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Gregor Mendel developed the principles of segregation and independent assortment in the mid-1800s based on his detailed analysis of several traits in pea plants. Those principles, now called Mendels laws, in fact, explain the behavior of genes and alleles during meiosis and are now understood to underlie Mendelian inheritance of a wide range of traits and diseases across organisms. When asked to give examples of inheritance that do NOT follow Mendels laws, in other words, examples of non-Mendelian inheritance, students sometimes list incomplete dominance, codominance, multiple alleles, sex-linked traits, and multigene traits and cite as their sources the Khan Academy, Wikipedia, and other online sites. Against this background, the goals of this Perspective are to (1) explain to students, healthcare workers, and other stakeholders why the examples above, in fact, display Mendelian inheritance, as they obey Mendels laws of segregation and independent assortment, even though they do not produce classic Mendelian phenotypic ratios and (2) urge individuals with an intimate knowledge of genetic principles to monitor the accuracy of learning resources and work with us and those resources to correct information that is misleading.

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

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The evolution of sexual dimorphisms requires divergence between sexes in the evolutionary trajectories of the traits involved. Discerning how genetic architecture could facilitate such divergence has proven challenging because of the difficulty in estimating non-additive and sex-linked genetic variances using traditional quantitative genetic designs. Here we use a three-generation, double-first-cousin pedigree design to estimate additive, sex-linked and dominance (co)variances for 12 traits in the water strider, Aquarius remigis. Comparisons among these traits, which have size ratios ranging from 1 to 5 (larger/smaller), allow us to ask if sexual dimorphisms are associated with characteristic patterns of quantitative genetic variation. We frame our analysis around three main questions, derived from existing theory and empirical evidence: Are sexual dimorphisms associated with (1) lower additive inter-sex genetic correlations, (2) higher proportions of sex-linked variance, or (3) differences between sexes in autosomal additive and dominance genetic variances? For questions (1) and (2), we find weak and non-significant trends in the expected directions, which preclude definitive conclusions. However, in answer to question (3), we find strong evidence for a positive relationship between sexual dimorphism and differences between sexes in proportions of autosomal dominance variance. We also find strong interactions among the three genetic components indicating that their relative influence differs among traits and between sexes. These results highlight the need to include all three components of genetic (co)variance in both theoretical evolutionary models and empirical estimations of the genetic architecture of dimorphic traits.

Diploid lines (2n = 2x = 24) derived from tetraploid potato cultivars have been utilized to hybridize with wild diploid potato species, yielding fertile offsprings. Utilizing the pollen of Solanum tuberosum Group Phureja, such as IVP101, IVP35 and IVP48, as an inducer for wide hybridization with tetraploid cultivars represents a common method for producing diploids. In this study, we created a distant hybridization induced population of tetraploid potato cultivar Cooperation 88 (C88) and IVP101, and screened all diploids using flow cytometry and ploidyNGS. We investigated the genetic composition of chloroplast and nuclear genomes in 43 diploid offsprings. We found that all diploid offsprings share the same chloroplast genomic sequence as C88 and no evidence of paternal chloroplast inheritance was found. Used SNP data to calculate the theoretical introgression index of IVP101 with diploid offsprings. The results showed that the inducer’s nuclear genome was involved in the nuclear genome of the diploid offsprings with purple stem trait, indicating that the inducer nuclear genome was not completely eliminated in the nuclear genome during distant hybridization. Furthermore, we conducted a comparative analysis of the chloroplast genomes of the Solanum genus. The results indicated that (1) the chloroplast genome sizes of the 14 Solanum species ranged from 154,289 bp to 155,614 bp, with a total number of genes ranging 128-141, and with ycf1 and rps19 pseudogenes appearing at the IRB/SSC and IRA/LSC boundaries, respectively; (2) eight divergent hotspots distributed in the LSC and SSC regions of the Solanum chloroplast genomes were identified; (3) positive selection was detected in the clpP, rbcL, rps15, and rps4 genes, likely contributing to the adaptation of Solanum species to different habitats. These results reveal the variation and evolutionary characteristics of chloroplast genomes in Solanum plants.

In order to investigate the effect of FecB on litter size and growth and development traits of Suhu meat sheep and the inheritance patterns of FecB between parents and offspring in the population. In this experiment, 2241 sheep from the Suhu meat sheep population were tested for FecB using capillary electrophoresis. We combined the lambing records of 473 ewes, the growth trait records of 881 sheep at both the birth and weaning (2-month-old) stages, and the complete genealogical records of 643 lambs to analysis the distribution of FecB in the Suhu meat sheep breeding population, its effect on litter size of ewes, growth and development of lambs, and the inheritance patterns of FecB. The results showed that there were three genotypes of FecB in the Suhu meat sheep population, namely the AA genotype, AG genotype, and GG genotype. FecB in this population has a moderate polymorphism (0.25 < PIC < 0.5), and deviates from Hardy–Weinberg disequilibrium (p < 0.05). The litter size of GG genotype ewes was significantly higher than that with the AG and AA genotypes (p < 0.01). A Chi-square test showed that the inheritance patterns of FecB follows Mendel's Laws of Inheritance (p > 0.05). An association analysis of different genotypes of FecB with body weight and body size of Suhu meat sheep at birth and weaning revealed that FecB adversely affects the early growth and development of Suhu meat sheep. In summary, FecB can improve the litter size of ewes but it has negative effects on the early growth and survival rate of lambs in sheep. Therefore, FecB test results and feeding management measures should be comprehensively applied to improve the reproductive performance of ewes, the survival rate and production performance of lambs in sheep production, and thus improve the economic benefits of sheep farms. [ABSTRACT FROM AUTHOR]

