Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Mitochondrial extracellular vesicles, autoimmunity and myocarditis

For many decades viral infections have been suspected as ‘triggers’ of autoimmune disease, but mechanisms for how this could occur have been difficult to establish. Recent studies have shown that viral infections that are commonly associated with viral myocarditis and other autoimmune diseases such as coxsackievirus B3 (CVB3) and SARS-CoV-2 target mitochondria and are released from cells in mitochondrial vesicles that are able to activate the innate immune response. Studies have shown that Toll-like receptor (TLR)4 and the inflammasome pathway are activated by mitochondrial components. Autoreactivity against cardiac myosin and heart-specific immune responses that occur after infection with viruses where the heart is not the primary site of infection (e.g., CVB3, SARS-CoV-2) may occur because the heart has the highest density of mitochondria in the body. Evidence exists for autoantibodies against mitochondrial antigens in patients with myocarditis and dilated cardiomyopathy. Defects in tolerance mechanisms like autoimmune regulator gene (AIRE) may further increase the likelihood of autoreactivity against mitochondrial antigens leading to autoimmune disease. The focus of this review is to summarize current literature regarding the role of viral infection in the production of extracellular vesicles containing mitochondria and virus and the development of myocarditis

Cohesinopathies of a feather flock together.

Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS) are severe developmental maladies that present with nearly an identical suite of multi-spectrum birth defects. Not surprisingly, RBS and CdLS arise from mutations within a single pathway--here involving cohesion. Sister chromatid tethering reactions that comprise cohesion are required for high fidelity chromosome segregation, but cohesin tethers also regulate gene transcription, promote DNA repair, and impact DNA replication. Currently, RBS is thought to arise from elevated levels of apoptosis, mitotic failure, and limited progenitor cell proliferation, while CdLS is thought to arise, instead, from transcription dysregulation. Here, we review new information that implicates RBS gene mutations in altered transcription profiles. We propose that cohesin-dependent transcription dysregulation may extend to other developmental maladies; the diagnoses of which are complicated through multi-functional proteins that manifest a sliding scale of diverse and severe phenotypes. We further review evidence that cohesinopathies are more common than currently posited

Developmental and cytological phenotypes of cohesinopathies and potentially related maladies.

<p>Partial list of developmental and cytological effects in response to cohesion pathway mutations.</p>*<p>Craniofacial dysmorphia include micrognathia, ear abnormalities, wide-set eyes, beaked or prominent nose, arched eyebrows, or low-set ears.</p>+<p>Limb reductions are often symmetric and involve all four limbs in RBS but predominant in upper extremities in CdLS. Limb reduction appears limited to the radius in NBS and FA.</p>**<p>Organ abnormalities may include renal, urinary, gonadal, gastroesophageal, and others.</p>++<p>Detection of cryptic HR/PCS may require cell exposure to mitomycin. ND (Not Diagnostic): most studies document that HR/PCS is not elevated in CdLS cells <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Revenkova1" target="_blank">[17]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Castronovo1" target="_blank">[18]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Vrouwe1" target="_blank">[20]</a>, but see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Kaur1" target="_blank">[48]</a>. While HR/PCS is thus not efficacious as a diagnostic tool, numerous chromosomal aberrations are evident in CdLS cells upon exposure to genotoxic agents <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Vrouwe1" target="_blank">[20]</a>, revealing that CdLS cells may be predispositioned to PCS/HR. Bolded text represents examples of historical cytological diagnostic markers (HR/PCS for RBS, Clastogen sensitivity for FA). Phenotypes shown for potentially cohesinopathic-related developmental maladies (Ribosomopathies TCS and DBA, Nijmegen Breakage Disease, Fanconi Anemia—last four columns) that we speculate are similarly predicated on transcriptional dysregulation <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Vega1" target="_blank">[1]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Schule1" target="_blank">[2]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Musio1" target="_blank">[5]</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Krantz1" target="_blank">[8]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Morita1" target="_blank">[14]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Liu1" target="_blank">[26]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Gimigliano1" target="_blank">[33]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Leem1" target="_blank">[41]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Kaur1" target="_blank">[48]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-vanderLelij1" target="_blank">[55]</a>–<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-CapoChichi1" target="_blank">[57]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-vanderLelij3" target="_blank">[61]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Kee1" target="_blank">[63]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Auerbach1" target="_blank">[78]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004036#pgen.1004036-Genetics1" target="_blank">[79]</a>.</p

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways