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Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification., Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals. Here, Oetjens et al. systematically study the contribution of common genetic variation to variable expressivity of RGDs and find it is frequently influenced by polygenic factors identified in genome-wide association studies of relevant traits.

Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells. Here, the Brain Somatic Mosaicism Network conducted a coordinated, multi-institutional study to: (i) examine the ability of existing methods to detect simulated somatic single nucleotide variants (SNVs) in DNA mixing experiments; (ii) generate multiple replicates of whole genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual; (iii) devise strategies to discover somatic SNVs; and (iv) apply various approaches to validate somatic SNVs. These efforts led to the identification of 43 bona fide somatic SNVs that ranged in variant allele fractions from ~0.005 to ~0.28. Guided by these results, we devised best practices for calling mosaic SNVs from 250X whole genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrated that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees. Thus, this study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.

The male specific regions of primate Y-chromosomes (MSY) are enriched for multi-copy genes highly expressed in the testis. These genes are located in large repetitive sequences arranged as palindromes, inverted-, and tandem-repeats termed amplicons. In humans, these genes have critical roles in male fertility and are essential for the production of sperm. The structure of human and chimpanzee amplicon sequences show remarkable difference relative to the remainder of the genome, a difference that may be the result of intense selective pressure on male fertility. Four populations of common chimpanzees have undergone extended periods of isolation and appear to be in the early process of speciation. A recent study found amplicons enriched for testis-expressed genes on the primate X-chromosome the target of hard selective sweeps, and male-fertility genes on the Y-chromosome may also be the targets of selection. However, little is understood about Y-chromosome amplicon diversity within and across chimpanzee populations. Here, we analyze 9 common chimpanzee (representing three subspecies: Pan troglodytes schweinfurthii, Pan troglodytes ellioti, and Pan troglodytes verus) and two bonobo (Pan paniscus) male whole-genome sequences to assess Y ampliconic copy-number diversity across the Pan genus. We observe that the copy-number of Y chromosome amplicons is variable amongst chimpanzees and bonobos, and identify several lineage-specific patterns, including variable copy-number of azoospermia candidates RBMY and DAZ. We detect recurrent switchpoints of copy-number change along the ampliconic tracts across chimpanzee populations, which may be the result of localized genome instability or selective forces.

Advances in genotyping technology have, over the past decade, enabled the focused search for common genetic variation associated with human diseases and traits. With the recently increased availability of detailed phenotypic data from electronic health records and epidemiological studies, the impact of one or more genetic variants on the phenome is starting to be characterized both in clinical and population-based settings using phenome-wide association studies (PheWAS). These studies reveal a number of challenges that will need to be overcome to unlock the full potential of PheWAS for the characterization of the complex human genome-phenome relationship.

Background Most genetic analyses of ancient and modern dogs have focused on variation in the autosomes or on the mitochondria. Mitochondrial DNA is more easily obtained from ancient samples than nuclear DNA and mitochondrial analyses have revealed important insights into the evolutionary history of canids. Utilizing a recently published dog Y-chromosome reference, we analyzed Y-chromosome sequence across a diverse collection of canids and determined the Y haplogroup of three ancient European dogs. Results We identified 1121 biallelic Y-chromosome SNVs using whole-genome sequences from 118 canids and defined variants diagnostic to distinct dog Y haplogroups. Similar to that of the mitochondria and previous more limited studies of Y diversity, we observe several deep splits in the Y-chromosome tree which may be the result of retained Y-chromosome diversity which predates dog domestication or post-domestication admixture with wolves. We find that Y-chromosomes from three ancient European dogs (4700–7000 years old) belong to distinct clades. Conclusions We estimate that the time to the most recent comment ancestor of dog Y haplogroups is 68–151 thousand years ago. Analysis of three Y-chromosomes from the Neolithic confirms long stranding population structure among European dogs. Electronic supplementary material The online version of this article (10.1186/s12864-018-4749-z) contains supplementary material, which is available to authorized users.

