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Weaning performance of 2857 purebred calves (660 male and 2197 female) born from 1498 cows mated with 78 sire were analised in seven farms. Genetic- and environmental variance and heritability, breeding value of weaning weight (VS), preweaning daily gain (SGY) and 205-day weight (KVS) were calculated. Farm, year of birth, season of birth, sex, number of calving as fixed, while sire as a random effect was treated. Data were analyzed with SPSS 9.0 and Harvey’s (1990) Least Square Maximum Likelihood Computer Program. The environmental factors examined had an effect on all traits. The overall mean value and standard error (SE) of VS, SGY and KVS were 208±3.31 kg, 887±15.66 g/day and 199±14.774 kg, respectively. The heritability of the investigated traits was 0.24, 0.25 and 0.25. The results of the examination show that the 205-day weight was increased to seventh calving. The male calves were hevier than females, the difference was 22 kg (10,5%).

The first and second observational runs of Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) have marked the first direct detections of gravitational waves, either from black hole binaries or, in one case, from coalescing neutron stars. These observations opened up the era of gravitational wave astronomy, but also of gravitational wave cosmology, in the form of an independent derivation of the Hubble constant. They were equally important to prove false a plethora of modified gravity theories predicting gravitational wave propagation speed different from that of light. For a continued and improved testing of general relativity, the precise description of compact binary dynamics, not only in the final coalescence phase but also earlier, when precessional effects dominate, are required. We report on the derivation of the full secular dynamics for compact binaries, valid over the precessional time-scale, in the form of an autonomous closed system of differential equations for the set of spin angles and periastron. The system can be applied for mapping the parameter space for the occurrence of the spin flip-flop effect and for more accurately analyzing the spin-flip effect, which could explain the formation of X-shaped radio galaxies.

Presents an abstract of the article "Urorectal Septum Malformation (URSM) Sequence: A 5 Year Review of the Spectrum of Phenotypes Ascertained by the Perinatal Pathology/Genetics Team in Birmingham," by Sarah Bowdin, P.M. Cox, T.G. Marton, N.S. Ostojic, and L. Brueton.

During the sixth millennium BCE, the first farmers of Central Europe rapidly expanded across a varied mosaic of forested environments. Such environments would have offered important sources of mineral-rich animal feed and shelter, prompting the question: to what extent did early farmers exploit forests to raise their herds? Here, to resolve this, we have assembled multi-regional datasets, comprising bulk and compound-specific stable isotope values from zooarchaeological remains and pottery, and conducted cross-correlation analyses within a palaeo-environmental framework. Our findings reveal a diversity of pasturing strategies for cattle employed by early farmers, with a notable emphasis on intensive utilization of forests for grazing and seasonal foddering in some regions. This experimentation with forest-based animal feeds by early farmers would have enhanced animal fertility and milk yields for human consumption, concurrently contributing to the expansion of prehistoric farming settlements and the transformation of forest ecosystems. Our study emphasizes the intricate relationship that existed between early farmers and forested landscapes, shedding light on the adaptive dynamics that shaped humans, animals and environments in the past., Competing Interests: Competing interests: The authors state there are no competing interests., (© 2024. The Author(s).)

Introduction: Twin-twin transfusion syndrome (TTTS) complicates approximately 10%-15% of all monochorionic twin pregnancies. The aim of this review was to evaluate the placental architectural characteristics within TTTS twins following laser and elucidate their impact on fetal outcomes and operative success., Material and Methods: Five databases were searched from inception to August 2023. Studies detailing post-delivery placental analysis within TTTS twins post-laser were included. Studies were categorized into two main groups: (1) residual anastomoses following laser and (2) abnormal cord insertion: either velamentous and/or marginal or proximate. The primary outcome was to determine the proportion of TTTS placentas with residual anastomoses and abnormal cord insertions post-laser. Secondary outcomes included assessing residual anastomoses on post-laser fetal outcomes and assessing the relationship between abnormal cord insertion and TTTS development. Study bias was critiqued using the Joanna Briggs Institute checklists and Cochrane risk of bias tool. Random-effects meta-analysis was used, and results were reported as pooled proportions or odds ratio (OR) with 95% confidence interval (CI). PROSPERO registration: CRD42023476875., Results: Twenty-six studies, comprising 4013 monochorionic twins, were included for analysis. The proportion of TTTS placentas with residual anastomoses following laser was 24% (95% CI, 0.12-0.41), with a mean and standard deviation of 4.03 ± 2.95 anastomoses per placenta. Post-laser residual anastomoses were significantly associated with intrauterine fetal death (OR, 2.38 [95% CI, 1.33-4.26]), neonatal death (OR, 3.37 [95% CI, 1.65-6.88]), recurrent TTTS (OR, 24.33 [95% CI, 6.64-89.12]), and twin anemia polycythemia sequence (OR, 13.54 [95% CI, 6.36-28.85]). Combined abnormal cord (velamentous and marginal), velamentous cord, and marginal cord insertions within one or both twins following laser were reported at rates of 49% (95% CI, 0.39-0.59), 27% (95% CI, 0.18-0.38), and 28% (95% CI, 0.21-0.36), respectively. Combined, velamentous and marginal cord insertions were not significantly associated with TTTS twins requiring laser (p = 0.72, p = 0.38, and p = 0.71, respectively) vs non-TTTS monochorionic twins., Conclusions: To the best of our knowledge, this is the first review to conjointly explore outcomes of residual anastomoses and abnormal cord insertions within TTTS twins following laser. A large prospective study is necessitated to assess the relationship between abnormal cord insertion and residual anastomoses development post-laser., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Homozygous plakophilin-2 ( PKP2 ) variants have been identified as a cause of a lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET) in three cases. We report three more cases from two families with homozygous pathogenic PKP2 variants and perinatal-onset, lethal DCM-ET. Identification of the genetic abnormalities played a key role in decision-making and family counselling in these cases. This case series supports the published evidence that biallelic loss of function PKP2 variants cause a lethal, perinatal-onset cardiomyopathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Human placenta is an intensively growing tissue. Phosphatidylinositol (PI) and its derivatives are part of the signaling pathway in the regulation of trophoblast cell differentiation. There are two different enzymes that take part in the direct PI synthesis: phosphatidylinositol synthase (PIS) and inositol exchange enzyme (IE). The presence of PIS is known in the human placenta, but IE activity has not been documented before. In our study, we describe the physiological properties of the two enzymes in vitro. PIS and IE were studied in different Mn 2+ and Mg 2+ concentrations that enabled us to separate the individual enzyme activities. Enzyme activity was measured by incorporation of 3[H]inositol in human primordial placenta tissue or microsomes. Optimal PIS activity was achieved between 0.5 and 2.0 mM Mn 2+ concentration, but higher concentrations inhibit enzyme activity. In the presence of Mg 2+ , the enzyme activity increases continuously up to a concentration of 100 mM. PIS was inhibited by nucleoside di- and tri-phosphates. PI production increases between 0.1 and 10 mM Mn 2+ concentration. The incorporation of [3H]inositol into PI increased by 57% when adding stabile GTP analog. The described novel pathway of inositol synthesis may provide an additional therapeutic approach of inositol supplementation before and during pregnancy.

