Postnatal genetic and neurodevelopmental assessment in infants born at term with severely low birth weight of non-placental origin.

OBJECTIVE: To determine the frequency of genetic syndromes and childhood neurodevelopmental impairment in non-malformed infants born at term with severely low birth weight and no evidence of placental insufficiency. METHODS: This case series was constructed from the data of infants delivered at term between 2013 and 2018 with severely low birth weight, defined as birth weight more than 2.5 SD below the mean, with normal maternal and fetal Doppler (umbilical artery, fetal middle cerebral artery, cerebroplacental ratio and uterine artery) and no maternal hypertensive disorder during pregnancy or fetal structural anomaly on prenatal ultrasound examination. Clinical exome sequencing and copy number variation (CNV) analysis were performed using DNA extracted from the children's saliva. Cognitive and psychomotor development was evaluated using the Bayley Scales of Infant and Toddler Development, 3rd edition or the Wechsler Intelligence Scale for Children, 5th edition tests, according to the child's age at testing. RESULTS: Among the 36 405 infants born within the study period, 274 (0.75%) had a birth weight below -2.5 SD, of whom 98 met the inclusion criteria. Among the 63 families contacted, seven (11%) reported a postnatal diagnosis of a genetic syndrome and a further 18 consented to participate in the study. Median gestational age at delivery was 38.0 (interquartile range (IQR), 37.3-38.5) weeks and median birth weight was 2020 (IQR, 1908-2248) g. All 18 children showed a normal result on clinical exome sequencing and CNV analysis, but six (33%) obtained a low score on neurodevelopmental testing. CONCLUSION: Non-malformed severely small term infants with no clinical or Doppler signs of placental insufficiency present a high rate of genetic syndromes and neurodevelopmental impairment during childhood. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Relative contribution of Imprinting, X chromosome and Litter effects to phenotypic variation in economic traits of sheep.

Data on Zandi sheep were analysed to quantify maternal and paternal imprinting, X chromosome and litter effects' contribution to phenotypic variation in birth weight (BW), weaning weight (WW), growth rate (GR), Kleiber ratio (KR), efficiency of growth (EF) and relative growth rate (RGR). To this end, a two-step approach was adopted. In the first step, each trait was analysed with a series of 16 animal models, which were identical for fixed and autosomal additive genetic effects but differed for combinations of maternal permanent environmental, maternal genetic, X chromosome and litter effects. For each trait, the best model was selected by the Akaike information criterion (AIC) and likelihood ratio tests (LRTs). In the second step, three additional models were fitted by adding maternal imprinting, paternal imprinting or both (models 17, 18 and 19) to the best model selected in the first step. Estimators of bias, dispersion and accuracy of breeding values estimated within 19 models with whole, and partial data were used to evaluate how well were the 19 models in estimating breeding values for the animals when their records were masked. For all traits studied, fitting the litter effect led to a better data fit. Also, it resulted in noticeable decreases in residual variance and other maternal variances. For growth traits, models containing the X-linked effects fitted the data substantially better than corresponding models without the X-linked effects. For BW, WW and GR, estimates of X-linked heritability ( h s 2 ) ranged between 0.09 (GR) and 0.14 (BW). Ignoring X-linked effects from the genetic evaluation model resulted in significant inflated autosomal additive genetic variance. For BW, WW, EF and RGR, models containing the imprinting effects provided a better fit of the data than otherwise identical models. Imprinting effects contributed significantly to the phenotypic variation of these traits in a range between 5% (RGR) and 8% (BW, WW). A sharp decline was observed in autosomal additive genetic variance following including imprinting effects in the model (27% to 40% depending on the trait). The least bias and dispersion, as well as greater accuracies for breeding values of focal animals, were for a model which included imprinting, X-linked and litter effects. It was concluded that imprinting, X-linked and litter effects need to be included in the genetic evaluation models for growth and efficiency-related traits of Zandi lambs.

Assessment of between-founder heterogeneity in inbreeding depression for reproductive traits in Baluchi sheep.

