Heritability of DNA-damage-induced apoptosis and its relationship with age in lymphocytes from female twins

Apoptosis is a physiological form of cell death important in normal processes such as morphogenesis and the functioning of the immune system. In addition, defects in the apoptotic process play a major role in a number of important areas of disease, such as autoimmune diseases and cancer. DNA-damage-induced apoptosis plays a vital role in the maintenance of genomic stability by the removal of damaged cells. Previous studies of the apoptotic response (AR) to radiation-induced DNA damage of lymphoid cells from individuals carrying germline TP53 mutations have demonstrated a defective AR compared with normal controls. We have also previously demonstrated that AR is reduced as individuals age. Results from the current study on 108 twins aged 18–80 years confirm these earlier findings that the AR of lymphoid cells to DNA damage is significantly reduced with increasing age. In addition this twin study shows, for the first time, that DNA-damage-induced AR has a strong degree of heritability of 81% (95% confidence interval 67–89%). The vital role of DNA-damage-induced apoptosis in maintaining genetic stability, its relationship with age and its strong heritability underline the importance of this area of biology and suggest areas for further study

Added Value Measures in Education Show Genetic as Well as Environmental Influence

Does achievement independent of ability or previous attainment provide a purer measure of the added value of school? In a study of 4000 pairs of 12-year-old twins in the UK, we measured achievement with year-long teacher assessments as well as tests. Raw achievement shows moderate heritability (about 50%) and modest shared environmental influences (25%). Unexpectedly, we show that for indices of the added value of school, genetic influences remain moderate (around 50%), and the shared (school) environment is less important (about 12%). The pervasiveness of genetic influence in how and how much children learn is compatible with an active view of learning in which children create their own educational experiences in part on the basis of their genetic propensities

Birth weight and melanoma risk: a population-based case–control study

We investigated whether lower birth weight was associated with lower risk of melanoma later in life. This population-based case–control study included all incident cases of histologically verified invasive melanoma diagnosed until 31 December 2003 in the Norwegian population born between 1967 and 1986 (n=709). The control group without malignant disease was established by random sampling from the same source population as the cases (n=108 209). Data on birth weight, gender, mother's residence and parental age at the time of birth were collected from the Medical Birth Registry of Norway and data on cancer from the Cancer Registry of Norway. The Mantel–Haenszel test of linear trend showed no trend in risk across the birth weight categories: individuals in the highest quartile of birth weight (⩾3860 g) had an odds ratio (OR) of 1.19 (95% confidence interval, CI: 0.77–1.84) compared to individuals with birth weight <2500 g. The adjusted OR was 0.81 (95% CI: 0.52–1.26) for birth weight below 2500 g (exposed). Though not statistically significant, the results suggest that low birth weight might influence the risk of melanoma later in life

Breastfeeding, Maternal Education and Cognitive Function: A Prospective Study in Twins

The effect of breastfeeding on cognitive abilities is examined in the offspring of highly educated women and compared to the effects in women with low or middle educational attainment. All offspring consisted of 12-year old mono- or dizygotic twins and this made it possible to study the effect of breastfeeding on mean cognition scores as well as the moderating effects of breastfeeding on the heritability of variation in cognition. Information on breastfeeding and cognitive ability was available for 6,569 children. Breastfeeding status was prospectively assessed in the first years after birth of the children. Maternal education is positively associated with performance on a standardized test for cognitive ability in offspring. A significant effect of breastfeeding on cognition was also observed. The effect was similar for offspring with mothers with a high, middle, and low educational level. Breast-fed children of highly educated mothers score on average 7.6 point higher on a standardized test of cognitive abilities (CITO test; range 500–550; effects size = .936) than formula-fed children of mothers with a low education. Individual differences in cognition scores are largely accounted for by additive genetic factors (80%) and breastfeeding does not modify the effect of genetic factors in any of the three strata of maternal education. Heritability was slightly lower in children with a mother with a middle-level education

The emerging landscape of health research based on biobanks linked to electronic health records: Existing resources, statistical challenges, and potential opportunities

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154448/1/sim8445_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154448/2/sim8445.pd

QTL analysis and genomic selection using RADseq derived markers in Sitka spruce: the potential utility of within family data

Sitka spruce (Picea sitchensis (Bong.) Carr) is the most common commercial plantation species in Britain and a breeding programme based on traditional lines has been in operation since the early 1960s. Rotation lengths of 40-years have led breeders to adopt a process of indirect selection at younger ages based on traits well correlated with final selection, but still the generation interval is unlikely to reduce much below twenty years. Recent successful developments with genomic selection in animal breeding have led tree breeders to consider the application of this technology. In this study a RAD sequence assay was developed as a means of investigating the potential of molecular breeding in a non-model species. DNA was extracted from nearly 500 clonally replicated trees growing in a single full-sibling family at one site in Britain. The technique proved successful in identifying 132 QTLs for 5-year bud-burst and 2 QTLs for 6-year height. In addition, the accuracy of predicting phenotypes by genomic selection was strikingly high at 0.62 and 0.59 respectively. Sensitivity analysis with 200 offspring found only a slight fall in correlation values (0.54 and 0.38) although when the training population reduced to 50 offspring predictive values fell further (0.33 and 0.25). This proved an encouraging first investigation into the potential use of genomic selection in the breeding of Sitka spruce. The authors investigate how problems associated with effective population size and linkage disequilibrium can be avoided and suggest a practical way of incorporating genomic selection into a dynamic breeding programme