Introduction: Stigma is a well-known barrier to HIV testing and treatment and is an emerging barrier to pre-exposure prophylaxis (PrEP) use. To guide future research, measurement and interventions, we developed a conceptual framework for PrEP stigma among adolescent girls and young women (AGYW) in sub-Saharan Africa, a priority population for PrEP., Methods: A literature review, expert consultations and focus group discussions (FGDs) were conducted to adapt the Health Stigma and Discrimination Framework, describing the stigmatization process nested within the socio-ecological framework. We reviewed all articles on PrEP stigma and on HIV, contraceptive or sexuality stigma among AGYW from 2009 to 2019. Expert consultations were conducted with 10 stigma or PrEP researchers and two Kenyan youth advisory boards to revise the framework. Finally, FGDs were conducted with AGYW PrEP users (4 FGDs; n = 20) and key influencers (14 FGDs; n = 72) in Kenya with the help of a Youth Research Team who aided in FGD conduct and results interpretation. Results from each phase were reviewed and the framework was updated to incorporate new and divergent findings. This was validated against an updated literature search from 2020 to 2023., Results: The conceptual framework identifies potential drivers, facilitators and manifestations of PrEP stigma, its outcomes and health impacts, and relevant intersecting stigmas. The main findings include: (1) PrEP stigma is driven by HIV, gender and sexuality stigmas, and low PrEP community awareness. (2) Stigma is facilitated by factors at multiple levels: policy (e.g. targeting of PrEP to high-risk populations), health systems (e.g. youth-friendly service availability), community (e.g. social capital) and individual (e.g. empowerment). (3) Similar to other stigmas, manifestations include labelling, violence and shame. (4) PrEP stigma results in decreased access to and acceptability of PrEP, limited social support and community resistance, which can impact mental health and decrease PrEP uptake and adherence. (5) Stigma may engender resilience by motivating AGYW to think of PrEP as an exercise in personal agency., Conclusions: Our PrEP stigma conceptual framework highlights potential intervention targets at multiple levels in the stigmatization process. Its adoption would enable researchers to develop standardized measures and compare stigma across timepoints and populations as well as design and evaluate interventions., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background Sudden infant death syndrome (SIDS) is the leading cause of death up to age 1. Sudden unexplained death in childhood (SUDC) is similar but affects mostly toddlers aged 1 to 4. SUDC is rarer than SIDS, and although cardiogenetic testing (molecular autopsy) identifies an underlying cause in a fraction of SIDS, less is known about SUDC. Methods and Results Seventy-seven SIDS and 16 SUDC cases underwent molecular autopsy with 25 definitive-evidence arrhythmia-associated genes. In 18 cases, another 76 genes with varying degrees of evidence were analyzed. Parents were offered cascade screening. Double-blind review of clinical-genetic data established genotype-phenotype correlations. The yield of likely pathogenic variants in the 25 genes was higher in SUDC than in SIDS (18.8% [3/16] versus 2.6% [2/77], respectively; P =0.03), whereas novel/ultra-rare variants of uncertain significance were comparably represented. Rare variants of uncertain significance and likely benign variants were found only in SIDS. In cases with expanded analyses, likely pathogenic/likely benign variants stemmed only from definitive-evidence genes, whereas all other genes contributed only variants of uncertain significance. Among 24 parents screened, variant status and phenotype largely agreed, and 3 cases positively correlated for cardiac channelopathies. Genotype-phenotype correlations significantly aided variant adjudication. Conclusions Genetic yield is higher in SUDC than in SIDS although, in both, it is contributed only by definitive-evidence genes. SIDS/SUDC cascade family screening facilitates establishment or dismissal of a diagnosis through definitive variant adjudication indicating that anonymity is no longer justifiable. Channelopathies may underlie a relevant fraction of SUDC. Binary classifications of genetic causality (pathogenic versus benign) could not always be adequate.

