year interval of observation a progressive equalization of mortality in the birth weight classes near the mean was found both for perinatal mortality as a whole and for its two components, stillbirth and mortality within the 1st week of life. The relaxation of selection on this metric trait is confirmed by the analysis of the variation over time of intensity of selection. A comparison of the Japanese population with other populations so far studied is also presented.

Natural selection associated with birth weight. VI. Towards the end of the stabilizing component.

The secular trend for stabilizing selection on birth weight has been analysed in Italy from 1954 to 1985 in order to study changes in the forces of natural selection which have occurred as a consequence of progress in health care. In previous papers we demonstrated a very rapid relaxation of stabilizing selection on birth weight. In this paper we show that in the last few years this kind of selection has been coming to an end for the vast majority of Italian newborns.

Stabilizing selection in man: the effect of mother's age on birthweight variance.

In order to study the effect of mother's age on birthweight variance, data were collected from Official Vital Statistics of the USA, Japan and Italy. Birthweight means and variances were calculated for all single births and for live births only. The results demonstrated that birthweight variance regularly increases in babies born to mothers of increasingly older age (with the exception of the youngest mothers). Moreover, the higher the variance in all births, the more the variance diminishes after late fetal selection. Therefore, a feedback phenomenon takes place in the stabilizing component of selection, i.e. the difference between the variance of all births and that of live births. As a consequence, at least part of the higher number of fetal losses experienced by older mothers can be attributed to the increased birthweight variance of their children.

Natural selection associated with birth weight. V. The secular relaxation of the stabilizing component.

The secular trend of stabilizing selection on birth weight has been studied during the last decades in 17 countries, representative of America, Asia and Europe. A relaxation of the intensity of selection is regularly observed, which can probably be attributed to a progressive reduction of the environmental component of birth weight variance.

Genotype-environment relationships: an analysis of stature distribution curves during the last century in Italy.

The secular trend of stature in Italy from 1874 to 1960 has been examined using military records concerning nearly complete samples of males born in Italy in given years. The national mean value increased by nine cm (about one cm/decade) and the averages of the different Italian regions tend progressively to aggregate towards higher values (the north) and lower ones (the south). The rate of increase of stature was more or less constant up to subjects born in 1945, but in the period 1945-55 a very steep increase was observed. In more recent times, a clear slowing down has taken place both at national and regional level. The following moments around the mean were investigated: (1) variance--the national value has remained more or less constant and regional values pass from very diverse figures to very similar ones; (2) skewness--the initially negative national value has become slightly positive; in the regions, from very diverse negative values a close aggregation around zero is recently attained; (3) kurtosis--initial national hyperkurtosis has reduced to values typical of the Normal distribution; the same is true for regional figures which, moreover, have become closely aggregated. The increasing fit of stature distribution to the Normal distribution agrees with the hypothesis of an increasing expression of the genetic endowment in consequence of a progressive improvement in living conditions.

Effects of environmental changes on the phenotypic expression of human polygenic traits.

The very large increase in adult stature during the last century is well documented for many countries and this phenomenon has been associated with the rapid improvement of environmental conditions. In the case of Italy, data relative to its regions and drawn from the military records of the last century showed a rapid normalization (i.e. elimination of both negative skewness and hyperkurtosis) of the distribution (1874-1938), followed by acceleration of the average increase (1938-57), which is now approaching a plateau (1957-64). Two different interactions between genotype and environment are hypothesized: the curve normalization is interpreted as being due to the elimination of extremely unfavourable conditions which inhibit growth, while the rapid stature increase is possibly due to the achievement of an environmental threshold, such as to permit a complete expression of the genetic potential. In fact, under the multifactorial model, a perfectly normal distribution is expected, unless there is differential selection before age 18.

Sex differential patterns in perinatal deaths in Italy.

In industrialized countries, male excess is generally found in early deaths, despite the overall decrease in mortality. We studied the association between sex and some factors generally considered crucial for babies' survival, such as mother's age and education, birth order, and gestational age, in order to gain insight into the causes underlying the persisting higher vulnerability of male sex in early life. The analysis was performed on babies dying during the perinatal period. These were subdivided into those who were stillborn and those who died during the first week of extrauterine life. A higher male excess among babies dying during the neonatal period than among those who were stillborn was always found in all classes of all factors. The finding of such generalized male overmortality in the early extrauterine period of life, together with the patterns shown by the temporal sex ratio in stillbirths and in early deaths, supports the hypothesis of a postponement of male risk from late fetal into neonatal life.

Sex ratio and selection by early mortality in humans: fifty-year analysis in different ethnic groups.

We studied the sex ratio (M/F) in representative populations of the main human ethnic groups, namely, US whites, US blacks, and Japanese. The data cover a period of over 50 years. For intra-ethnic comparison, we included analogous data on Italians. The populations studied show heterogeneous patterns: the US white and Italian populations are the most similar, with no drastic variations in live-birth sex ratio throughout the period. Comparison of sex ratio data for live-borns and 1-year-old infants yields a similar pattern in all groups; the differences between the two sex ratio values are constantly reducing. It can be hypothesized that in the near future the sex ratio observed at birth will be maintained up to reproductive age. If this value is stabilized by natural selection, as is likely, new relationships between the sex ratio and selection are expected to evolve in the populations of developed countries.

