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Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7 . The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved. Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al . identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”

Large-scale family pedigrees are commonly used across medical, evolutionary, and forensic genetics. These pedigrees are tools for identifying genetic disorders, tracking evolutionary patterns, and establishing familial relationships via forensic genetic identification. However, there is a lack of software to accurately simulate different pedigree structures along with genomes corresponding to those individuals in a family pedigree. This limits simulation-based evaluations of methods that use pedigrees. We have developed a python command-line-based tool called py_(p)ed_(s)im that facilitates the simulation of pedigree structures and the genomes of individuals in a pedigree. py_(p)ed_(s)im represents pedigrees as directed acyclic graphs, enabling conversion between standard pedigree formats and integration with the forward population genetic simulator, SLiM. Notably, py_(p)ed_(s)im allows the simulation of varying numbers of offspring for a set of parents, with the capacity to shift the distribution of sibship sizes over generations. We additionally add simulations for events of misattributed paternity, which offers a way to simulate half-sibling relationships, and simulations to extend the breadth of a family pedigree. We validated the accuracy of both our genome simulator and pedigree simulator. We show that we can simulate genomes onto family pedigrees with levels of expected kinship. py_(p)ed_(s)im is a user-friendly and open-source solution for simulating pedigree structures and conducting pedigree genome simulations. It empowers medical, forensic, and evolutionary genetics researchers to gain deeper insights into the dynamics of genetic inheritance and relatedness within families.

Pedigree inference, for example determining whether two persons are second cousins or unrelated, can be done by comparing their genotypes at a selection of genetic markers. When the data for one or more of the persons is from low-coverage next generation sequencing (lcNGS), currently available computational methods either ignore genetic linkage or do not take advantage of the probabilistic nature of lcNGS data, relying instead on first estimating the genotype. We provide a method and software (see familias.name/lcNGS) bridging the above gap. Simulations indicate how our results are considerably more accurate compared to some previously available alternatives. Our method, utilizing a version of the Lander-Green algorithm, uses a group of symmetries to speed up calculations. This group may be of further interest in other calculations involving linked loci.

Background The ubiquity of pedigrees in many scientific areas calls for versatile and user-friendly software. Previously published online pedigree tools have limited support for complex pedigrees and do not provide analysis of relatedness between pedigree members. Results We introduce QuickPed, a web application for interactive pedigree creation and analysis. It supports complex inbreeding and comes with a rich built-in library of common and interesting pedigrees. The program calculates all standard coefficients of relatedness, including inbreeding, kinship and identity coefficients, and offers specialised plots for visualising relatedness. It also implements a novel algorithm for describing pairwise relationships in words. Conclusion QuickPed is a user-friendly pedigree tool aimed at researchers, case workers and teachers. It contains a number of features not found in other similar tools, and represents a significant addition to the body of pedigree software by making advanced relatedness analyses available for non-bioinformaticians.

Genome-enabled prediction plays an essential role in wheat breeding because it has the potential to increase the rate of genetic gain relative to traditional phenotypic and pedigree-based selection. Since the performance of wheat lines is highly influenced by environmental stimuli, it is important to accurately model the environment and its interaction with genetic factors in prediction models. Arguably, multi-environmental best linear unbiased prediction (BLUP) may deliver better prediction performance than single-environment genomic BLUP. We evaluated pedigree and genome-based prediction using 35,403 wheat lines from the Global Wheat Breeding Program of the International Maize and Wheat Improvement Center (CIMMYT). We implemented eight statistical models that included genome-wide molecular marker and pedigree information as prediction inputs in two different validation schemes. All models included main effects, but some considered interactions between the different types of pedigree and genomic covariates via Hadamard products of similarity kernels. Pedigree models always gave better prediction of new lines in observed environments than genome-based models when only main effects were fitted. However, for all traits, the highest predictive abilities were obtained when interactions between pedigree, genomes, and environments were included. When new lines were predicted in unobserved environments, in almost all trait/year combinations, the marker main-effects model was the best. These results provide strong evidence that the different sources of genetic information (molecular markers and pedigree) are not equally useful at different stages of the breeding pipelines, and can be employed differentially to improve the design and prediction of the outcome of future breeding programs.