Objectives: Pre-eclampsia (PE) is a leading cause of obstetric morbidity, with no definitive therapy other than delivery. We aimed to compare complement markers in maternal and fetal circulation, and placental tissue, between women with PE and healthy pregnant controls., Study Design: Maternal and umbilical cord blood was tested for iC3b, C3, C4, properdin, Ba and C5b-9, and placental tissue for C3d, C4d, C9 and C1q, from women with PE (n = 34) and healthy pregnant controls (n = 33). Maternal properdin and Ba tests were repeated in a separate validation cohort (PE n = 35; healthy pregnant controls n = 35)., Main Outcome Measures: Complement concentrations in maternal and umbilical cord blood, and placental immunohistochemical complement deposition., Results: Women with PE had significantly lower concentrations of properdin (mean: 4828 vs 6877 ng/ml, p < 0.001) and C4 (mean: 0.20 vs 0.31 g/l, p < 0.001), and higher Ba (median: 150 vs 113 ng/ml, p = 0.012), compared to controls. After controlling for gestational age at blood draw, average properdin concentration was 1945 ng/ml lower in PE vs controls (95 % CI: 1487-2402, p < 0.001). Of the cord blood markers assessed, only Ba differed significantly between PE and controls (median: 337 vs 233 ng/ml, p = 0.004). C4d staining of the syncytiotrophoblast membrane was increased in PE vs controls (median immunoreactivity score 3 vs 0, p < 0.001). Maternal properdin and C4 were significantly negatively correlated with placental C4d staining., Conclusions: Our data confirm excessive placental complement deposition associated with significant concurrent changes in maternal and fetal circulating complement biomarkers in PE. Inhibition of complement activation is a potential therapeutic target., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

We report a fetus with hydrops, congenital heart disease and bilateral radioulnar synostosis caused by a novel pathogenic MECOM variant. The female fetus was referred for post-mortem examination after fetal hydrops and intrauterine death was diagnosed at 20 weeks gestation. Post-mortem examination confirmed fetal hydrops, pallor, truncus arteriosus and bilateral radioulnar synostosis. Trio whole genome sequencing analysis detected a novel de novo heterozygous pathogenic loss-of-function variant in MECOM (NM&#95;004991), associated with a diagnosis of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT-2). RUSAT-2 is a variable condition associated postnatally with bone marrow failure, radioulnar synostosis and congenital anomalies. RUSAT-2 is not currently associated with a prenatal phenotype or fetal demise, and was not present on diagnostic NHS prenatal gene panels at time of diagnosis. This case highlights the diagnostic value of detailed phenotyping with post-mortem examination, and of using a broad sequencing approach., (© 2023 John Wiley & Sons Ltd.)

Background: Input from end-users during preclinical phases can support market fit for new HIV prevention technologies. With several long-acting pre-exposure prophylaxis (PrEP) implants in development, we aimed to understand young women's preferences for PrEP implants to inform optimal design., Methods: We developed a discrete choice experiment and surveyed 800 young women in Harare, Zimbabwe and Tshwane, South Africa between September-November 2020. Women aged 18-30 years who were nulliparous, postpartum, or exchanged sex for money, goods or shelter in prior year were eligible; quotas were set for each subgroup. The DCE asked participants to choose between two hypothetical implants for HIV prevention in a series of nine questions. Implants were described by: size, number of rods and insertion sites, duration (6-months, 1-year, 2-years), flexibility, and biodegradability. Random-parameters logit models estimated preference weights., Results: Median age was 24 years (interquartile range 21-27). By design, 36% had used contraceptive implants. Duration of protection was most important feature, with strong preference for a 2-year over 6-month implant. In Zimbabwe, the number of rods/insertion sites was second most important and half as important as duration. Nonetheless, to achieve an implant lasting 2-years, 74% were estimated to accept two rods, one in each arm. In South Africa, preference was for longer, flexible implants that required removal, although each of these attributes were one-third as important as duration. On average, biodegradability and size did not influence Zimbabwean women's choices. Contraceptive implant experience and parity did not influence relative importance of attributes., Conclusions: While duration of protection was a prominent attribute shaping women's choices for PrEP implants, other characteristics related to discreetness were relevant. Optimizing for longest dosing while also ensuring minimal detection of implant placement seemed most attractive to potential users., (© 2023. The Author(s).)

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years 1 . Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions 2,3 . Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank 4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation-proxies for these drivers-provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The heterozygous diploid genome of Candida albicans displays frequent genomic rearrangements, in particular loss-of-heterozygosity (LOH) events, which can be seen on all eight chromosomes and affect both laboratory and clinical strains. LOHs, which are often the consequence of DNA damage repair, can be observed upon stresses reminiscent of the host environment, and result in homozygous regions of various sizes depending on the molecular mechanisms at their origins. Recent studies have shed light on the biological importance of these frequent and ubiquitous LOH events in C. albicans . In diploid Saccharomyces cerevisiae , LOH facilitates the passage of recessive beneficial mutations through Haldane's sieve, allowing rapid evolutionary adaptation. This also appears to be true in C. albicans , where the full potential of an adaptive mutation is often only observed upon LOH, as illustrated in the case of antifungal resistance and niche adaptation. To understand the genome-wide dynamics of LOH events in C. albicans , we constructed a collection of 15 strains, each one carrying a LOH reporter system on a different chromosome arm. This system involves the insertion of two fluorescent marker genes in a neutral genomic region on both homologs, allowing spontaneous LOH events to be detected by monitoring the loss of one of the fluorescent markers using flow cytometry. Using this collection, we observed significant LOH frequency differences between genomic loci in standard laboratory growth conditions; however, we further demonstrated that comparable heterogeneity was also observed for a given genomic locus between independent strains. Additionally, upon exposure to stress, three outcomes could be observed in C. albicans , where individual strains displayed increases, decreases, or no effect of stress in terms of LOH frequency. Our results argue against a general stress response triggering overall genome instability. Indeed, we showed that the heterogeneity of LOH frequency in C. albicans is present at various levels, inter-strain, intra-strain, and inter-chromosomes, suggesting that LOH events may occur stochastically within a cell, though the genetic background potentially impacts genome stability in terms of LOH throughout the genome in both basal and stress conditions. This heterogeneity in terms of genome stability may serve as an important adaptive strategy for the predominantly clonal human opportunistic pathogen C. albicans, by quickly generating a wide spectrum of genetic variation combinations potentially permitting subsistence in a rapidly evolving environment.

