Human aggression and music evolution: a model

Together with language, music is perhaps our most distinctive behavioral trait. Following the lead of paleolinguistic research, different hypotheses have been proposed to explain why only humans perform music and how this ability might have evolved in the species. In this paper, we advance a new model of music evolution that builds on the theory of self-domestication, according to which the human phenotype is, at least in part, the outcome of a process similar to mammal domestication, triggered by a progressive reduction in reactive aggression levels in response to environmental changes. In the paper, we specifically argue that changes in aggression management through the course of human cultural evolution can account for the behaviors conducive to the emergence and evolution of music. We hypothesize 4 stages in the evolutionary development of music under the influence of environmental changes and evolution of social organization: starting from musilanguage, proto-music gave rise to personal and private forms of timbre-oriented music, then to small-group ensembles of pitch-oriented music, at first of indefinite and then definite pitch, and finally to collective (tonal) music. These stages parallel what has been hypothesized for languages and encompass the diversity of music types and genres described worldwide. Overall, music complexity emerges in a gradual fashion under the effects of enhanced abilities for cultural niche construction, resulting from the stable trend of reduction in reactive aggression towards the end of the Pleistocene, leading to the rise of hospitality codes, and succeeded by increase in proactive aggression from the beginning of the Holocene onward. This paper addresses numerous controversies in the literature on the evolution of music by providing a clear structural definition of music, identifying its structural features that distinguish it from oral language, and summarizing the typology of operational functions of music and formats of its transmission. The proposed framework of structural approach to music arms a researcher with means to identify and comparatively analyze different schemes of tonal organization of music, placing them in the context of human social and cultural evolution. Especially valuable contribution to the understanding of transition from animal communication to human music and language is the theory of so-called “personal song”, described and analyzed here from ethological, social, cultural, cognitive, and musicological perspectives. The emergence of personal song and its development into a social institution are interlinked with the evolution of kinship and placed into the timeline of cultural evolution, based on totality of ethnographic, archaeological, anthropological, genetic, and paleoclimatic data.

Deep Phenotypic Analysis for Transposition of the Great Arteries and Prognosis Implication

Background Transposition of the great arteries (TGA) consists of about 3% of all congenital heart diseases and 20% of cyanotic congenital heart diseases. It is always accompanied by a series of other cardiac malformations that affect the surgical intervention strategy as well as prognosis. In this study, we comprehensively analyzed the phenotypes of the patients who had TGA with concordant atrioventricular and discordant ventriculoarterial connections and explored their association with prognosis. Methods and Results We retrospectively reviewed 666 patients with a diagnosis of TGA with concordant atrioventricular and discordant ventriculoarterial connections in Fuwai Hospital from 1997 to 2019. Under the guidance of the Human Phenotype Ontology database, patients were classified into 3 clusters. The Kaplan‐Meier method was used to analyze the prognosis, and the Cox proportional regression model was used to investigate the risk factors. In this 666‐patient TGA cohort, the overall 5‐year survival rate was 94.70% (92.95%–96.49%). Three clusters with distinct phenotypes were obtained by the Human Phenotype Ontology database. Kaplan‐Meier analysis revealed a significant difference in freedom from reintervention among 3 clusters ( P <0.001). To eliminate the effect of surgeries, we analyzed patients who only received an arterial switch operation and still found a significant difference in reintervention ( P =0.019). Conclusions We delineated a big cardiovascular phenotypic profile of an unprecedentedly large TGA cohort and successfully risk stratified them to reveal prognostic significance. Also, we reported the outcomes of a large TGA population in China.

Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation

Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1H595D/+;I596I/+;Y597Y/+ mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1H595D/+;I596I/+;Y597Y/+ mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.