Magnitude of inbreeding depression could be different among descendants of various founder animals, when recessive genetic composition of a population is unevenly distributed among founder animal genomes. Reproductive records of Baluchi sheep for the litter variables size at birth (LSB), size at weaning (LSW), mean weight/lamb born (LMWLB), mean weight/lamb weaned (LMWLW), total weight at birth/ewe lambing (TLWB) and total weight at weaning/ewe lambing (TLWW) were used to examine heterogeneity in inbreeding depression between founder animals. Pedigree-based inbreeding coefficients were proportioned into components coming from founder animals and Mendellian contribution from non-founder animals. Two approaches were used to assess effects of inbreeding: overall inbreeding coefficients or partial inbreeding of the four main founder animals as possible covariates included in statistical models. Among the traits evaluated, there were effects on LMWLB, LMWLW and TLWW of inbreeding with there being a -8, -48, and -95 g decrease per 1% increase in inbreeding, respectively. Linear regressions of traits on partial inbreeding coefficients due to founder animals were of different magnitudes and ranged between -0.12 and +0.128. Heterogeneous contribution of founder animals to inbreeding depression occurred for LSB, LMWLB, and TLWW. These results indicate there was uneven distribution of recessive genetic composition among genomes of founder animals or differences in selection pressures on unfavorable alleles between different founder lines. The observed variation in founder-specific inbreeding depression indicates a small number of alleles with major effects are contributing to inbreeding depression.

Spontaneous Version of Fetal Presentation in Twin Pregnancies During Third Trimester: Longitudinal Assessment.

Little is known about longitudinal changes of the first twin presentation in twin gestations. This is a retrospective cohort study including 411 women who were admitted consecutively and delivered live-born twins at 36 weeks of gestation or more. Longitudinal assessment of the first twin presentation was conducted during gestation and at birth in all cases. Gestational age at antenatal assessment was divided into two intervals: early-third trimester (28-31 weeks) and mid-third trimester (32-35 weeks). Fetal presentation was categorized as vertex or non-vertex. We analyzed change of fetal presentation between antepartum intervals and birth. First twin presentation at early-third trimester had the same presentation at birth in 87.6% (360/411) of the study population. In this 'no change' group, vertex presentation was seen in 95.6% (283/296) and non-vertex was seen in 67.0% (77/115) of cases. In total, 96.1% (395/411) of the study population maintained their presentation between mid-third trimester and birth. Vertex presentation was seen in 98.4% (310/315) and non-vertex was seen in 88.5% (85/96) of cases. When comparing vertex with non-vertex, vertex presentation during third trimester was a more reliable predictor of presentation at birth (p < .001). The only factor that contributed significantly to spontaneous version of the first twin during mid-third trimester and birth was a lower birth weight of the first twin compared with the second twin. In conclusion, first twin presentation with vertex during third trimester is not likely to change into non-vertex at birth. We concluded that vertex presentation in twin gestations at early- and mid-third trimester is very predictable. In contrast, a non-vertex first twin presentation is relatively unstable.

Contribution of semen trait selection, artificial insemination technique, and semen dose to the profitability of pig production systems: A simulation study.

The economic impact of selection for semen traits on pig production systems and potential interaction with artificial insemination (AI) technique and semen dose remains partially understood. The objectives of this study were to compare the financial indicators (gross return, net profit, cost) in a three-tier pig production system under one of two selection strategies: a traditional strategy including nine paternal and maternal traits (S9) and an advanced strategy that adds four semen traits (S13). Maternal traits included the number of pigs born alive, litter birth weight, adjusted 21-day litter weight, and the number of pigs at 21 days, and paternal traits included days to 113.5 kg, back fat, average daily gain, feed efficiency, and carcass lean percentage. The four semen traits included volume, concentration, progressive motility of spermatozoa, and abnormal spermatozoa. Simultaneously, the impact of two AI techniques and a range of fresh refrigerated semen doses including cervical AI with 3 × 10(9) (CAI3) and 2 × 10(9) (CAI2) sperm cells/dose, and intrauterine AI with 1.5 × 10(9) (IUI1.5), 0.75 × 10(9) (IUI0.75), and 0.5 × 10(9) (IUI0.5) sperm cells/dose were evaluated. These factors were also evaluated using a range of farrowing rates (60%-90%), litter sizes (8-14 live-born pigs), and a selected semen collection frequency. The financial impact of the factors was assessed through simulation of a three-way crossbreeding system (maternal nucleus lines A and B and paternal nucleus line C) using ZPLAN. The highest return on investment (profit/cost) of boars was observed at 2.33 collections/wk (three periods of 24 hours between collections). Under this schedule, a significant (P < 0.0001) interaction between the selection strategy and the AI technique-dose combination was identified for the gross return; meanwhile, significant (P < 0.0001) additive effects of the selection strategy and AI technique-dose combination were observed for the net profit. The highest gross return was obtained under S13 with IUI0.75 and IUI0.5. The net profit of S13 was 34.37% higher than the traditional S9 (P < 0.0001). The net profit favored IUI0.5 with relative differences of 4.13%, 2.41%, 1.72%, and 0.43% compared to CAI3, CAI2, IUI1.5, and IUI0.75, respectively. The advanced selection strategy proposed including four semen traits is recommended on the basis of the higher profitability relative to the traditional strategy.

Epigenetic regulation of Newborns' imprinted genes related to gestational growth: patterning by parental race/ethnicity and maternal socioeconomic status.

BACKGROUND: Children born to parents with lower income and education are at risk for obesity and later-life risk of common chronic diseases, and epigenetics has been hypothesised to link these associations. However, epigenetic targets are unknown. We focus on a cluster of well-characterised genomically imprinted genes because their monoallelic expression is regulated by DNA methylation at differentially methylated regions (DMRs), are critical in fetal growth, and DNA methylation patterns at birth have been associated with increased risk of birth weight extremes and overweight status or obesity in early childhood. METHODS: We measured DNA methylation at DMRs regulating genomically imprinted domains (IGF2/H19, DLK1/MEG3, NNAT and PLAGL1) using umbilical cord blood leucocytes from 619 infants recruited in Durham, North Carolina in 2010-2011. We examined differences in DNA methylation levels by race/ethnicity of both parents, and the role that maternal socioeconomic status (SES) may play in the association between race/ethnic epigenetic differences. RESULTS: Unadjusted race/ethnic differences only were evident for DMRs regulating MEG3 and IGF2; race/ethnic differences persisted in IGF2/H19 and NNAT after accounting for income and education. CONCLUSIONS: Results suggest that parental factors may not only influence DNA methylation, but also do so in ways that vary by DMR. Findings support the hypothesis that epigenetics may link the observed lower SES during the prenatal period and poor outcomes such as low birth weight; lower birth weight has previously been associated with adult-onset chronic diseases and conditions that include cardiovascular diseases, diabetes, obesity and some cancers.

Application of multivariate heavy-tailed distributions to residuals in the estimation of genetic parameters of growth traits in beef cattle.

Assumptions of normality in most animal breeding applications may make inferences vulnerable to the presence of outliers. Heavy-tail densities are viable alternatives to normal distributions and provide robustness against unusual or outlying observations when used to model the densities of residual effects. Our objective is to compare estimates of genetic parameters by fitting multivariate normal (MN) or heavy-tail distributions [multivariate Student's t (MSt) and multivariate slash (MS)] for residuals in data of body birth weight (BBW), weaning (WW), and yearling (YW) weight traits in beef cattle. A total of 17,019 weight records for BBW, WW, and YW from 1998 through 2010 from a large commercial cow/calf operation in the sand hills of Nebraska were analyzed. Models included fixed effects of contemporary group and sire breed whereas animal and maternal effects were random and the degrees of freedom (v) was treated as unknown for MSt and MS. Model comparisons using deviance information criteria (DIC) favored MSt over MS and MN models, respectively. The posterior means [and 95% posterior probability intervals (PPI)] of v for the MSt and MS models were 5.28 (4.80, 5.85) and 1.88 (1.76, 2.00), respectively. Smaller values of posterior densities of v for MSt and MS models confirm that the assumption of normally distributed residuals is not adequate for the analysis of BBW, WW, and YW datasets. Posterior mean (PM) and posterior median (PD) estimates of direct and maternal genetic variances were the same and posterior densities of these parameters were found to be symmetric. The 95% PPI estimates from MN and MSt models for BBW did not overlap, which indicates significant difference between PM estimates from MN or MSt models. The observed antagonistic relationship between additive direct and additive maternal effects indicated that genetic evaluation and selection strategies will be sensitive to the assumed model for residuals.