Purpose Ecoinvent applies a method for estimation of default standard deviations for flow data from characteristics of these flows and the respective processes that are turned into uncertainty factors in a pedigree matrix, starting from qualitative assessments. The uncertainty factors are aggregated to the standard deviation. This approach allows calculating uncertainties for all flows in the ecoinvent database. In ecoinvent 2 the uncertainty factors were provided based on expert judgment, without (documented) empirical foundation. This paper presents (1) a procedure to obtain an empirical foundation for the uncertainty factors that are used in the pedigree approach and (2) a proposal for new uncertainty factors, received by applying the developed procedure. Both the factors and the procedure are a result of a first phase of an ecoinvent project to refine the pedigree matrix approach. A separate paper in the same edition, also the result of the aforementioned project, deals with extending the developed approach to other probability distributions than lognormal (Muller et al.). Methods Uncertainty is defined here simply as geometric standard deviation (GSD) of intermediate and elementary exchanges at the unit process level. This fits to the lognormal probability distribution that is assumed as default in ecoinvent 2, and helps to overcome scaling effects in the analysed data. In order to provide the required empirical basis, a broad portfolio of data sources is analysed; it is especially important to consider sources outside of the ecoinvent database to avoid circular reasoning. The ecoinvent pedigree matrix from version 2 is taken as a starting point, skipping the indicator “sample size” since it will not be used in ecoinvent 3. This leads to a pedigree matrix with five data quality indicators, each having five score values. The analysis is conducted as follows: for each matrix indicator and for each data source, indicator scores are set in relation to data sets, building groups of data sets that represent the different data quality indicator scores in the pedigree matrix. The uncertainty in each of the groups is calculated. The uncertainty obtained for the group with the ideal indicator score is set as a reference, and uncertainties for the other groups are set in relation to this reference uncertainty. The obtained ratio will be different from 1, it represents the unexplained uncertainty, additional uncertainty due to a lower data quality, and can be directly used as uncertainty factor candidates. Results and discussion The developed approach was able to derive empirically based uncertainty factor candidates for the pedigree matrix in ecoinvent. Uncertainty factors were obtained for all data quality indicators and for almost all indicator scores in the matrix. The factors are the result of the first analysis of several data sources, further analyses and discussions should be used to strengthen their empirical basis. As a consequence, the provided uncertainty factors can change in future. Finally, a few of the qualitative score descriptions in the pedigree matrix left room for interpretation, making their application not ambiguous. Conclusions and perspectives An empirical foundation for the uncertainty factors in the pedigree matrix overcomes one main argument against their use, which in turn strengthens the whole pedigree approach for quantitative uncertainty assessment in ecoinvent. This paper provides an approach to obtain an empirical basis for the uncertainty factors, and it provides also empirically based uncertainty factors, for indicator scores in the pedigree matrix. Basic uncertainty factors are not provided, it is recommended to use the factors from ecoinvent 2 for the time being. In the developed procedure, using GSD as the uncertainty measure is essential to overcome scaling effects; it should therefore also be used if the analysed data do not follow a lognormal distribution. As a consequence, uncertainty factors obtained as GSD ratios need to be translated to range estimators relevant for these other distributions. Formulas for this step are provided in a separate paper (Muller et al.). The work presented in this paper could be the starting point for a much broader study to provide a better basis for input uncertainty in LCA, not only in ecoinvent.

Applications of genetic-based estimates of population size are expanding, especially for species for which traditional demographic estimation methods are intractable due to the rarity of adult encounters. Estimates of breeding population size (𝑁𝑆) are particularly amenable to genetic-based approaches as the parameter can be estimated using pedigrees reconstructed from genetic data gathered from discrete juvenile cohorts, therefore eliminating the need to sample adults in the population. However, a critical evaluation of how genotyping and sampling effort influence bias in pedigree reconstruction, and how these biases subsequently influence estimates of 𝑁𝑆, is needed to evaluate the efficacy of the approach under a range of scenarios. We simulated a model system to understand the interactive effects of genotyping and sampling effort on error in genetic pedigrees reconstructed from the program COLONY. We then evaluated how errors in pedigree reconstruction influenced bias and precision in estimates of 𝑁𝑆 using three different rarefaction estimators. Results indicated that pedigree error can be minimal when adequate genetic data are available, such as when juvenile sample sizes are large and/or individuals are genotyped at many informative loci. However, even in cases for which data are limited, using results of the simulation analysis to understand the magnitude and sources of bias in reconstructed pedigrees can still be informative when estimating 𝑁𝑆. We applied results of the simulation analysis to evaluate 𝑁𝑆 for a population of federally endangered Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) in the Delaware River, USA. Our results indicated that 𝑁𝑆 is likely to be three orders of magnitude lower compared with historic breeding population sizes, which is a considerable advancement in our understanding of the population status of Atlantic sturgeon in the Delaware River. Our analyses are broadly applicable in the design and interpretation of studies seeking to estimate 𝑁𝑆 and can help to guide conservation decisions when ecological uncertainty is high. The utility of these results is expected to grow as rapid advances in genetic technologies increase the popularity of genetic population monitoring and estimation.