CRISPR/Cas gene drives can bias transgene inheritance through different mechanisms. Homing drives are designed to replace a wild-type allele with a copy of a drive element on the homologous chromosome. In Aedes aegypti, the sex-determining locus is closely linked to the white gene, which was previously used as a target for a homing drive element (wGDe). Here, through an analysis using this linkage we show that in males inheritance bias of wGDe did not occur by homing, rather through increased propagation of the donor drive element. We test the same wGDe drive element with transgenes expressing Cas9 with germline regulatory elements sds3, bgcn, and nup50. We only find inheritance bias through homing, even with the identical nup50-Cas9 transgene. We propose that DNA repair outcomes may be more context dependent than anticipated and that other previously reported homing drives may, in fact, bias their inheritance through other mechanisms.

The emergence of the field of transgenerational epigenetics inheritance (TEI) has profoundly reshaped our understanding of the relationships between environment, soma, and germ cells as well as of heredity. TEI refers to the changes in chromatin state, gene expression, and/or phenotypes that are transmitted across several generations without involving changes to the DNA sequences. TEI has direct connections with, and feeds from, the fields of molecular biology, genetics, developmental biology, and reproductive biology, among others. However, the expansion of TEI-related research, has profoundly reshaped boundaries within each field and often led to the erosion of theories and concepts considered as tenets of biology. We first explore how the molecularization of biology has shifted the definition of epigenetics to include the notion of heredity and how epigenetics has refined our understanding of the central dogma of biology. The demonstrated transfer of environmental information from soma to germ cell through extracellular vesicles and subsequent alteration of health outcomes in offspring has put a definite end to the long-held principle of the Weismann barrier. TEI has also simultaneously led to the revival of the inheritance of acquired characteristics while further eroding the concept of an epigenetic "blank slate" in mammals. Using an historical framework, and via the exploration of central studies in the field, in this perspective article, we will draw a compelling argument for the revolutionary aspect of TEI in biology.

BackgroundDNA sequencing is increasingly incorporated into the routine care of cancer patients, many of whom also carry inherited, moderate/high-penetrance variants associated with other diseases. Yet, the prevalence and consequence of such variants remain unclear.MethodsWe analyzed the germline genomes of 10,389 adult cancer cases in the TCGA cohort, identifying pathogenic/likely pathogenic variants in autosomal-dominant genes, autosomal-recessive genes, and 59 medically actionable genes curated by the American College of Molecular Genetics (i.e., the ACMG 59 genes). We also analyzed variant- and gene-level expression consequences in carriers.ResultsThe affected genes exhibited varying pan-ancestry and population-specific patterns, and overall, the European population showed the highest frequency of pathogenic/likely pathogenic variants. We further identified genes showing expression consequence supporting variant functionality, including altered gene expression, allelic specific expression, and mis-splicing determined by a massively parallel splicing assay.ConclusionsOur results demonstrate that expression-altering variants are found in a substantial fraction of cases and illustrate the yield of genomic risk assessments for a wide range of diseases across diverse populations.

Copyright of Koomesh: Journal of Semnan University of Medical Sciences is the property of Koomesh: Journal of Semnan University of Medical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: There are many studies which strongly suggest that the pathophysiology of Temporomandibular joint Disorder (TMD) may also be influenced by genetic conditions. The current study was aimed to evaluate the hypothesis that the polymorphism of estrogen receptor genes, estrogen receptor 1 and 2 (ESR1 and ESR2), and the gene Catechol-O-Methyl-Transferase (COMT) could be Predisposing factor for TMD. Methods: In this case-control study, blood sample were taken from 100 TMD diagnosed patients based on Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and 103 healthy individuals as the control group. Tetra ARMS-PCR method was used to amplify and identify COMT rs4680, ESR1 rs1643821, and ESR2 rs1676303 gene polymorphism. Results: ESR1 genotype AA and GA showed significantly increase probability (OR= 4.80, OR=2.98, respectively) of TMD. ESR2 T/T homozygosity was associated with decreased risk for TMD (OR=0.41). The relationship between COMT and TMD was not statistically significant (p>00.05). The relationship between the severity of TMD and ESR1 was significant (p=0.003). According to the inheritance pattern the COMT and ESR1 gene, in the dominant pattern can be susceptible to TMD and in ESR2 gene, in the recessive pattern can be protective to TMD. Conclusion: It seems that SNPs of ESR1 rs1643821 has a susceptible role and ESR2 rs1676303 has a protective role against TMD. Also, we add evidences that various genotype of COMT rs4680 were not statistically different between case and control, but allele A in the dominant inherence pattern can be susceptible to TMD. [ABSTRACT FROM AUTHOR]