Birth weight, infant mortality, and race: twin comparisons and genetic/environmental inputs.

Genetic and environmental inputs may shape population health disparities in varying ways. In this article, we use unique variation involved in twin births to attempt to untangle how genetic and prenatal environmental variation may make different contributions to infant health among white and black populations in the United States. Using twin fixed effects models and data from the 1995-1997 Matched Multiple Birth Dataset we compare birth weight-mortality associations across twin sex composition, zygosity, and race. Findings reveal suggestive differences between fraternal and imputed identical twin estimates for white and black twin pairs.

The interplay of variants near LEKR and CCNL1 and social stress in relation to birth size.

BACKGROUND: We previously identified via a genome wide association study variants near LEKR and CCNL1 and in the ADCY5 genes lead to lower birthweight. Here, we study the impact of these variants and social stress during pregnancy, defined as social adversity and neighborhood disparity, on infant birth size. We aimed to determine whether the addition of genetic variance magnified the observed associations. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed data from the Northern Finland Birth Cohort 1986 (n=5369). Social adversity was defined by young maternal age (<20 years), low maternal education (<11 years), and/or single marital status. Neighborhood social disparity was assessed by discrepancy between neighborhoods relative to personal socio-economic status. These variables are indicative of social and socioeconomic stress, but also of biological risk. The adjusted multiple regression analysis showed smaller birth size in both infants of mothers who experienced social adversity (birthweight by -40.4 g, 95%CI -61.4, -19.5; birth length -0.14 cm, 95%CI -0.23, -0.05; head circumference -0.09 cm 95%CI -0.15, -0.02) and neighborhood disparity (birthweight -28.8 g, 95%CI -47.7, -10.0; birth length -0.12 cm, 95%CI -0.20, -0.05). The birthweight-lowering risk allele (SNP rs900400 near LEKR and CCNL1) magnified this association in an additive manner. However, likely due to sample size restriction, this association was not significant for the SNP rs9883204 in ADCY5. Birth size difference due to social stress was greater in the presence of birthweight-lowering alleles. CONCLUSIONS/SIGNIFICANCE: Social adversity, neighborhood disparity, and genetic variants have independent associations with infant birth size in the mutually adjusted analyses. If the newborn carried a risk allele rs900400 near LEKR/CCNL1, the impact of stress on birth size was stronger. These observations give support to the hypothesis that individuals with genetic or other biological risk are more vulnerable to environmental influences. Our study indicates the need for further research to understand the mechanisms by which genes impact individual vulnerability to environmental insults.

Intergenerational correlations in size at birth and the contribution of environmental factors: The Uppsala Birth Cohort Multigenerational Study, Sweden, 1915-2002.

Sizes at birth of parents and their children are known to be correlated, reflecting in part the influence of fetal and maternal genes. Sociodemographic factors, regarded as aspects of the shared environment across generations, would also be expected to contribute, but evidence is limited. In the present study, the authors aimed to quantify the role of the shared environment in explaining intergenerational correlations in birth weight and length by using data across 3 consecutive generations from the Uppsala Birth Cohort Multigenerational Study in Uppsala, Sweden. That study included birth and sociodemographic data on 7,657 singletons born in Uppsala in 1915-1929 (generation 1) and their grandchildren (generation 3). Standard regression and biometric models were used to study the correlations in size at birth of generation 1-generation 3 pairs. The data showed stronger correlations in maternal pairs than in paternal pairs for birth weight (0.125 vs. 0.096, P = 0.02) but not for birth length (0.097 vs. 0.093, P = 0.77). These correlations were not reduced by adjustment for sociodemographic factors in regression models. In contrast, significant shared-environment contributions to the intergenerational correlations were identified in biometric models, averaging 14% for both birth measures. These models assumed a common latent factor for the sociodemographic variables. The present results show that the shared environment moderately but significantly contributes to intergenerational correlations.