• Apple (Malus × domestica) has commercial and nutritional value, but breeding constraints of tree crops limit varietal improvement. Marker-assisted selection minimises these drawbacks, but breeders lack applications for targeting fruit phytochemicals. To understand genotype–phytochemical associations in apples, we have developed a high-throughput integration strategy for genomic and multiplatform metabolomics data. • Here, 124 apple genotypes, including members of three pedigree-connected breeding families alongside diverse cultivars and wild selections, were genotyped and phenotyped. Metabolite genome-wide association studies (mGWAS) were conducted with c. 10 000 single nucleotide polymorphisms and phenotypic data acquired via LC–MS and ¹H NMR untargeted metabolomics. Putative metabolite quantitative trait loci (mQTL) were then validated via pedigree-based analyses (PBA). • Using our developed method, 519, 726 and 177 putative mQTL were detected in LC–MS positive and negative ionisation modes, and NMR, respectively. mQTL were indicated on each chromosome, with hotspots on linkage groups 16 and 17. A chlorogenic acid mQTL was discovered on chromosome 17 via mGWAS and validated with a two-step PBA, enabling discovery of novel candidate gene–metabolite relationships. • Complementary data from three metabolomics approaches and dual genomics analyses increased confidence in validity of compound annotation and mQTL detection. Our platform demonstrates the utility of multiomic integration to advance data-driven, phytochemical-based plant breeding.

Inbreeding depression (reduced fitness of individuals with related parents) has long been a major focus of ecology, evolution, and conservation biology. Despite decades of research, we still have a limited understanding of the strength, underlying genetic mechanisms, and demographic consequences of inbreeding depression in the wild. Studying inbreeding depression in natural populations has been hampered by the inability to precisely measure individual inbreeding. Fortunately, the rapidly increasing availability of high‐throughput sequencing data means it is now feasible to measure the inbreeding of any individual with high precision. Here, we review how genomic data are advancing our understanding of inbreeding depression in the wild. Recent results show that individual inbreeding and inbreeding depression can be measured more precisely with genomic data than via traditional pedigree analysis. Additionally, the availability of genomic data has made it possible to pinpoint loci with large effects contributing to inbreeding depression in wild populations, although this will continue to be a challenging task in many study systems due to low statistical power. Now that reliably measuring individual inbreeding is no longer a limitation, a major focus of future studies should be to more accurately quantify effects of inbreeding depression on population growth and viability.

Pedigree files are ubiquitously used within bioinformatics and genetics studies to convey critical information about relatedness, sex and affected status of study samples. While the text based format of ped files is efficient for computational methods, it is not immediately intuitive to a bioinformatician or geneticist trying to understand family structures, many of which encode the affected status of individuals across multiple generations. The visualization of pedigrees into connected nodes with descriptive shapes and shading provides a far more interpretable format to recognize visual patterns and intuit family structures. Despite these advantages of a visual pedigree, it remains difficult to quickly and accurately visualize a pedigree given a pedigree text file. Here we describe ped_(d)raw a command line and web tool as a simple and easy solution to pedigree visualization. Ped_(d)raw is capable of drawing complex multi-generational pedigrees and conforms to the accepted standards for depicting pedigrees visually. The command line tool can be used as a simple one liner command, utilizing graphviz to generate an image file. The web tool, https://peddraw.github.io, allows the user to either: paste a pedigree file, type to construct a pedigree file in the text box or upload a pedigree file. Users can save the generated image file in various formats. We believe ped_(d)raw is a useful pedigree drawing tool that improves on current methods due to its ease of use and approachability. Ped_(d)raw allows users with various levels of expertise to quickly and easily visualize pedigrees.