Domestic dogs have experienced population bottlenecks, recent inbreeding, and strong artificial selection. These processes have simplified the genetic architecture of complex traits, allowed deleterious variation to persist, and increased both identity-by-descent (IBD) segments and runs of homozygosity (ROH). As such, dogs provide an excellent model for examining how these evolutionary processes influence disease. We assembled a dataset containing 4,414 breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 markers and data for clinical and morphological phenotypes. Breed dogs have an enrichment of IBD and ROH, relative to both village dogs and wolves, and we use these patterns to show that breed dogs have experienced differing severities of bottlenecks in their recent past. We then found that ROH burden is associated with phenotypes in breed dogs, such as lymphoma. We next test the prediction that breeds with greater ROH have more disease alleles reported in the Online Mendelian Inheritance in Animals (OMIA). Surprisingly, the number of causal variants identified correlates with the popularity of that breed rather than the ROH or IBD burden, suggesting an ascertainment bias in OMIA. Lastly, we use the distribution of ROH across the genome to identify genes with depletions of ROH as potential hotspots for inbreeding depression and find multiple exons where ROH are never observed. Our results suggest that inbreeding has played a large role in shaping genetic and phenotypic variation in dogs and that future work on understudied breeds may reveal new disease-causing variation.

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

What defines whether the interaction between environment and organism creates a genetic memory able to be transferred to subsequent generations? Bacteria and the products of their metabolism are the most ubiquitous biotic environments to which every living organism is exposed. Both microbiota and host establish a framework where environmental and genetic factors are integrated to produce adaptive life traits, some of which can be inherited. Thus, the interplay between host and microbe is a powerful model to study how phenotypic plasticity is inherited. Communication between host and microbe can occur through diverse molecules such as small RNAs (sRNAs) and the RNA interference machinery, which have emerged as mediators and carriers of heritable environmentally induced responses. Notwithstanding, it is still unclear how the organism integrates sRNA signaling between different tissues to orchestrate a systemic bacterially induced response that can be inherited. Here we discuss current evidence of heritability produced by the intestinal microbiota from several species. Neurons and gut are the sensing systems involved in transmitting changes through transcriptional and post-transcriptional modifications to the gonads. Germ cells express inflammatory receptors, and their development and function are regulated by host and bacterial metabolites and sRNAs thus suggesting that the dynamic interplay between host and microbe underlies the hosts capacity to transmit heritable behaviors. We discuss how the host detects changes in the microbiota that can modulate germ cells genomic functions. We also explore the nature of the interactions that leave permanent or long-term memory in the host and propose mechanisms by which the microbiota can regulate the development and epigenetic reprogramming of germ cells, thus influencing the inheritance of the host. We highlight the vast contribution of the bacterivore nematode C. elegans and its commensal and pathogenic bacteria to the understanding on how behavioral adaptations can be inter and transgenerational inherited.

Obesity and metabolic disorders have become a worldwide pandemic affecting millions of people. Although obesity is a multifaceted disease, there is growing evidence supporting the obesogen hypothesis, which proposes that exposure to a subset of endocrine disrupting chemicals (EDCs), known as obesogens, promotes obesity. While these effects can be observed in vitro using cell models, in vivo and human epidemiological studies have strengthened this hypothesis. Evidence from animal models showed that the effects of obesogen exposure can be inherited transgenerationally through at least the F4 generation. Transgenerational effects of EDC exposure predispose future generations to undesirable phenotypic traits and diseases, including obesity and related metabolic disorders. The exact mechanisms through which phenotypic traits are passed from an exposed organism to their offspring, without altering the primary DNA sequence, remain largely unknown. Recent research has provided strong evidence suggesting that a variety of epigenetic mechanisms may underlie transgenerational inheritance. These include differential DNA methylation, histone methylation, histone retention, the expression and/or deposition of non-coding RNAs and large-scale alterations in chromatin structure and organization. This review highlights the most recent advances in the field of epigenetics with respect to the transgenerational effects of environmental obesogens. We highlight throughout the paper the strengths and weaknesses of the evidence for proposed mechanisms underlying transgenerational inheritance and why none of these is sufficient to fully explain the phenomenon. We propose that changes in higher order chromatin organization and structure may be a plausible explanation for how some disease predispositions are heritable through multiple generations, including those that were not exposed. A solid understanding of these possible mechanisms is essential to fully understanding how environmental exposures can lead to inherited susceptibility to diseases such as obesity.

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., leptin) is high or low relative to its distribution. Leptin concentrations are strongly related to adiposity, whose heritability is quantile dependent. Whether inheritance of leptin concentrations is quantile dependent, and whether this explains the greater heritability in women than men in accordance with their greater adiposity, and explains other gene-environment interactions, remains to be determined. Therefore, leptin and leptin receptor concentrations from 3068 siblings in 1133 sibships from the Framingham Heart Study Third Generation Cohort were analyzed. Free leptin index (FLI) was calculated as the ratio of leptin to soluble leptin receptor concentrations. Full-sib (βFS) regression slopes were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. The analyses showed βFS increased significantly with increasing percentiles of the offspring's age- and sex-adjusted leptin distribution (Plinear = 0.0001), which was accelerated at the higher concentrations (Pquadratic = 0.0003). βFS at the 90th percentile (0.418 ± 0.066) was 4.7-fold greater than at the 10th percentile (0.089 ± 0.032, Pdifference = 3.6 × 10-6). Consistent with quantile-dependent expressivity, the βFS was greater in female sibs, which was attributable to their higher leptin concentrations. Reported gene-environment interactions involving adiposity and LEP, LEPR, MnSOD, PPARγ, PPARγ2, and IRS-1 polymorphisms were consistent with quantile-dependent expressivity of leptin concentrations. βFS for leptin receptor concentrations and free leptin index also increased significantly with increasing percentiles of their distributions (Plinear = 0.04 and Plinear = 8.5 × 10-6, respectively). In conclusion, inherited genetic and shared environmental effects on leptin concentrations were quantile dependent, which likely explains male-female differences in heritability and some gene-environment interactions.