Assessment of positional candidate genes myf5 and igf1 for growth on bovine chromosome 5 in commercial lines of Bos taurus.

Quantitative trait loci for growth traits in beef cattle have been previously reported and fine-mapped in three chromosomal regions of 0 to 30 cM, 55 to 70 cM, and 70 to 80 cM of bovine chromosome 5. In this study, we further examined the association between gene-specific single nucleotide polymorphisms (SNP) of two positional candidate genes, bovine myogenic factor 5 (myf5) and insulin-like growth factor-1 (igf1), in the QTL regions and the birth weight (BWT), preweaning average daily gain (PWADG), and average daily gain on feed (ADGF) in commercial lines of Bos taurus. The QTL regions for the growth traits identified using a haplotype association analysis, which included the gene-specific SNP markers for both genes in this study, were in agreement with previous studies. The gene-specific SNP marker association analysis indicated that the SNP in myf5 had a significant additive effect on PWADG in the M1 line of Beefbooster Inc. (P < 0.10), and a significant additive effect (P < 0.05) and a significant dominance effect (P < 0.10) on ADGF in the M3 line of Beefbooster Inc. When the data from the two commercial lines were pooled, the SNP in myf5 showed a significant association with PWADG (P < 0.10) and with ADGF (P < 0.05). The association between the SNP and BWT, however, did not reach a significance level in the M1 line, the M3 line, or across the lines. For igf1, no significant association between the SNP and the growth traits was detected in either the M1 line or the M3 line, whereas there was only a significant dominance effect (P < 0.10) on BWT detected for the SNP in igfl when the data from the two commercial lines were pooled. These results suggest that myf5 is a strong candidate gene that influences PWADG and ADGF in beef cattle. The SNP of igf1 may not be a causative or close to the causative mutation that affects the three growth traits in the populations of beef cattle examined in this study. Other SNP of igf1 and myf5 or other genes in their respective chromosomal regions, however, should also be studied.

Investigation of breeding strategies to increase the probability that German shepherd dog and Labrador retriever dog guides would attain optimum size.

An optimum-sized dog guide weighs 18 to 32 kg and measures 53 to 64 cm in height at the withers when mature body size is attained. Effects of selection index with and without restrictions, independent trait selection, directional selection, stabilizing selection, and negative assortative mating were modeled using data from German shepherd dogs and Labrador retrievers raised by the Seeing Eye, Inc., Morristown, NJ from 1979 to 1997. The selection goals were to decrease mature weight and mature height in German shepherd dogs and to decrease mature weight and increase mature height in Labrador retrievers. Mature weights were recorded for 1,333 German shepherd dog offspring and their 69 dams and 17 sires, and 1,081 Labrador retriever offspring and their 51 dams and 13 sires. Mature heights also were recorded for offspring and parents, including 871 German shepherd dogs from 70 dams and 15 sires, and 793 Labrador retrievers from 40 dams and 13 sires. Selecting on mature weight alone produced the highest aggregate genetic-economic gain for German shepherd dogs compared with the selection indices with and without restrictions, generating a 2.10-kg decrease in mature weight and a correlated 0.36-cm decrease in mature height. In Labrador retrievers, selecting for mature height alone produced the highest aggregate genetic-economic gain but caused an increase in mature weight. Weighting the two traits equally but in the opposite direction without restrictions was the only index that produced the desired effect of decreasing mature weight and increasing mature height in Labrador retrievers. Response to selection for one generation of directional selection for a single trait included a 0.50-kg decrease in mature weight for German shepherd dogs, a 0.59-kg decrease in mature weight for Labrador retrievers, a 0.18-cm decrease in mature height for German shepherd dogs, and a 0.91-cm increase in mature height for Labrador retrievers. Increasing the percentage of dogs attaining optimum size may decrease the cost of production for the Seeing Eye, Inc., because fewer dogs would need to be raised and trained to provide assistance to the same number of blind individuals.

Genetic evaluation of an index of birth weight and yearling weight to improve efficiency of beef production.