Context.—: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear., Objective.—: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Design.—: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19., Results.—: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs., Conclusions.—: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

Background: Pregnant women with SARS-CoV-2 infection experience higher rates of stillbirth and preterm birth. A unique pattern of chronic histiocytic intervillositis (CHI) and/or massive perivillous fibrin deposition (MPFD) has emerged, coined as SARS-CoV-2 placentitis., Methods: The aim of this study was to describe a cohort of placentas diagnosed with SARS-CoV-2 placentitis during October 2020-March 2021. Cases with a histological diagnosis of SARS-CoV-2 placentitis and confirmatory immunohistochemistry were reported. Maternal demographic data, pregnancy outcomes and placental findings were collected., Findings: 59 mothers delivered 61 infants with SARS-CoV-2 placentitis. The gestational age ranged from 19 to 41 weeks with most cases (78.6%) being third trimester. 30 infants (49.1%) were stillborn or late miscarriages. Obese mothers had higher rates of pregnancy loss when compared with those with a BMI <30 [67% (10/15) versus 41% (14/34)]. 47/59 (79 . 7%) mothers had a positive SARS-CoV-2 PCR test either at the time of labour or in the months before, of which 12 (25 . 5%) were reported to be asymptomatic. Ten reported only CHI, two cases showed MPFD only and in 48 placentas both CHI and MPFD was described., Interpretation: SARS-CoV2 placentitis is a distinct entity associated with increased risk of pregnancy loss, particularly in the third trimester. Women can be completely asymptomatic and still experience severe placentitis. Unlike 'classical' MPFD, placentas with SARS-CoV-2 are generally normal in size with adequate fetoplacental weight ratios. Further work should establish the significance of the timing of maternal SARS-CoV-2 infection and placentitis, the significance of SARS-CoV2 variants, and rates of vertical transmission associated with this pattern of placental inflammation., Funding: There was not funding associated with this study., Competing Interests: We declare no competing interests., (© 2022 The Author(s).)

Aims: TRAPPC11, a subunit of the transport protein particle (TRAPP) complex, is important for complex integrity and anterograde membrane transport from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment. Several individuals with TRAPPC11 mutations have been reported with muscle weakness and other features including brain, liver, skeletal and eye involvement. A detailed analysis of brain and muscle pathology will further our understanding of the presentation and aetiology of TRAPPC11 disease., Methods: We describe five cases of early-onset TRAPPC11-related muscular dystrophy with a systematic review of muscle pathology in all five individuals, post-mortem brain pathology findings in one and membrane trafficking assays in another., Results: All affected individuals presented in infancy with muscle weakness, motor delay and elevated serum creatine kinase (CK). Additional features included cataracts, liver disease, intellectual disability, cardiomyopathy, movement disorder and structural brain abnormalities. Muscle pathology in all five revealed dystrophic changes, universal hypoglycosylation of alpha-dystroglycan and variably reduced dystrophin-associated complex proteins. Membrane trafficking assays showed defective Golgi trafficking in one individual. Neuropathological examination of one individual revealed cerebellar atrophy, granule cell hypoplasia, Purkinje cell (PC) loss, degeneration and dendrite dystrophy, reduced alpha-dystroglycan (IIH6) expression in PC and dentate neurones and absence of neuronal migration defects., Conclusions: This report suggests that recessive mutations in TRAPPC11 are linked to muscular dystrophies with hypoglycosylation of alpha-dystroglycan. The structural cerebellar involvement that we document for the first time resembles the neuropathology reported in N-linked congenital disorders of glycosylation (CDG) such as PMM2-CDG, suggesting defects in multiple glycosylation pathways in this condition., (© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

DNA double-strand breaks (DSBs) are highly toxic lesions that can be mended via several DNA repair pathways. Multiple factors can influence the choice and the restrictiveness of repair towards a given pathway in order to warrant the maintenance of genome integrity. During V(D)J recombination, RAG-induced DSBs are (almost) exclusively repaired by the non-homologous end-joining (NHEJ) pathway for the benefit of antigen receptor gene diversity. Here, we review the various parameters that constrain repair of RAG-generated DSBs to NHEJ, including the peculiarity of DNA DSB ends generated by the RAG nuclease, the establishment and maintenance of a post-cleavage synaptic complex, and the protection of DNA ends against resection and (micro)homology-directed repair. In this physiological context, we highlight that certain DSBs have limited DNA repair pathway choice options., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Libri, Marton and Deriano.)