Europe has played a major role in dog evolution, harbouring the oldest uncontested Palaeolithic remains and having been the centre of modern dog breed creation. Here we sequence the genomes of an Early and End Neolithic dog from Germany, including a sample associated with an early European farming community. Both dogs demonstrate continuity with each other and predominantly share ancestry with modern European dogs, contradicting a previously suggested Late Neolithic population replacement. We find no genetic evidence to support the recent hypothesis proposing dual origins of dog domestication. By calibrating the mutation rate using our oldest dog, we narrow the timing of dog domestication to 20,000–40,000 years ago. Interestingly, we do not observe the extreme copy number expansion of the AMY2B gene characteristic of modern dogs that has previously been proposed as an adaptation to a starch-rich diet driven by the widespread adoption of agriculture in the Neolithic., The European continent is thought to have played a major role in the origins of modern dogs. Here, analysing two ancient dog genomes from Germany, the authors find significant genetic continuity throughout the Neolithic period and time dog domestication to ∼20,000–40,000 years ago.

The prevalence of obesity has been increasing globally, resulting in increased rates of type 2 diabetes, cardiovascular disease, and certain cancers (1). Risk factors for obesity include a sedentary lifestyle, overconsumption of energy, and genetic susceptibility (2, 3). Recent genome-wide association studies have identified several common genetic variants associated with body mass index (BMI; weight (kg)/height (m)2), a measure of adiposity (4, 5). However, the mechanisms underlying these associations have yet to be characterized. Given that macronutrient consumption plays a key role in obesity (6), understanding the biological links between inherited genetic variation and components of energy intake may suggest strategies for reducing the increasing prevalence of obesity (7). To date, at least 32 independent loci have been found to be associated with BMI (8). Many of the genes involved, such as the brain-derived neurotrophic factor gene (BDNF), the melanocortin 4 receptor gene (MC4R), and the fat mass and obesity-associated gene (FTO), are expressed in the central nervous system (9–11), suggesting that they may act through the neurological control of various aspects of energy balance. Indeed, studies have found that obesity risk variants in intron 1 of the FTO gene are associated with greater energy consumption (12–17) or frequency of energy consumption (18) and a reduction in satiety (19–21) and intake control (12, 22, 23). In a recent study of approximately 2,100 adults of mostly European descent (77%), McCaffery et al. (18) found that FTO rs1421085 was associated with percentage of calories derived from fat. Additionally, this and another study found that obesity risk variants in the potassium channel tetramerization domain-containing 15 gene (KCTD15) and BDNF were associated with macronutrient intake (24) or increased meat and dairy intake (18). However, many of these previous studies were conducted in populations of primarily European descent. To further understand the relationship between obesity single-nucleotide polymorphisms (SNPs) and energy consumption, we investigated, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study (25), the relationship between 6 obesity risk variants and intake of macronutrients (carbohydrate, protein, ethanol, and fat and its subtypes) among type 2 diabetes-free adults from 5 racial/ethnic groups.

Background: The ADME Core Panel assays 184 variants across 34 pharmacogenes, many of which are difficult to accurately genotype with standard multiplexing methods. Methods: We genotyped 326 frequently medicated individuals of European descent in Vanderbilt’s biorepository linked to de-identified electronic medical records, BioVU, on the ADME Core Panel to assess quality and performance of the assay. We compared quality control metrics and determined the extent of direct and indirect marker overlap between the ADME Core Panel and the Illumina Omni1-Quad. Results: We found the quality of the ADME Core Panel data to be high, with exceptions in select copy number variants and markers in certain genes (notably CYP2D6). Most of the common variants on the ADME panel are genotyped by the Omni1, but absent rare variants and copy number variants could not be accurately tagged by single markers. Conclusion: Our frequently medicated study population did not convincingly differ in allele frequency from reference populations, suggesting that heterogeneous clinical samples (with respect to medications) have similar allele frequency distributions in pharmacogenetics genes compared with reference populations. Original submitted 25 October 2012; Revision submitted 20 March 2013