This retrospective study identifies patients with RP at the Inherited Retinal Disease Clinic at the University of Minnesota (UMN)/M Health System who had genetic testing via next generation sequencing. A database was curated to record history and examination, genetic findings, and ocular imaging. Causative pathogenic and likely pathogenic variants were recorded. Disease status was further characterized by ocular coherence tomography (OCT) and fundus autofluorescence (AF). Our study cohort included a total of 199 patients evaluated between 1 May 2015–5 August 2022. The cohort included 151 patients with non-syndromic RP and 48 with syndromic RP. Presenting symptoms included nyctalopia (85.4%) photosensitivity/hemeralopia (60.5%), and decreased color vision (55.8%). On average, 38.9% had visual acuity of worse than 20/80. Ellipsoid zone band width on OCT scan of less than 1500 μm was noted in 73.6%. Ninety-nine percent had fundus autofluorescence (AF) findings of a hypo- or hyper-fluorescent ring within the macula and/or peripheral hypo-AF. Of the 127 subjects who underwent genetic testing, a diagnostic pathogenic and/or likely pathogenic variant was identified in 67 (52.8%) patients—33.3% of syndromic RP and 66.6% of non-syndromic RP patients had a diagnostic gene variant identified. It was found that 23.6% of the cohort had negative genetic testing results or only variants of uncertain significance identified, which were deemed as non-diagnostic. We concluded that patients with RP often present with advanced disease. In our population, next generation sequencing panels identified a genotype consistent with the exam in just over half the patients. Additional work will be needed to identify the underlying genetic etiology for the remainder. [ABSTRACT FROM AUTHOR]

Cas9/gRNA-mediated gene-drive systems have advanced development of genetic technologies for controlling vector-borne pathogen transmission. These technologies include population suppression approaches, genetic analogs of insecticidal techniques that reduce the number of insect vectors, and population modification (replacement/alteration) approaches, which interfere with competence to transmit pathogens. Here, we develop a recoded gene-drive rescue system for population modification of the malaria vector, Anopheles stephensi, that relieves the load in females caused by integration of the drive into the kynurenine hydroxylase gene by rescuing its function. Non-functional resistant alleles are eliminated via a dominantly-acting maternal effect combined with slower-acting standard negative selection, and rare functional resistant alleles do not prevent drive invasion. Small cage trials show that single releases of gene-drive males robustly result in efficient population modification with ≥95% of mosquitoes carrying the drive within 5-11 generations over a range of initial release ratios.

How gene expression can evolve depends on the mechanisms driving gene expression. Gene expression is controlled in different ways in different developmental stages; here we ask whether different developmental stages show different patterns of regulatory evolution. To explore the mode of regulatory evolution, we used the early stages of embryonic development controlled by two different genomes, that of the mother and that of the zygote. During embryogenesis in all animals, initial developmental processes are driven entirely by maternally provided gene products deposited into the oocyte. The zygotic genome is activated later, when developmental control is handed off from maternal gene products to the zygote during the maternal-to-zygotic transition. Using hybrid crosses between sister species of Drosophila (Dsimulans, D. sechellia, and D. mauritiana) and transcriptomics, we find that the regulation of maternal transcript deposition and zygotic transcription evolve through different mechanisms. We find that patterns of transcript level inheritance in hybrids, relative to parental species, differ between maternal and zygotic transcripts, and maternal transcript levels are more likely to be conserved. Changes in transcript levels occur predominantly through differences in trans regulation for maternal genes, while changes in zygotic transcription occur through a combination of both cis and trans regulatory changes. Differences in the underlying regulatory landscape in the mother and the zygote are likely the primary determinants for how maternal and zygotic transcripts evolve.

CRISPR-Cas9-based gene drive systems possess the inherent capacity to spread progressively throughout target populations. Here we describe two self-copying (or active) guide RNA-only genetic elements, called e-CHACRs and ERACRs. These elements use Cas9 produced in trans by a gene drive either to inactivate the cas9 transgene (e-CHACRs) or to delete and replace the gene drive (ERACRs). e-CHACRs can be inserted at various genomic locations and carry two or more gRNAs, the first copying the e-CHACR and the second mutating and inactivating the cas9 transgene. Alternatively, ERACRs are inserted at the same genomic location as a gene drive, carrying two gRNAs that cut on either side of the gene drive to excise it. e-CHACRs efficiently inactivate Cas9 and can drive to completion in cage experiments. Similarly, ERACRs, particularly those carrying a recoded cDNA-restoring endogenous gene activity, can drive reliably to fully replace a gene drive. We compare the strengths of these two systems.