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Genomic rearrangements have been associated with the acquisition of adaptive phenotypes, allowing organisms to efficiently generate new favorable genetic combinations. The diploid genome of Candida albicans is highly plastic, displaying numerous genomic rearrangements that are often the by-product of the repair of DNA breaks. For example, DNA double-strand breaks (DSB) repair using homologous-recombination pathways are a major source of loss-of-heterozygosity (LOH), observed ubiquitously in both clinical and laboratory strains of C. albicans. Mechanisms such as break-induced replication (BIR) or mitotic crossover (MCO) can result in long tracts of LOH, spanning hundreds of kilobases until the telomere. Analysis of I-SceI-induced BIR/MCO tracts in C. albicans revealed that the homozygosis tracts can ascend several kilobases toward the centromere, displaying homozygosis from the break site toward the centromere. We sought to investigate the molecular mechanisms that could contribute to this phenotype by characterizing a series of C. albicans DNA repair mutants, including pol32-/-, msh2-/-, mph1-/-, and mus81-/-. The impact of deleting these genes on genome stability revealed functional differences between Saccharomyces cerevisiae (a model DNA repair organism) and C. albicans. In addition, we demonstrated that ascending LOH tracts toward the centromere are associated with intrinsic features of BIR and potentially involve the mismatch repair pathway which acts upon natural heterozygous positions. Overall, this mechanistic approach to study LOH deepens our limited characterization of DNA repair pathways in C. albicans and brings forth the notion that centromere proximal alleles from DNA break sites are not guarded from undergoing LOH., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Consanguineous unions occur when a couple are related outside marriage and is associated with adverse genetic and perinatal outcomes for affected offspring. The objectives of this study were to evaluate: (i) background characteristics, (ii) uptake of prenatal and postnatal investigation and (iii) diagnostic outcomes of UK consanguineous couples presenting with a fetal structural anomaly., Material and Methods: This was a retrospective and partly prospective cohort study comparing consanguineous (n = 62) and non-consanguineous (n = 218) pregnancies with current or previous fetal structural anomalies reviewed in a UK prenatal genetic clinic from 2008 to 2019. Outcomes were compared using odds ratios (OR)., Results: Most consanguineous couples were of Pakistani ethnicity (odds ratio [OR] 29, 95% confidence interval [95% CI] 13-62) and required use of an interpreter [OR 9, 95% CI 4-20). In the consanguineous group, the uptake of prenatal invasive testing was lower (OR 0.4, 95% CI 0.2-0.7) and the number declining follow up was greater (OR 10, 95% CI 3-34) than in the non-consanguineous group. This likely explained the lower proportion of consanguineous couples where a final definitive unifying diagnosis to explain the fetal structural anomalies was reached (OR 0.3, 95% CI 0.2-0.6). When a diagnosis was obtained in this group, it was always postnatal and most often using genomic sequencing technologies (OR 6, 95% CI 1-27). The risk of perinatal death was greater (OR 3, 95% CI 1-6) in the consanguineous group, as was the risk of fetal structural anomaly recurrence in a subsequent pregnancy (OR 4, 95% CI 1-13). There was no difference in the uptake of perinatal autopsy or termination of pregnancy between groups., Conclusions: Consanguineous couples are a vulnerable group in the prenatal setting. Although adverse perinatal outcomes in this group are more common secondary to congenital anomalies, despite the evolution of genomic sequencing technologies, due to a lower uptake of prenatal testing it is less likely that a unifying diagnosis is obtained and recurrence can occur. There is a need for proactive genetic counseling and education from the multidisciplinary team, addressing language barriers as well as religious and cultural beliefs in an attempt to optimize reproductive options., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.)

Most of our knowledge relating to molecular mechanisms of human fungal pathogenesis in Candida albicans relies on reverse genetics approaches, requiring strain engineering. DNA-mediated transformation of C. albicans has been described as highly mutagenic, potentially accentuated by the organism's genome plasticity, including the acquisition of genomic rearrangements, notably upon exposure to stress. The advent of CRISPR-Cas9 has vastly accelerated the process of genetically modifying strains, especially in diploid (such as C. albicans ) and polyploid organisms. The effects of unleashing this nuclease within the genome of C. albicans are unknown, although several studies in other organisms report Cas9-associated toxicity and off-target DNA breaks. Upon the construction of a C. albicans strain collection, we took the opportunity to compare strains which were constructed using CRISPR-Cas9-free and CRISPR-Cas9-dependent transformation strategies, by quantifying and describing transformation-induced loss-of-heterozygosity and hyperploidy events. Our analysis of 57 strains highlights the mutagenic effects of transformation in C. albicans , regardless of the transformation protocol, but also underscores interesting differences in terms of genomic changes between strains obtained using different transformation protocols. Indeed, although strains constructed using the CRISPR-Cas9-free transformation method display numerous concomitant genomic changes randomly distributed throughout their genomes, the use of CRISPR-Cas9 leads to a reduced overall number of genome changes, particularly hyperploidies. Overall, in addition to facilitating strain construction by reducing the number of transformation steps, the CRISPR-Cas9-dependent transformation strategy in C. albicans appears to limit transformation-associated genome changes. IMPORTANCE Genome editing is essential to nearly all research studies aimed at gaining insight into the molecular mechanisms underlying various biological processes, including those in the opportunistic pathogen Candida albicans The adaptation of the CRISPR-Cas9 system greatly facilitates genome engineering in many organisms. However, our understanding of the effects of CRISPR-Cas9 technology on the biology of C. albicans is limited. In this study, we sought to compare the extents of transformation-induced genomic changes within strains engineered using CRISPR-Cas9-free and CRISPR-Cas9-dependent transformation methods. CRISPR-Cas9-dependent transformation allows one to simultaneously target both homologs and, importantly, appears less mutagenic in C. albicans , since strains engineered using CRISPR-Cas9 display an overall decrease in concomitant genomic changes., (Copyright © 2020 Marton et al.)