Familial Resemblance for Loneliness

Social isolation and loneliness in humans have been associated with physical and psychological morbidity, as well as mortality. This study aimed to assess the etiology of individual differences in feelings of loneliness. The genetic architecture of loneliness was explored in an extended twin-family design including 8,683 twins, siblings and parents from 3,911 families. In addition, 917 spouses of twins participated. The presence of assortative mating, genetic non-additivity, vertical cultural transmission, genotype–environment (GE) correlation and interaction was modeled. GE interaction was considered for several demographic characteristics. Results showed non-random mating for loneliness. We confirmed that loneliness is moderately heritable, with a significant contribution of non-additive genetic variation. There were no effects of vertical cultural transmission. With respect to demographic characteristics, results indicated that marriage, having offspring, more years of education, and a higher number of siblings are associated with lower levels of loneliness. Interestingly, these effects tended to be stronger for men than women. There was little evidence of changes in genetic architecture as a function of these characteristics. We conclude that the genetic architecture of loneliness points to non-additive genetic influences, suggesting it may be a trait that was not neutral to selection in our evolutionary past. Sociodemographic factors that influence the prevalence of loneliness do not affect its genetic architecture

Collaborative Action of Brca1 and CtIP in Elimination of Covalent Modifications from Double-Strand Breaks to Facilitate Subsequent Break Repair

Topoisomerase inhibitors such as camptothecin and etoposide are used as anti-cancer drugs and induce double-strand breaks (DSBs) in genomic DNA in cycling cells. These DSBs are often covalently bound with polypeptides at the 3′ and 5′ ends. Such modifications must be eliminated before DSB repair can take place, but it remains elusive which nucleases are involved in this process. Previous studies show that CtIP plays a critical role in the generation of 3′ single-strand overhang at “clean” DSBs, thus initiating homologous recombination (HR)–dependent DSB repair. To analyze the function of CtIP in detail, we conditionally disrupted the CtIP gene in the chicken DT40 cell line. We found that CtIP is essential for cellular proliferation as well as for the formation of 3′ single-strand overhang, similar to what is observed in DT40 cells deficient in the Mre11/Rad50/Nbs1 complex. We also generated DT40 cell line harboring CtIP with an alanine substitution at residue Ser332, which is required for interaction with BRCA1. Although the resulting CtIPS332A/−/− cells exhibited accumulation of RPA and Rad51 upon DNA damage, and were proficient in HR, they showed a marked hypersensitivity to camptothecin and etoposide in comparison with CtIP+/−/− cells. Finally, CtIPS332A/−/−BRCA1−/− and CtIP+/−/−BRCA1−/− showed similar sensitivities to these reagents. Taken together, our data indicate that, in addition to its function in HR, CtIP plays a role in cellular tolerance to topoisomerase inhibitors. We propose that the BRCA1-CtIP complex plays a role in the nuclease-mediated elimination of oligonucleotides covalently bound to polypeptides from DSBs, thereby facilitating subsequent DSB repair

The effect of birth-weight with genetic susceptibility on depressive symptoms in childhood and adolescence

Low birth-weight has been associated with depression and related outcomes in adults, and with problem behaviours in children. This study aimed to examine the association between low birth-weight for gestation and depressive symptoms in children and adolescents and to examine whether the relationship is moderated by genetic risk for depression. An epidemiological, genetically sensitive design was used including 2,046 twins aged 8–17 years (1,023 families). Data were obtained by parental report and analysed using regression analysis. A small but significant association between birth-weight for gestation and early depressive symptoms was observed. The unit increase in depressive symptoms per unit decrease in birth-weight for gestation was greater for individuals at genetic or familial risk for depression. For low birth-weight children, genetic risk for depression moderated the influence of birth-weight for gestation in predicting early depressive symptoms. Birth-weight for gestation is moderated by genetic and familial risk for depression in influencing early depression symptoms. These observations have clinical implications in that the impact of being small for gestational age on depressive symptoms is greater in children at familial/genetic risk although the association between birth weight and depression does not imply causality

Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c

Cortico-basal ganglia circuits are critical for speech and language and are implicated in autism spectrum disorder, in which language function can be severely affected. We demonstrate that in the mouse striatum, the gene Foxp2 negatively interacts with the synapse suppressor gene Mef2c. We present causal evidence that Mef2c inhibition by Foxp2 in neonatal mouse striatum controls synaptogenesis of corticostriatal inputs and vocalization in neonates. Mef2c suppresses corticostriatal synapse formation and striatal spinogenesis, but can itself be repressed by Foxp2 through direct DNA binding. Foxp2 deletion de-represses Mef2c, and both intrastriatal and global decrease of Mef2c rescue vocalization and striatal spinogenesis defects of Foxp2-deletion mutants. These findings suggest that Foxp2-Mef2C signaling is critical to corticostriatal circuit formation. If found in humans, such signaling defects could contribute to a range of neurologic and neuropsychiatric disorders.National Institutes of Health (U.S.) (Grant R37 HD028341)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Award R37 HD028341