Shape is a critical element of the visual appeal of strawberry fruit and is influenced by both genetic and non-genetic determinants. Current fruit phenotyping approaches for external characteristics in strawberry often rely on the human eye to make categorical assessments. However, fruit shape is an inherently multi-dimensional, continuously variable trait and not adequately described by a single categorical or quantitative feature. Morphometric approaches enable the study of complex, multi-dimensional forms but are often abstract and difficult to interpret. In this study, we developed a mathematical approach for transforming fruit shape classifications from digital images onto an ordinal scale called the Principal Progression of k Clusters (PPKC). We use these human-recognizable shape categories to select quantitative features extracted from multiple morphometric analyses that are best fit for genetic dissection and analysis. We transformed images of strawberry fruit into human-recognizable categories using unsupervised machine learning, discovered 4 principal shape categories, and inferred progression using PPKC. We extracted 68 quantitative features from digital images of strawberries using a suite of morphometric analyses and multivariate statistical approaches. These analyses defined informative feature sets that effectively captured quantitative differences between shape classes. Classification accuracy ranged from 68% to 99% for the newly created phenotypic variables for describing a shape. Our results demonstrated that strawberry fruit shapes could be robustly quantified, accurately classified, and empirically ordered using image analyses, machine learning, and PPKC. We generated a dictionary of quantitative traits for studying and predicting shape classes and identifying genetic factors underlying phenotypic variability for fruit shape in strawberry. The methods and approaches that we applied in strawberry should apply to other fruits, vegetables, and specialty crops.

"Quantile-dependent expressivity" is a dependence of genetic effects on whether the phenotype (e.g., triglycerides) is high or low relative to its distribution in the population. Quantile-specific offspring-parent regression slopes (βOP) were estimated by quantile regression for 6227 offspring-parent pairs. Quantile-specific heritability (h2), estimated by 2βOP/(1 + rspouse), decreased 0.0047 ± 0.0007 (P = 2.9 × 10-14) for each one-percent decrement in fasting triglyceride concentrations, i.e., h2 ± SE were: 0.428 ± 0.059, 0.230 ± 0.030, 0.111 ± 0.015, 0.050 ± 0.016, and 0.033 ± 0.010 at the 90th, 75th, 50th, 25th, and 10th percentiles of the triglyceride distribution, respectively. Consistent with quantile-dependent expressivity, 11 drug studies report smaller genotype differences at lower (post-treatment) than higher (pre-treatment) triglyceride concentrations. This meant genotype-specific triglyceride changes could not move in parallel when triglycerides were decreased pharmacologically, so that subtracting pre-treatment from post-treatment triglyceride levels necessarily created a greater triglyceride decrease for the genotype with a higher pre-treatment value (purported precision-medicine genetic markers). In addition, sixty-five purported gene-environment interactions were found to be potentially attributable to triglyceride's quantile-dependent expressivity, including gene-adiposity (APOA5, APOB, APOE, GCKR, IRS-1, LPL, MTHFR, PCSK9, PNPLA3, PPARγ2), gene-exercise (APOA1, APOA2, LPL), gene-diet (APOA5, APOE, INSIG2, LPL, MYB, NXPH1, PER2, TNFA), gene-alcohol (ALDH2, APOA5, APOC3, CETP, LPL), gene-smoking (APOC3, CYBA, LPL, USF1), gene-pregnancy (LPL), and gene-insulin resistance interactions (APOE, LPL).

Memory performance results from plasticity, the ability to change with experience. We show that benefit from practice over a few trials, learning slope, is predictive of long-term recall and hippocampal volume across a broad age range and a long period of time, relates to memory training benefit, and is heritable. First, in a healthy lifespan sample (n = 1825, age 4-93 years), comprising 3483 occasions of combined magnetic resonance imaging (MRI) scans and memory tests over a period of up to 11 years, learning slope across 5 trials was uniquely related to performance on a delayed free recall test, as well as hippocampal volume, independent from first trial memory or total memory performance across the five learning trials. Second, learning slope was predictive of benefit from memory training across ten weeks in an experimental subsample of adults (n = 155). Finally, in an independent sample of male twins (n = 1240, age 51-50 years), learning slope showed significant heritability. Within-session learning slope may be a useful marker beyond performance per se, being heritable and having unique predictive value for long-term memory function, hippocampal volume and training benefit across the human lifespan.