Sex ratio and natural selection in humans: a comparative analysis of two Caucasian populations.

In the course of the last century industrialized countries have experienced significant changes in mortality rates. Since the sex ratio of a population may be considered a function of, among other factors, differential mortality in the two sexes, it is expected to correlate with changes in sex-specific mortality rates. In this paper secular changes in the sex ratio at birth and after the action of relevant components of early selection (stillbirth, mortality within the first month and within the first year of life) have been studied in the Italian and in the USA White populations. The results can be summarized as follows. (i) In the past, extra male-specific mortality appeared to reduce the relatively large values of the sex ratio observed at birth, and this held true in both populations. (ii) In more recent times, male-specific mortality has been decreasing in all age groups, and the sex ratios before and after the action of early selection now tend to identical values. Therefore, it can be envisaged that in the near future the sex ratio observed at birth will be maintained up to the reproductive age. If the reproductive value is stabilized by natural selection, as is likely, new relationships between sex ratio and selection may be expected to develop in a relatively short time.

Factors affecting the sex ratio in humans: multivariate analysis of the Italian population.

Several studies have shown that the human secondary sex ratio is affected by a wide range of biological and environmental factors. Here, we describe a partitioning of the sex ratio variability as observed in the Italian population over the last two generations. This period has seen drastic changes in the environmental conditions of Italy. As a consequence, demographic and biological variables that can affect the sex ratio have also changed dramatically. In an attempt to isolate any specific effect, we used a stepwise multiple regression to analyze the covariation over time of the sex ratio and of relevant parameters, such as stillbirth rate, maternal age, firstborn proportion, and birth order. The results show that a quadratic function of the firstborn proportion and mother's age is a fairly good predictor of sex ratio values.

Changes in twinning rate: Italy 1950-1996.

BACKGROUND: In the wide-ranging debate about the potential monitors of population fertility, twinning rate has been considered a candidate. In the developed countries, a decline in spontaneous twinning rate began around 1950 and continued until the late 1970s. The decrease in mean maternal age at delivery and the number of children per family have been considered as possible reasons for the decrease. The rise in twinning rates, which began in the 1980s, is probably due to the spread of assisted reproduction, at least for older mothers. METHODS: The temporal trend in twinning rate and the relationship with maternal age at delivery and birth order in the Italian population were analysed. RESULTS: The recent increase in twinning rate can be mainly attributed to the recourse to assisted reproduction techniques, as demonstrated by the twinning frequency among older primiparae. The twinning rate recently observed in young mothers approximates to the value of the 1950s, which is assumed to represent a 'natural' fertility condition. CONCLUSIONS: On the assumption that twinning is an indicator of fertility, and hence of population fitness, the present data seem to suggest that natural fertility has been slightly increasing in the Italian population.

Heterogeneous effects of natural selection on the Italian newborns.

We have studied the impact of natural selection through stillbirth on the Italian population, taking into account the socio-economic heterogeneity of the country. The results suggest that older age at delivery and lower cultural level of the mothers, indicators of critical biological and socio-economic conditions, even at present increase stillbirth risk. Moreover, in the less favourable environment of the southern regions, selection is still sex-specific.

The effects of demographic transition on the opportunity for selection: changes during the last century in Italy.

The index of opportunity for selection proposed by Crow has been calculated for the Italian population during the last century. The evolution of its two components, the pre-reproductive mortality and the variance in fertility, has been also analysed and compared with similar data for the United States. The results clearly show the relevance of socio-economic changes to the evolution of selective patterns in our species; in particular the relative incidence of mortality and fertility to selection intensity: the total index has in fact been reduced by 75% during the last century, the relative amount due to fertility increasing from 57 to 89%. The probable different relevance of genetic factors in the two components has also been discussed.

Changes of selection opportunities with a changing environment: regional heterogeneity in Italy.

The mortailty and fertility components of the index of opportunity for selection (the Crow index) have been studied in the various Italian regions during the last century. To estimate the relevance of environmental factors on both components, their trends and those of their interregional variances have been compared with illiteracy. The results show that the selection opportunities due to mortality have decreased in a smiliar way in all the regions with a trend parallel to that of the national percentage of illiteracy, suggesting that this component is directly affected by the general socio-cultural level. As to the component due to fertility differentials, the regions, though scattered in the time scale, show a characteristic cycle of rise and fall. Moreover, the interregional variances of this component and of illiteracy are quite parallel, thus supporting the hypothesis that the reproductive pattern is strongly influenced by the individual cultural level.

Natural selection associated with birth weight. I. Selection intensity and selective deaths from birth to one month of life.

Differential mortality as a function of birth weight was studied up to the 4th week of life in all single births in Italy in 1974. It was found that: (i) Both selection intensity and selective mortality are much higher with increasing immaturity. (ii) For babies born at term or after 8 months of pregnancy selection intensity tends to relax as early as one week after birth, while for those born after 7 months selection is at work for a longer period. (iii) Selective mortality, on the other hand, keeps increasing after birth but its relevance is relatively decreasing since average mortality after birth continues to decrease.