Objective: To (a) evaluate the proportion of women where a unifying genetic diagnosis was obtained following assessment of an observed pattern of fetal anomalies and (b) assess trends in genetic testing in a joint fetal-medicine genetic clinic., Method: Retrospective cohort study of all women attending the clinic. Outcomes included (a) indication for referral, (b) genetic test performed and (c) diagnoses obtained., Results: From 2008 to 2019, 256 patients were referred and reviewed, of which 23% (n = 59) were consanguineous. The main indication for referral was the observed pattern of fetal anomalies. Over 10 years, the number of patients reviewed increased from 11 to 35 per annum. A unifying genetic diagnosis was obtained in 43.2% (n = 79/183), the majority of which were diagnosed prenatally (50.6% [n = 40/79]). The main investigation(s) that was the ultimate diagnostic test was targeted gene panel sequencing 34.2% (n = 27/79), with this and exome sequencing becoming the dominant genetic test by 2019. Pregnancies reviewed due to an abnormal karyotype or microarray decreased as an indication for referral during the study period (21.6% [n = 16/74] 2008-2012 vs 16.5% [n = 30/182] in 2012-2019)., Conclusion: A prenatal genetic clinic with a structured multi-disciplinary team approach may be successful in obtaining a unifying prenatal genetic diagnosis., (© 2020 John Wiley & Sons, Ltd.)

Introduction: According to the Hungarian law, placental examination is not mandatory, although it is known from the international practice that it can give valuable information in cases of stillbirth or in conditions, where the neonate has difficulty in the postnatal adaptation. Aim: It can be useful in the early detection of diseases, which otherwise would have gone undetected until late in life. This article is unique in Hungary, as no similar guideline exists in Hungarian language. Method: The recommendation of the Royal College of Pathologists (United Kingdom) determines those conditions where essential information can be obtained from the placental examination in not normal pregnancies. It serves as a useful guide in the medical practice. The journal titled "Placenta", first published in 1980 with impact factor above two, just underlines this statement. Results: In this article, the authors present the recent guideline of the RCPath and finish with the presentation of established clinicopathological association that might help clinicians to get the most valuable information from placental examination. Conclusion: The present article aims to summarise updated recommendations and present clinicopathological correlations. Orv Hetil. 2019; 160(48): 1894-1903.

A rare complication of umbilical venous catheter (UVC) insertion is the extravasation of the infusate into the peritoneal cavity. We report 3 cases of abdominal extravasation of parenteral nutrition (PN) fluid via UVCs. Two of these cases presented as "acute abdomen" which were assumed to be necrotizing enterocolitis clinically; however, during postmortem, PN ascites and liver necrosis were found. A further case is described in an infant with congenital diaphragmatic hernia. While we were unable to ascertain direct vessel perforation by the catheter in any of these cases, based on pathological and histological examination, the proposed mechanism of PN fluid extravasation is leakage through microinjuries of liver vessel walls and necrotic parenchyma. PN extravasation should be considered as a differential diagnosis of acute abdomen when PN is infused via an UVC presumably as PN may have a direct irritant effect on the peritoneum.

Doubt is subjective uncertainty about one's perceptions and recall. It can impair decision-making and is a prominent feature of obsessive-compulsive disorder (OCD). We propose that evaluation of doubt during decision-making provides a useful endophenotype with which to study the underlying pathophysiology of OCD and potentially other psychopathologies. For the current study, we developed a new instrument, the Doubt Questionnaire, to clinically assess doubt. The random dot motion task was used to measure reaction time and subjective certainty, at varying levels of perceptual difficulty, in individuals who scored high and low on doubt, and in individuals with and without OCD. We found that doubt scores were significantly higher in OCD cases than controls. Drift diffusion modeling revealed that high doubt scores predicted slower evidence accumulation than did low doubt scores; and OCD diagnosis lower than controls. At higher levels of dot coherence, OCD participants exhibited significantly slower drift rates than did controls (q<0.05 for 30%, and 45% coherence; q<0.01 for 70% coherence). In addition, at higher levels of coherence, high doubt subjects exhibited even slower drift rates and reaction times than low doubt subjects (q<0.01 for 70% coherence). Moreover, under high coherence conditions, individuals with high doubt scores reported lower certainty in their decisions than did those with low doubt scores. We conclude that the Doubt Questionnaire is a useful instrument for measuring doubt. Compared to those with low doubt, those with high doubt accumulate evidence more slowly and report lower certainty when making decisions under conditions of low uncertainty. High doubt may affect the decision-making process in individuals with OCD. The dimensional doubt measure is a useful endophenotype for OCD research and could enable computationally rigorous and neurally valid understanding of decision-making and its pathological expression in OCD and other disorders., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To determine the diagnostic yield of combined exome sequencing (ES) and autopsy in fetuses/neonates with prenatally identified structural anomalies resulting in termination of pregnancy, intrauterine, neonatal, or early infant death., Methods: ES was undertaken in 27 proband/parent trios following full autopsy. Candidate pathogenic variants were classified by a multidisciplinary clinical review panel using American College of Medical Genetics and Genomics (ACMG) guidelines., Results: A genetic diagnosis was established in ten cases (37%). Pathogenic/likely pathogenic variants were identified in nine different genes including four de novo autosomal dominant, three homozygous autosomal recessive, two compound heterozygous autosomal recessive, and one X-linked. KMT2D variants (associated with Kabuki syndrome postnatally) occurred in two cases. Pathogenic variants were identified in 5/13 (38%) cases with multisystem anomalies, in 2/4 (50%) cases with fetal akinesia deformation sequence, and in 1/4 (25%) cases each with cardiac and brain anomalies and hydrops fetalis. No pathogenic variants were detected in fetuses with genitourinary (1), skeletal (1), or abdominal (1) abnormalities., Conclusion: This cohort demonstrates the clinical utility of molecular autopsy with ES to identify an underlying genetic cause in structurally abnormal fetuses/neonates. These molecular findings provided parents with an explanation of the developmental abnormality, delineated the recurrence risks, and assisted the management of subsequent pregnancies.