Aim: We sought to identify potential pleiotropy involving pharmacogenes. Methods: We tested 184 functional variants in 34 pharmacogenes for associations using a custom grouping of International Classification and Disease, Ninth Revision billing codes extracted from deidentified electronic health records of 6892 patients. Results: We replicated several associations including ABCG2 (rs2231142) and gout (p = 1.73 × 10-7; odds ratio [OR]: 1.73; 95% CI: 1.40–2.12); and SLCO1B1 (rs4149056) and jaundice (p = 2.50 × 10-4; OR: 1.67; 95% CI: 1.27–2.20). Conclusion: In this systematic screen for phenotypic associations with functional variants, several novel genotype–phenotype combinations also achieved phenome-wide significance, including SLC15A2 rs1143672 and renal osteodystrophy (p = 2.67 × 10- 6; OR: 0.61; 95% CI: 0.49–0.75).

Population stratification or confounding by genetic ancestry is a potential cause of false associations in genetic association studies. Estimation of and adjustment for genetic ancestry has become common practice thanks in part to the availability of ancestry informative markers on genome-wide association study (GWAS) arrays. While array data is now widespread, these data are not ubiquitous as several large epidemiologic and clinic-based studies lack genome-wide data. One such large epidemiologic-based study lacking genome-wide data accessible to investigators is the National Health and Nutrition Examination Surveys (NHANES), population-based cross-sectional surveys of Americans linked to demographic, health, and lifestyle data conducted by the Centers for Disease Control and Prevention. DNA samples (n=14,998) were extracted from biospecimens from consented NHANES participants between 1991-1994 (NHANES III, phase 2) and 1999-2002 and represent three major self-identified racial/ethnic groups: non-Hispanic whites (n=6,634), non-Hispanic blacks (n=3,458), and Mexican Americans (n=3,950). We as the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study genotyped candidate gene and GWAS-identified index variants in NHANES as part of the larger Population Architecture using Genomics and Epidemiology (PAGE) I study for collaborative genetic association studies. To enable basic quality control such as estimation of genetic ancestry to control for population stratification in NHANES san genome-wide data, we outline here strategies that use limited genetic data to identify the markers optimal for characterizing genetic ancestry. From among 411 and 295 autosomal SNPs available in NHANES III and NHANES 1999-2002, we demonstrate that markers with ancestry information can be identified to estimate global ancestry. Despite limited resolution, global genetic ancestry is highly correlated with self-identified race for the majority of participants, although less so for ethnicity. Overall, the strategies outlined here for a large epidemiologic study can be applied to other datasets accessible for genotype phenotype studies but are sans genome-wide data.

Helitrons are a recently discovered superfamily of eukaryotic transposable elements. They are known for their ability to capture and mobilize gene fragments and, in turn, significantly contribute to the lack of gene colinearity widely reported among different maize inbred lines. As judged by present evidence, Helitrons differ fundamentally from Class I and Class II families of transposable elements in both structure and the mechanism of transposition. These elements are poorly understood despite their massive abundance, their structural diversity and the important role they apparently play in the evolution of maize genome. Although evidence for recent Helitron movement has been reported in maize, autonomous Helitron activity has not been reported. Helitrons are postulated to transpose via a so-called rolling circle (RC) mechanism involving strand replacement catalyzed by helicase and replicase enzymes encoded by an autonomous element. However, no experimental evidence in support of this hypothesis has been reported. Several models for gene piece capture have been proposed based on the structural features of Helitrons and the comparison of captured gene fragments of related elements. However no supporting evidence is extant for any of the models proposed. A better understanding of these elements requires concrete evidence of their transposition in the present day genome, establishment of a system to assay their transposition and an analysis of additional indigenous Helitrons in other species. This review critically analyses the proposed mechanisms of Helitron transposition, their impact on genome evolution and the process by which these enigmatic elements capture and multiply host genes.

Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition., Children's Discovery Institute, March of Dimes Birth Defects Foundation, National Institute of General Medical Sciences (U.S.) (T32 GM081739), Washington University (Saint Louis, Mo.), Washington University (Saint Louis, Mo.) (Mr. and Mrs. Spencer T. Olin Fellowship for Women in Graduate Study), Sigrid Jusélius stiftelse, Signe and Anne Gyllenberg Foundation, Academy of Finland