A 22q11.2-microdeletiós szindróma klinikai jellemzői

Összefoglaló. Bevezetés: A sokszínű tünetspektrummal jellemezhető DiGeorge-szindróma leggyakoribb oka a 22q11.2-microdeletio; incidenciája 1/4000–6000. Célkitűzés: A DiGeorge-szindrómára gyanús hazai betegcsoport 22q11.2-microdeletióval társult tüneteinek/panaszainak részletes feltérképezése, a betegség incidenciájának becslése és egy magyarországi 22q11.2-microdeletiós szindróma regiszter létrehozása. Módszer: 2005 és 2019 között a Semmelweis Egyetem II. Gyermekgyógyászati Klinikájára DiGeorge-szindróma gyanújával beutalt és a Veleszületett Rendellenességek Országos Nyilvántartása által regisztrált DiGeorge-szindrómás betegek adatait dolgoztuk fel. A fenotípusjegyeket a Humán Fenotípus Ontológia kódrendszer alapján határoztuk meg. Eredmények: A vizsgálatba 114, igazolt DiGeorge-szindrómás és 113, FISH-vizsgálattal microdeletiót nem hordozó, de klinikailag a DiGeorge-szindróma tüneteit mutató beteget vontunk be. A diagnózis felállításakor a betegek átlagéletkora 5,88 (± 9,66 SD) év volt, eddig a betegek 54,9%-a legalább egy szívműtéten átesett. A betegek leggyakoribb tünetei a kamrai sövényhiány, a mélyen ülő fülek, a gótikus szájpad, a motoros fejlődési elmaradás és a visszatérő fertőzések voltak. Megbeszélés: A DiGeorge-szindróma becsült incidenciája hazánkban 1/12 500, közöttük magas a többszörösen veszélyeztetett újszülöttek és a műtéti korrekcióra szorulók aránya. A diagnózis hazánkban 2–3 évvel korábban történik a nemzetközi átlaghoz viszonyítva. Következtetés: A létrehozott regiszterünk alapján Magyarországon a kórkép aluldiagnosztizált. Minden conotruncalis szívfejlődési rendellenesség vagy jelentős kamrai sövényhiány esetén citogenetikai vizsgálat javasolt a DiGeorge-szindróma felmerülő gyanúja miatt. Negatív lelet esetén az atípusos töréspontú microdeletiók azonosítására komparatív genomiális hibridizáció vagy multiplex ligatiofüggő próbaamplifikációs vizsgálat javasolt. A betegek számára multidiszciplináris ellátás szükséges, III-as progresszivitási szintű újszülött intenzív részlegen, gyermekkardiológus és klinikai genetikus részvételével. Orv Hetil. 2022; 163(1): 21–30. Summary. Introduction: The 22q11.2 microdeletion syndrome is the most common cause of DiGeorge syndrome, showing a wide phenotypic spectrum and has an estimated incidence of 1/4000–6000 livebirths. Objective: Detailed characterization of the clinical signs/symptoms associated with 22q11.2 deletion, estimation of the national incidence via establishing a Hungarian register. Method: Retrospective data between 2005 and 2019 from the 2nd Department of Paediatrics, Semmelweis University and from national database of congenital anomalies were obtained. Phenotypic abnormalities were described using the Human Phenotype Ontology nomenclature. Results: A cohort of 114 DiGeorge patients and 113 patients negative for FISH testing were included. The mean age of patients at diagnosis was 5.88 (± 9.66 SD) years and 54.9% of patients had at least one heart surgery until diagnosis. The main identified symptoms were ventricular septal defect, low-set ears, recurrent infections, high narrow palate and motor development delay. Discussion: The estimated incidence of DiGeorge syndrome in Hungary is 1/12 500 births, the frequency of infants at high risk and in need for surgery is high. Diagnosis is established 2–3 years earlier as compared to the international average. Conclusion: Based on the established Hungarian register, the incidence is lower compared to international data. In the case of conotruncal heart anomaly and ventricular septal defects, cytogenetic testing is recommended for the increased probability of DiGeorge syndrome. For second-tier testing, comparative genome hybridization or multiplex ligation-dependent probe amplification are recommended to identify atypical microdeletions. Newborns with DiGeorge syndrome require special care in perinatal intensive centers including pediatric cardiology and genetic counseling. Orv Hetil. 2022; 163(1): 21–30.

Identification of HOX Signatures Contributing to Oral Cancer Phenotype

Purpose: Evolutionarily conserved homeobox-containing HOX genes as transcriptional regulators in the developmental specification of organisms is well known. The contribution of HOX genes involvement in oral cancer phenotype has yet to be fully ascertained.Methods: GEO datasets (GSE72627, GSE30784, GSE37991) were accessed and analyzed using GEO2R. TCGA-HNSC HTSeq-counts and clinical data were retrieved from the GDC portal for oral cavity neoplasms. Differential HOX gene expression was profiled using the DESeq2 R package with a log2 fold change cut-off (-1 and +1) and Benjamini-Hochberg p-adjusted value at <0.01. Gene set over-representation analysis and semantic analysis associated with the disease ontology were performed using ClusterProfiler R package and pathway over-representation analysis was performed using IMPaLa. HOX protein interaction network was constructed using the Pathfind R package. HOX phenotype associations were performed using Mammalian Phenotype Ontology, Human Phenotype Ontology, PhenGenI associations, Jensen tissues, and OMIM entries. Drug connectivity mapping was carried out with Dr. Insight R Package.Results: HOXB2 and HOXA5 genes were upregulated in oral dysplasia but silenced during tumor progression. Loss of HOXB2 expression was consistent through potentially malignant dysplastic oral lesions (PMOL) to primary tumor formation. HOXA10, HOXB7, HOXC6, HOXC10 and HOXD10 showed consistent upregulation from premalignancy to malignancy and were notably associated with risk factors. Overrepresentation analysis suggested HOXA10 was involved in the transcriptional misregulation leading to oral cancer phenotype. HOX subnetwork analysis showed crucial interactions with cell cycle regulators, growth responsive elements, and proto-oncogenes.Conclusion: Phenotype associations specific to the oral region involving HOX genes provide intrinsic cues to tumor development. The 5’ HOX genes were aberrantly deregulated which reflects their posterior prevalence during oral carcinogenesis.