The heterozygous diploid genome of Candida albicans is highly plastic, with frequent loss of heterozygosity (LOH) events. In the SC5314 laboratory strain, while LOH events are ubiquitous, a chromosome homozygosis bias is observed for certain chromosomes, whereby only one of the two homologs can occur in the homozygous state. This suggests the occurrence of recessive lethal allele(s) (RLA) preventing large-scale LOH events on these chromosomes from being stably maintained. To verify the presence of an RLA on chromosome 7 (Chr7), we utilized a system that allows (i) DNA double-strand break (DSB) induction on Chr7 by the I- Sce I endonuclease and (ii) detection of the resulting long-range homozygosis. I- Sce I successfully induced a DNA DSB on both Chr7 homologs, generally repaired by gene conversion. Notably, cells homozygous for the right arm of Chr7B were not recovered, confirming the presence of RLA(s) in this region. Genome data mining for RLA candidates identified a premature nonsense-generating single nucleotide polymorphism (SNP) within the HapB allele of C7&#95;03400c whose Saccharomyces cerevisiae ortholog encodes the essential Mtr4 RNA helicase. Complementation with a wild-type copy of MTR4 rescued cells homozygous for the right arm of Chr7B, demonstrating that the mtr4 K880* RLA is responsible for the Chr7 homozygosis bias in strain SC5314. Furthermore, we observed that the major repeat sequences (MRS) on Chr7 acted as hot spots for interhomolog recombination. Such recombination events provide C. albicans with increased opportunities to survive DNA DSBs whose repair can lead to homozygosis of recessive lethal or deleterious alleles. This might explain the maintenance of MRS in this species. IMPORTANCE Candida albicans is a major fungal pathogen, whose mode of reproduction is mainly clonal. Its genome is highly tolerant to rearrangements, in particular loss of heterozygosity events, known to unmask recessive lethal and deleterious alleles in heterozygous diploid organisms such as C. albicans By combining a site-specific DSB-inducing system and mining genome sequencing data of 182  C. albicans isolates, we were able to ascribe the chromosome 7 homozygosis bias of the C. albicans laboratory strain SC5314 to an heterozygous SNP introducing a premature STOP codon in the MTR4 gene. We have also proposed genome-wide candidates for new recessive lethal alleles. We additionally observed that the major repeat sequences (MRS) on chromosome 7 acted as hot spots for interhomolog recombination. Maintaining MRS in C. albicans could favor haplotype exchange, of vital importance to LOH events, leading to homozygosis of recessive lethal or deleterious alleles that inevitably accumulate upon clonality., (Copyright © 2019 Marton et al.)

Arbuscular mycorrhizal fungi (AMF) are known to improve plant fitness through the establishment of mycorrhizal symbioses. Genetic and phenotypic variations among closely related AMF isolates can significantly affect plant growth, but the genomic changes underlying this variability are unclear. To address this issue, we improved the genome assembly and gene annotation of the model strain Rhizophagus irregularis DAOM197198, and compared its gene content with five isolates of R. irregularis sampled in the same field. All isolates harbor striking genome variations, with large numbers of isolate-specific genes, gene family expansions, and evidence of interisolate genetic exchange. The observed variability affects all gene ontology terms and PFAM protein domains, as well as putative mycorrhiza-induced small secreted effector-like proteins and other symbiosis differentially expressed genes. High variability is also found in active transposable elements. Overall, these findings indicate a substantial divergence in the functioning capacity of isolates harvested from the same field, and thus their genetic potential for adaptation to biotic and abiotic changes. Our data also provide a first glimpse into the genome diversity that resides within natural populations of these symbionts, and open avenues for future analyses of plant-AMF interactions that link AMF genome variation with plant phenotype and fitness., (© 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.)

Background: Whilst hypocalcemic complications from vitamin D deficiency are considered rare in high-income countries, they are highly prevalent among Black, Asian and Minority Ethnic (BAME) group with darker skin. To date, the extent of osteomalacia in such infants and their family members is unknown. Our aim was to investigate clinical, cardiac and bone histomorphometric characteristics, bone matrix mineralization in affected infants and to test family members for biochemical evidence of osteomalacia., Case Presentation: Three infants of BAME origin (aged 5-6 months) presented acutely in early-spring with cardiac arrest, respiratory arrest following seizure or severe respiratory distress, with profound hypocalcemia (serum calcium 1.22-1.96 mmol/L). All infants had dark skin and vitamin D supplementation had not been addressed during child surveillance visits. All three had severely dilated left ventricles (z-scores + 4.6 to + 6.5) with reduced ejection fraction (25-30%; normal 55-70), fractional shortening (7 to 15%; normal 29-40) and global hypokinesia, confirming hypocalcemic dilated cardiomyopathy. They all had low serum levels of 25 hydroxyvitamin D (25OHD < 15 nmol/L), and elevated parathyroid hormone (PTH; 219-482 ng/L) and alkaline phosphatase (ALP; 802-1123 IU/L), with undiagnosed rickets on radiographs. One infant died from cardiac arrest. At post-mortem examination, his growth plate showed a widened, irregular zone of hypertrophic chondrocytes. Histomorphometry and backscattered electron microscopy of a trans-iliac bone biopsy sample revealed increased osteoid thickness (+ 262% of normal) and osteoid volume/bone volume (+ 1573%), and extremely low bone mineralization density. Five of the nine tested family members had vitamin D deficiency (25OHD < 30 nmol/L), three had insufficiency (< 50 nmol/L) and 6/9 members had elevated PTH and ALP levels., Conclusions: The severe, hidden, cardiac and bone pathology described here exposes a failure of public health prevention programs, as complications from vitamin D deficiency are entirely preventable by routine supplementation. The family investigations demonstrate widespread deficiency and undiagnosed osteomalacia in ethnic risk groups and call for protective legislation.