Walnut shell suture strength directly impacts the ability to maintain shell integrity during harvest and processing, susceptibility to insect damage and other contamination, and the proportion of kernel halves recovered during cracking. Suture strength is therefore an important breeding objective. Here, two methods of phenotyping this trait were investigated: 1) traditional, qualitative and rather subjective scoring on an interval scale by human observers, and; 2) quantitative and continuous measurements captured by a texturometer. The aim of this work was to increase the accuracy of suture strength phenotyping and to then apply two mapping approaches, quantitative trait loci (QTL) mapping and genome wide association (GWAS) models, in order to dissect the genetic basis of the walnut suture trait. Using data collected on trees within the UC Davis Walnut Improvement Program (n = 464), the genetic correlation between the texturometer method and qualitatively scored method was high (0.826). Narrow sense heritability calculated using quantitative measurements was 0.82. A major QTL for suture strength was detected on LG05, explaining 34% of the phenotypic variation; additionally, two minor QTLs were identified on LG01 and LG11. All three QTLs were confirmed with GWAS on corresponding chromosomes. The findings reported in this study are relevant for application towards a molecular breeding program in walnut.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10-8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Objective: Rare disease. Background: Ververi-Brady syndrome (VEBRAS) is an autosomal dominant condition associated with short stature, microcephaly, mild dysmorphic features, and learning disabilities. It was first described in 2018, and only 38 cases have been reported since then. All patients have mutation in the Glutamine-rich protein 1 (QRICH1) gene, yet clinical presentation has a broad spectrum and continues to expand. This report is of a mother and daughter pair with VEBRAS, associated with a new variant of the QRICH1 gene, NM_017730.3: c.337C>T; p.(Gln113*), and few previously undescribed phenotypic features. Case Reports: We present 2 new cases, a mother and daughter, with novel heterozygous nonsense variant NM_017730.3: c.337C>T; p.(Gln113*). The daughter was referred to a geneticist at the age of 17 years because of seizures, dysmorphic features, and magnetic resonance imaging suggestive of leukodystrophy. In addition to already described clinical features, she had diffuse infantile hemangiomatosis and occipital balding. She was accompanied by her mother, who shared similar phenotypic features, raising suspicion for a similar genetic condition. Unlike the daughter, the mother never had any significant health problems or concerns and described herself as perfectly healthy. Genetic testing was performed in both individuals, and a novel pathogenic QRICH1 variant was discovered. Conclusions: Considering the novelty of VEBRAS, every new clinical case contributes to the enlargement of the VEBRAS cohort, expanding the phenotypical and mutational spectrum, with potential improvement in the further care and observation of probands and their offspring. This report has highlighted the importance of clinical genetics in the identification of familial genetic disorders with complex phenotypes. [ABSTRACT FROM AUTHOR]

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

Heritability of LPA allele, apo(a) isoform sizes, and isoform-associated lipoprotein(a) [Lp(a)] levels was studied in 82 Caucasian and African-American families with two parents and two children (age: 6-74 years). We determined: 1) Lp(a) levels; 2) LPA allele sizes; 3) apo(a) isoform sizes; and 4) isoform-specific apo(a) levels (ISLs), the amount of Lp(a) carried by an individual apo(a) isoform. Trait heritability was estimated by mid-parent-offspring analysis. The ethnicity-adjusted heritability estimate for Lp(a) level was 0.95. Heritability for ISLs corresponding to the smaller LPA allele in a given allele-pair was higher than that corresponding to the larger LPA allele (0.91 vs. 0.59, P = 0.017). Although not statistically different, heritability for both apo(a) isoforms (0.90 vs. 0.70) and LPA alleles (0.98 vs. 0.82) was higher for the smaller versus larger sizes. Heritability was generally lower in African-Americans versus Caucasians with a 4-fold difference for the larger LPA allele (0.25 vs. 0.94, P = 0.001). In Caucasians, an overall higher heritability pattern was noted for the older (≥47 years) versus younger (

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

The rice XA21-mediated immune response is activated on recognition of the RaxX peptide produced by the bacterium Xanthomonas oryzae pv. oryzae (Xoo). The 60-residue RaxX precursor is post-translationally modified to form a sulfated tyrosine peptide that shares sequence and functional similarity with the plant sulfated tyrosine (PSY) peptide hormones. The 5-kb raxX-raxSTAB gene cluster of Xoo encodes RaxX, the RaxST tyrosylprotein sulfotransferase, and the RaxA and RaxB components of a predicted type I secretion system. To assess raxX-raxSTAB gene cluster evolution and to determine its phylogenetic distribution, we first identified rax gene homologues in other genomes. We detected the complete raxX-raxSTAB gene cluster only in Xanthomonas spp., in five distinct lineages in addition to X. oryzae. The phylogenetic distribution of the raxX-raxSTAB gene cluster is consistent with the occurrence of multiple lateral (horizontal) gene transfer events during Xanthomonas speciation. RaxX natural variants contain a restricted set of missense substitutions, as expected if selection acts to maintain peptide hormone-like function. Indeed, eight RaxX variants tested all failed to activate the XA21-mediated immune response, yet retained peptide hormone activity. Together, these observations support the hypothesis that the XA21 receptor evolved specifically to recognize Xoo RaxX.

Gene-drive systems developed in several organisms result in super-Mendelian inheritance of transgenic insertions. Here, we generalize this "active genetic" approach to preferentially transmit allelic variants (allelic-drive) resulting from only a single or a few nucleotide alterations. We test two configurations for allelic-drive: one, copy-cutting, in which a non-preferred allele is selectively targeted for Cas9/guide RNA (gRNA) cleavage, and a more general approach, copy-grafting, that permits selective inheritance of a desired allele located in close proximity to the gRNA cut site. We also characterize a phenomenon we refer to as lethal-mosaicism that dominantly eliminates NHEJ-induced mutations and favors inheritance of functional cleavage-resistant alleles. These two efficient allelic-drive methods, enhanced by lethal mosaicism and a trans-generational drive process we refer to as "shadow-drive", have broad practical applications in improving health and agriculture and greatly extend the active genetics toolbox.