A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene

PurposeWe sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause.MethodsExome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed.ResultsWe identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes.ConclusionWe describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.

Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency

BackgroundMucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I–IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described.MethodsIn this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis.ResultsThe phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS.ConclusionOur work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X.

Hybrid approach for disease comorbidity and disease gene prediction using heterogeneous dataset

High throughput analysis and large scale integration of biological data led to leading researches in the field of bioinformatics. Recent years witnessed the development of various methods for disease associated gene prediction and disease comorbidity predictions. Most of the existing techniques use network-based approaches and similarity-based approaches for these predictions. Even though network-based approaches have better performance, these methods rely on text data from OMIM records and PubMed abstracts. In this method, a novel algorithm (HDCDGP) is proposed for disease comorbidity prediction and disease associated gene prediction. Disease comorbidity network and disease gene network were constructed using data from gene ontology (GO), human phenotype ontology (HPO), protein-protein interaction (PPI) and pathway dataset. Modified random walk restart algorithm was applied on these networks for extracting novel disease-gene associations. Experimental results showed that the hybrid approach has better performance compared to existing systems with an overall accuracy around 85%.

Bridging the Species Gap: Morphological and Molecular Comparison of Feline and Human Intestinal Carcinomas

Limited availability of in vivo experimental models for invasive colorectal cancer (CRC) including metastasis and high tumor budding activity is a major problem in colorectal cancer research. In order to compare feline and human intestinal carcinomas, tumors of 49 cats were histologically subtyped, graded and further characterized according to the human WHO classification. Subsequently, feline tumors were compared to a cohort of 1004 human CRC cases. Feline intestinal tumors closely resembled the human phenotype on a histomorphological level. In both species, adenocarcinoma not otherwise specified (ANOS) was the most common WHO subtype. In cats, the second most common subtype of the colon (36.4%), serrated adenocarcinoma (SAC), was overrepresented compared to human CRC (8.7%). Mucinous adenocarcinoma (MAC) was the second most common subtype of the small intestine (12.5%). Intriguingly, feline carcinomas, particularly small intestinal, were generally of high tumor budding (Bd) status (Bd3), which is designated an independent prognostic key factor in human CRC. We also investigated the relevance of feline CTNNB1 exon 2 alterations by Sanger sequencing. In four cases of feline colonic malignancies (3 ANOS, 1 SAC), somatic missense mutations of feline CTNNB1 (p.D32G, p.D32N, p.G34R, and p.S37F) were detected, indicating that mutational alterations of the WNT/β-catenin signaling pathway potentially play an essential role in feline intestinal tumorigenesis comparable to humans and dogs. These results indicate that spontaneous intestinal tumors of cats constitute a useful but so far underutilized model for human CRC. Our study provides a solid foundation for advanced comparative oncology studies and emphasizes the need for further (molecular) characterization of feline intestinal carcinomas.

KBG Syndrome: Prospective Videoconferencing and Use of AI-driven Facial Phenotyping in 25 New Patients

Genetic variants in the gene Ankyrin Repeat Domain 11 (ANKRD11) and deletions in 16q24.3 are known to cause KBG syndrome, a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies. We report 25 unpublished individuals from 22 families, all with molecularly confirmed diagnoses of KBG syndrome. Twenty-one individuals have de novo variants, three have inherited variants, and one is inherited from a mother exhibiting low-level mosaicism. Of these variants, 20 are truncating (frameshift or nonsense), and five are missense. We created a novel protocol for collection and reporting of data, including prospectively interviewing these individuals and their families throughout eight countries via videoconferencing by a single clinician. Participants' medical records, including imaging, were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were submitted to GestaltMatcher and Face2Gene (FDNA Inc, USA) for facial analysis, and we found similar facial phenotypes among the participants. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Seventy-two percent of participants had gastrointestinal complaints and 80% had hearing loss. Three participants were started on growth hormone with positive results. Behavioral issues and global developmental delays were found in most participants. Neurologic abnormalities including seizures and/or EEG abnormalities were also very common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Twenty-four percent were diagnosed with attention deficit hyperactivity disorder (ADHD) and 28% were diagnosed with autism spectrum disorder (ASD). Additionally, we have identified minimally reported symptoms, including recurrent sinus infections (16%) and previously unreported migraines (20%). Based on the videoconferencing and these data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.