The CGC population is a stabilized composite of 1/2 Red Angus, 1/4 Charolais, and 1/4 Tarentaise germplasm. The objectives of this research were to estimate genetic parameters for weight traits of CGC and to evaluate genetic responses resulting from selection based on the following index: I = 365-d weight 3.2(birth weight). Phenotypes evaluated were birth weight (n = 5,083), 200-d weight (n = 4,902), 365-d weight (n = 4,626), and the index. In addition, there were 1,433 cows with at least one recorded weight, and 4,375 total observations of cow weight collected at the time their calves were weaned. In 1989, a randomly selected control line and a line selected for greater values of the index were established. Average generation intervals were 3.16 +/- 0.04 and 3.90 +/- 0.08 yr in the index and control lines, respectively. The index selection line (n = 950) accumulated approximately 212 kg more selection differential than the control line over three generations (n = 912). Heritability estimates for direct effects were 0.32 +/- 0.04, 0.49 +/- 0.05, 0.49 +/- 0.05, 0.30 +/- 0.04, and 0.70 +/- 0.04 for the index, birth weight, 365-d weight, 200-d weight, and cow weight, respectively. Heritability estimates for maternal effects were 0.05 +/- 0.02, 0.11 +/- 0.03, 0.04 +/- 0.02, and 0.19 +/- 0.04 for the index, birth weight, 365-d weight, and 200-d weight, respectively. In the control line, direct genetic changes for the index and its components were small. For the index selection line, direct genetic changes for the index, birth weight, 365-d weight, 200-d weight, and cow weight were 6.0 +/- 0.3, 0.45 +/- 0.09, 7.74 +/- 0.55, 3.42 +/- 0.25, and 6.3 +/- 0.9 kg/generation, respectively. Maternal genetic changes were generally small for both the control and index selection lines. Thus, selection for the index produced positive correlated responses for direct genetic effects on BW traits at all ages, with only minor effects on maternal genetic effects. Results demonstrate that despite a genetic antagonism that compromises selection response for decreased birth weight and increased postnatal growth, favorable genetic responses can be achieved with the selection index used in this study.

Low-weight neonatal survival paradox in the Czech Republic.

Analysis of vital statistics for the Czech Republic between 1986 and 1993, including 3,254 infant deaths from 350,978 first births to married and single women who conceived at ages 18-29 years, revealed a neonatal survival advantage for low-weight infants born to disadvantaged (single, less educated) women, particularly for deaths from congenital anomalies. This advantage largely disappeared after the neonatal period. The same patterns have been observed for low-weight infants born to black women in the United States. Since the Czech Republic had an ethnically homogenous population, virtually universal prenatal care, and uniform institutional conditions for delivery, Czech results must be attributed to social rather than to biologic or medical circumstances. This strengthens the contention that in the United States, the black neonatal survival paradox may be due as much to race-related social stigmatization and consequent disadvantage as to any hypothesized hereditary influences on birth-weight-specific survival.

Evaluation of mating systems involving five breeds for integrated beef production systems: I. Cow-calf segment.

Deterministic computer models were used to simulate the cow-calf segment of an integrated production system. Angus, Charolais, Hereford, Limousin, and Simmental breeds were included in three mating systems: pure-breeding (PB) or two- (2R) or three-breed (3R) rotational crossbreeding. Breed data were taken from the literature. Herds were evaluated over the production year. Sires represented breed averages and were available from sources outside their herds, and 100 replacement heifers were saved annually. Females in 3R had the highest average energy requirements (8,144 Mcal of ME.cow-1.yr-1) and production costs ($322.31.cow-1.yr-1), and PB females had the lowest average requirements (7,748 Mcal of ME.cow-1.yr-1) and costs ($313.2.cow-1.yr-1). Purebred systems were the least biologically and economically efficient (64.9 Mcal of ME/kg of steer equivalent, $2.35/kg of steer equivalent), respectively, and 3R systems were the most efficient (56.6 Mcal of ME/kg of steer equivalent, $1.95/kg of steer equivalent). On average, 3R systems were more efficient biologically and economically than 2R systems. However, some 2R systems were as efficient as some 3R systems. Crossbred combinations containing Angus and(or) Hereford ranked more biologically and economically efficient than other breed combinations. Conversely, British purebreds ranked more biologically efficient, whereas Continental purebreds ranked more economically efficient.