Heterochromatin spreading, the propagation of repressive chromatin along the chromosome, is a reaction critical to genome stability and defense, as well as maintenance of unique cell fates. Here, we discuss the intrinsic properties of the spreading reaction and circumstances under which its products, formed distal to DNA-encoded nucleation sites, can be epigenetically maintained. Finally, we speculate that the epigenetic properties of heterochromatin evolved together with the need to stabilize cellular identity.

A hereditary system that is based on double-helix DNA sequences provides a stable way to store inherited traits and is favored by most life forms on Earth. However, emerging studies on the phenomenon of non-DNA sequence-based inheritance in multiple species, including mammals, urges a rethinking of the nature of hereditary information carriers and the ways in which they encode heritable traits. In this short opinion piece, we discuss how potential hereditary information carriers such as DNA-associated proteins, epigenetic marks, RNAs and organelles could function via distinct and synergistic modes of action in encoding and transmitting ancestral traits, either inherited or acquired from the environment. In particular, we discuss how the 3D structure of chromatin, in addition to its DNA sequence, may represent a higher-order carrier of hereditary information.

The equal probability of transmission of alleles from either parent during sexual reproduction is a central tenet of genetics and evolutionary biology. Yet, there are many cases where this rule is violated. The preferential transmission of alleles or genotypes is termed transmission ratio distortion (TRD). Examples of TRD have been identified in many species, implying that they are universal, but the resolution of species-wide studies of TRD are limited. We have performed a species-wide screen for TRD in over 500 segregating F2 populations of Arabidopsis thaliana using pooled reduced-representation genome sequencing. TRD was evident in up to a quarter of surveyed populations. Most populations exhibited distortion at only one genomic region, with some regions being repeatedly affected in multiple populations. Our results begin to elucidate the species-level architecture of biased transmission of genetic material in A. thaliana, and serve as a springboard for future studies into the biological basis of TRD in this species.

Dilated cardiomyopathy (DCM) is a leading cause of morbidity and mortality worldwide; yet how genetic variation and environmental factors impact DCM heritability remains unclear. Here, we report that compound genetic interactions between DNA sequence variants contribute to the complex heritability of DCM. By using genetic data from a large family with a history of DCM, we discovered that heterozygous sequence variants in the TROPOMYOSIN 1 (TPM1) and VINCULIN (VCL) genes cose-gregate in individuals affected by DCM. In vitro studies of patient-derived and isogenic human-pluripotent-stem-cell-derived cardio-myocytes that were genome-edited via CRISPR to create an allelic series of TPM1 and VCL variants revealed that cardiomyocytes with both TPM1 and VCL variants display reduced contractility and sarcomeres that are less organized. Analyses of mice genetically engineered to harbour these human TPM1 and VCL variants show that stress on the heart may also influence the variable penetrance and expressivity of DCM-associated genetic variants in vivo. We conclude that compound genetic variants can interact combinatorially to induce DCM, particularly when influenced by other disease-provoking stressors.

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Transposable elements (TE) comprise roughly half of the human genome. Though initially derided as junk DNA, they have been widely hypothesized to contribute to the evolution of gene regulation. However, the contribution of TE to the genetic architecture of diseases remains unknown. Here, we analyze data from 41 independent diseases and complex traits to draw three conclusions. First, TE are uniquely informative for disease heritability. Despite overall depletion for heritability (54% of SNPs, 39 ± 2% of heritability), TE explain substantially more heritability than expected based on their depletion for known functional annotations. This implies that TE acquire function in ways that differ from known functional annotations. Second, older TE contribute more to disease heritability, consistent with acquiring biological function. Third, Short Interspersed Nuclear Elements (SINE) are far more enriched for blood traits than for other traits. Our results can help elucidate the biological roles that TE play in the genetic architecture of diseases.

Individual differences in white matter tract microstructure, measured with diffusion tensor imaging (DTI), demonstrate substantial heritability. However, it is unclear to what extent this heritability reflects global genetic influences or tract-specific genetic influences. The goal of the current study was to quantify the proportion of genetic and environmental variance in white matter tracts attributable to global versus tract-specific influences. We assessed fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) across 11 tracts and 22 subdivisions of these tracts in 392 middle-aged male twins from the Vietnam Era Twin Study of Aging (VETSA). In principal component analyses of the 11 white matter tracts, the first component, which represents the global signal, explained 50.1% and 62.5% of the variance in FA and MD, respectively. Similarly, the first principal component of the 22 tract subdivisions explained 38.4% and 47.0% of the variance in FA and MD, respectively. Twin modeling revealed that DTI measures of all tracts and subdivisions were heritable, and that genetic influences on global FA and MD accounted for approximately half of the heritability in the tracts or tract subdivisions. Similar results were observed for the AD and RD diffusion metrics. These findings underscore the importance of controlling for DTI global signals when measuring associations between specific tracts and outcomes such as cognitive ability, neurological and psychiatric disorders, and brain aging.

Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.