The loss of ANKRD11 gene confirms the diagnosis of KBG syndrome but does not elucidate the pediatric phenotype providing a counseling challenge. With the expansion of prenatal diagnosis, and the potential to perform whole-exome sequencing antenatally, we must describe the genetic abnormalities, antenatal ultrasound findings, and phenotype concurrently to facilitate counseling.

Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Here we investigate the population dynamics of Neolithization across Europe using a high-resolution genome-wide ancient DNA dataset with a total of 180 samples, of which 130 are newly reported here, from the Neolithic and Chalcolithic periods of Hungary (6000-2900 bc, n = 100), Germany (5500-3000 bc, n = 42) and Spain (5500-2200 bc, n = 38). We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways in which gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modelling approaches to elucidate multiple dimensions of historical population interactions.

At the Abony-Turjányos dűlő site, located in Central Hungary, a rescue excavation was carried out. More than 400 features were excavated and dated to the Protoboleráz horizon, at the beginning of the Late Copper Age in the Carpathian Basin, between 3780-3650 cal BC. Besides the domestic and economic units, there were two special areas, with nine-nine pits that differed from the other archaeological features of the site. In the northern pit group seven pits contained human remains belonging to 48 individuals. Some of them were buried carefully, while others were thrown into the pits. The aim of this study is to present the results of the paleopathological and molecular analysis of human remains from this Late Copper Age site. The ratio of neonates to adults was high, 33.3%. Examination of the skeletons revealed a large number of pathological cases, enabling reconstruction of the health profile of the buried individuals. Based on the appearance and frequency of healed ante- and peri mortem trauma, inter-personal (intra-group) violence was characteristic in the Abony Late Copper Age population. However other traces of paleopathology were observed on the bones that appear not to have been caused by warfare or inter-group violence. The remains of one individual demonstrated a rare set of bone lesions that indicate the possible presence of leprosy (Hansen's disease). The most characteristic lesions occurred on the bones of the face, including erosion of the nasal aperture, atrophy of the anterior nasal spine, inflammation of the nasal bone and porosity on both the maxilla and the bones of the lower legs. In a further four cases, leprosy infection is suspected but other infections cannot be excluded. The morphologically diagnosed possible leprosy case significantly modifies our knowledge about the timescale and geographic spread of this specific infectious disease. However, it is not possible to determine the potential connections between the cases of possible leprosy and the special burial circumstances.

Resistance mechanisms against antiangiogenic drugs are unclear. Here, we correlated the antitumor and antivascular properties of five different antiangiogenic receptor tyrosine kinase inhibitors (RTKIs) (motesanib, pazopanib, sorafenib, sunitinib, vatalanib) with their intratumoral distribution data obtained by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). In the first mouse model, only sunitinib exhibited broad-spectrum antivascular and antitumor activities by simultaneously suppressing vascular endothelial growth factor receptor-2 (VEGFR2) and desmin expression, and by increasing intratumoral hypoxia and inhibiting both tumor growth and vascularisation significantly. Importantly, the highest and most homogeneous intratumoral drug concentrations have been found in sunitinib-treated animals. In another animal model, where - in contrast to the first model - vatalanib was detectable at homogeneously high intratumoral concentrations, the drug significantly reduced tumor growth and angiogenesis. In conclusion, the tumor tissue penetration and thus the antiangiogenic and antitumor potential of antiangiogenic RTKIs vary among the tumor models and our study demonstrates the potential of MALDI-MSI to predict the efficacy of unlabelled small molecule antiangiogenic drugs in malignant tissue. Our approach is thus a major technical and preclinical advance demonstrating that primary resistance to angiogenesis inhibitors involves limited tumor tissue drug penetration. We also conclude that MALDI-MSI may significantly contribute to the improvement of antivascular cancer therapies., Competing Interests: The authors have declared that no competing interest exists. The funders had no role in study design, data collection, analysis and decision to publish or preparation of the paper.

Farming was established in Central Europe by the Linearbandkeramik culture (LBK), a well-investigated archaeological horizon, which emerged in the Carpathian Basin, in today's Hungary. However, the genetic background of the LBK genesis is yet unclear. Here we present 9 Y chromosomal and 84 mitochondrial DNA profiles from Mesolithic, Neolithic Starčevo and LBK sites (seventh/sixth millennia BC) from the Carpathian Basin and southeastern Europe. We detect genetic continuity of both maternal and paternal elements during the initial spread of agriculture, and confirm the substantial genetic impact of early southeastern European and Carpathian Basin farming cultures on Central European populations of the sixth-fourth millennia BC. Comprehensive Y chromosomal and mitochondrial DNA population genetic analyses demonstrate a clear affinity of the early farmers to the modern Near East and Caucasus, tracing the expansion from that region through southeastern Europe and the Carpathian Basin into Central Europe. However, our results also reveal contrasting patterns for male and female genetic diversity in the European Neolithic, suggesting a system of patrilineal descent and patrilocal residential rules among the early farmers., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)