Human genome variation has increasingly posed challenges and opportunities for patients, medical providers, and an increasing group of stakeholders including advocacy groups, disadvantaged communities, public health experts, and scientists. Here, advances in genomic sequencing and mapping technologies are discussed with particular attention to the increasing ability to detect personal and population genome variation and the potential for accurate integration of variation into health and disease-related care. Genome mapping, one technique used to create genome map scaffolds, has now been combined with long read sequencing. New technologies have led to improved variation detection, including cryptic structural variation and diverse variants with different degrees of disease association. Combined with advances in automated and medical interpretations, variation detection is increasingly being applied in healthcare. These advances promise to make disease diagnostics more rapid, and potentially more accessible, to those with medical needs. Consequentially, the need for medical genetics and genomics experts is increasing. Here, the opportunities and potential challenges for application of genome-scale variation detection in disease are examined. (<300 words). [ABSTRACT FROM AUTHOR]

Phenotypic plasticity is a heritable trait that provides sessile organisms a strategy to rapidly mitigate negative effects of environmental change. Yet, we have little understanding of the mode of inheritance and genetic architecture of plasticity in different focal traits relevant to agricultural applications. This study builds on our recent discovery of genes controlling temperature-mediated flower size plasticity in Arabidopsis thaliana and focuses on dissecting the mode of inheritance and combining ability of plasticity in the context of plant breeding. We created a full diallel cross using 12 A. thaliana accessions displaying different temperaturemediated flower size plasticities, scored as the fold change between two temperatures. Griffing's analysis of variance in flower size plasticity indicated that non-additive genetic action shapes this trait and pointed at challenges and opportunities when breeding for reduced plasticity. Our findings provide an outlook of flower size plasticity that is important for developing resilient crops for future climates. [ABSTRACT FROM AUTHOR]

Human genome variation has increasingly posed challenges and opportunities for patients, medical providers, and an increasing group of stakeholders including advocacy groups, disadvantaged communities, public health experts, and scientists. Here, advances in genomic sequencing and mapping technologies are discussed with particular attention to the increasing ability to detect personal and population genome variation and the potential for accurate integration of variation into health and disease-related care. Genome mapping, one technique used to create genome map scaffolds, has now been combined with long read sequencing. New technologies have led to improved variation detection, including cryptic structural variation and diverse variants with different degrees of disease association. Combined with advances in automated and medical interpretations, variation detection is increasingly being applied in healthcare. These advances promise to make disease diagnostics more rapid, and potentially more accessible, to those with medical needs. Consequentially, the need for medical genetics and genomics experts is increasing. Here, the opportunities and potential challenges for application of genome-scale variation detection in disease are examined. (

Phenotypic plasticity is a heritable trait that provides sessile organisms a strategy to rapidly mitigate negative effects of environmental change. Yet, we have little understanding of the mode of inheritance and genetic architecture of plasticity in different focal traits relevant to agricultural applications. This study builds on our recent discovery of genes controlling temperature-mediated flower size plasticity in Arabidopsis thaliana and focuses on dissecting the mode of inheritance and combining ability of plasticity in the context of plant breeding. We created a full diallel cross using 12 A. thaliana accessions displaying different temperature-mediated flower size plasticities, scored as the fold change between two temperatures. Griffing’s analysis of variance in flower size plasticity indicated that non-additive genetic action shapes this trait and pointed at challenges and opportunities when breeding for reduced plasticity. Our findings provide an outlook of flower size plasticity that is important for developing resilient crops for future climates.

Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)-salt-inducible kinase 3 (SIK3)-mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.

The heterochromatin spreading reaction is a central contributor to the formation of gene-repressive structures, which are re-established with high positional precision, or fidelity, following replication. How the spreading reaction contributes to this fidelity is not clear. To resolve the origins of stable inheritance of repression, we probed the intrinsic character of spreading events in fission yeast using a system that quantitatively describes the spreading reaction in live single cells. We show that spreading triggered by noncoding RNA-nucleated elements is stochastic, multimodal, and fluctuates dynamically across time. This lack of stability correlates with high histone turnover. At the mating type locus, this unstable behavior is restrained by an accessory cis-acting element REIII, which represses histone turnover. Further, REIII safeguards epigenetic memory against environmental perturbations. Our results suggest that the most prevalent type of spreading, driven by noncoding RNA-nucleators, is epigenetically unstable and requires collaboration with accessory elements to achieve high fidelity.

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on ∼400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser.

The theoretical ability of epigenetic variation to influence the heritable variation of complex traits is gaining traction in the study of adaptation. This theory posits that epigenetic marks can control adaptive phenotypes but the relative potential of epigenetic variation in comparison to genetic variation in these traits is not presently understood. To compare the potential of epigenetic and genetic variation in adaptive traits, we analyzed the influence of DNA methylation variation on the accumulation of chemical defense compounds glucosinolates from the order Brassicales. Several decades of work on glucosinolates has generated extensive knowledge about their synthesis, regulation, genetic variation and contribution to fitness establishing this pathway as a model pathway for complex adaptive traits. Using high-throughput phenotyping with a randomized block design of ddm1 derived Arabidopsis thaliana epigenetic Recombinant Inbred Lines, we measured the correlation between DNA methylation variation and mean glucosinolate variation and within line stochastic variation. Using this information, we identified epigenetic Quantitative Trait Loci that contained specific Differentially Methylated Regions associated with glucosinolate traits. This showed that variation in DNA methylation correlates both with levels and variance of glucosinolates and flowering time with trait-specific loci. By conducting a meta-analysis comparing the results to different genetically variable populations, we conclude that the influence of DNA methylation variation on these adaptive traits is much lower than the corresponding impact of standing genetic variation. As such, selective pressure on these traits should mainly affect standing genetic variation to lead to adaptation.