Temporal dynamics of woolly mammoth genome erosion prior to extinction.

A number of species have recently recovered from near-extinction. Although these species have avoided the immediate extinction threat, their long-term viability remains precarious due to the potential genetic consequences of population declines, which are poorly understood on a timescale beyond a few generations. Woolly mammoths (Mammuthus primigenius) became isolated on Wrangel Island around 10,000 years ago and persisted for over 200 generations before becoming extinct around 4,000 years ago. To study the evolutionary processes leading up to the mammoths' extinction, we analyzed 21 Siberian woolly mammoth genomes. Our results show that the population recovered quickly from a severe bottleneck and remained demographically stable during the ensuing six millennia. We find that mildly deleterious mutations gradually accumulated, whereas highly deleterious mutations were purged, suggesting ongoing inbreeding depression that lasted for hundreds of generations. The time-lag between demographic and genetic recovery has wide-ranging implications for conservation management of recently bottlenecked populations.

Effectiveness of inactivated COVID-19 vaccine CoronaVac in children aged less than 3 years old during Omicron wave in Hong Kong.

The COVID-19 pandemic has affected people of all ages worldwide. However, there is still no information on the vaccine effectiveness (VE) of inactivated COVID-19 vaccines in children aged less than 3 years old. This study highlighted that 2 doses of CoronaVac were effective in preventing COVID-19, with a VE of 83.1 %.

Neanderthal introgression in SCN9A impacts mechanical pain sensitivity.

The Nav1.7 voltage-gated sodium channel plays a key role in nociception. Three functional variants in the SCN9A gene (encoding M932L, V991L, and D1908G in Nav1.7), have recently been identified as stemming from Neanderthal introgression and to associate with pain symptomatology in UK BioBank data. In 1000 genomes data, these variants are absent in Europeans but common in Latin Americans. Analysing high-density genotype data from 7594 Latin Americans, we characterized Neanderthal introgression in SCN9A. We find that tracts of introgression occur on a Native American genomic background, have an average length of ~123 kb and overlap the M932L, V991L, and D1908G coding positions. Furthermore, we measured experimentally six pain thresholds in 1623 healthy Colombians. We found that Neanderthal ancestry in SCN9A is significantly associated with a lower mechanical pain threshold after sensitization with mustard oil and evidence of additivity of effects across Nav1.7 variants. Our findings support the reported association of Neanderthal Nav1.7 variants with clinical pain, define a specific sensory modality affected by archaic introgression in SCN9A and are consistent with independent effects of the Neanderthal variants on Nav1.7 function.

[Sociodemographic, clinical and ultrasound characterization of thyroid nodule pathology and its association with malignancy in a Colombian high-complexity center]. / Caracterización sociodemográfica, clínica y ecográfica de la enfermedad de nódulos tiroideos y su relación con la malignidad en un centro de alta complejidad colombiano.

BACKGROUND AND OBJECTIVE: Thyroid nodules are among the most frequent conditions, with a 10% risk of malignancy. The objective is to describe the frequency of demographic, clinical, and ultrasonographic characteristics of thyroid nodule pathology in adults and to explore the relationship with tumor malignancy. METHODS: An analytical, retrospective cross-sectional study in adults with thyroid nodules and nodular fine-needle aspiration performed in adult patients from a Colombian reference center between 2009-2019. Data were obtained from the clinical history, descriptive measures of the patient's demographic, clinical, and ultrasound variables were estimated, and their relationship with the malignancy of the tumor was explored. RESULTS: A total of 445 patients and 515 nodules were included. The median age was 55 years (IQR 44-64), 86.8% of women, and 54.8% had a single lesion. Percentages of 80.2 and 19.8 were benign and malignant nodules, with a median of 15.7mm (IQR 11-25) and 12.7mm (IQR 8.5-18.3), respectively (p<0.001). Hypothyroidism and levothyroxine consumption were higher in those with malignant nodules (p<0.001). The echographic characteristics were statistically different between the nodules. In the malignant ones, there was a higher frequency of solid composition, hypoechogenicity, and irregular margins. In contrast, in the benign ones, the absence of echogenic focus stood out (p<0.001). CONCLUSION: The ultrasound characteristics are essential to define the risk of malignancy of a thyroid nodule. Therefore, considering the most frequent ones can help in the most appropriate approach to primary care.

Automatic landmarking identifies new loci associated with face morphology and implicates Neanderthal introgression in human nasal shape.

We report a genome-wide association study of facial features in >6000 Latin Americans based on automatic landmarking of 2D portraits and testing for association with inter-landmark distances. We detected significant associations (P-value <5 × 10-8) at 42 genome regions, nine of which have been previously reported. In follow-up analyses, 26 of the 33 novel regions replicate in East Asians, Europeans, or Africans, and one mouse homologous region influences craniofacial morphology in mice. The novel region in 1q32.3 shows introgression from Neanderthals and we find that the introgressed tract increases nasal height (consistent with the differentiation between Neanderthals and modern humans). Novel regions include candidate genes and genome regulatory elements previously implicated in craniofacial development, and show preferential transcription in cranial neural crest cells. The automated approach used here should simplify the collection of large study samples from across the world, facilitating a cosmopolitan characterization of the genetics of facial features.

Genomics of adaptive evolution in the woolly mammoth.

Ancient genomes provide a tool to investigate the genetic basis of adaptations in extinct organisms. However, the identification of species-specific fixed genetic variants requires the analysis of genomes from multiple individuals. Moreover, the long-term scale of adaptive evolution coupled with the short-term nature of traditional time series data has made it difficult to assess when different adaptations evolved. Here, we analyze 23 woolly mammoth genomes, including one of the oldest known specimens at 700,000 years old, to identify fixed derived non-synonymous mutations unique to the species and to obtain estimates of when these mutations evolved. We find that at the time of its origin, the woolly mammoth had already acquired a broad spectrum of positively selected genes, including ones associated with hair and skin development, fat storage and metabolism, and immune system function. Our results also suggest that these phenotypes continued to evolve during the last 700,000 years, but through positive selection on different sets of genes. Finally, we also identify additional genes that underwent comparatively recent positive selection, including multiple genes related to skeletal morphology and body size, as well as one gene that may have contributed to the small ear size in Late Quaternary woolly mammoths.

Evolutionary consequences of genomic deletions and insertions in the woolly mammoth genome.

Woolly mammoths had a set of adaptations that enabled them to thrive in the Arctic environment. Many mammoth-specific single nucleotide polymorphisms (SNPs) responsible for unique mammoth traits have been previously identified from ancient genomes. However, a multitude of other genetic variants likely contributed to woolly mammoth evolution. In this study, we sequenced two woolly mammoth genomes and combined these with previously sequenced mammoth and elephant genomes to conduct a survey of mammoth-specific deletions and indels. We find that deletions are highly enriched in non-coding regions, suggesting selection against structural variants that affect protein sequences. Nonetheless, at least 87 woolly mammoth genes contain deletions or indels that modify the coding sequence, including genes involved in skeletal morphology and hair growth. These results suggest that deletions and indels contributed to the unique phenotypic adaptations of the woolly mammoth, and were potentially critical to surviving in its natural environment.

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans.

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.

Adolescents' attitudes to the COVID-19 vaccination.

Vaccines against COVID-19 are now available for adolescents in Hong Kong but vaccine hesitancy is a major barrier to herd immunity. This survey study explores Hong Kong adolescents' attitudes towards the COVID-19 vaccination. 2609 adolescents from across Hong Kong completed an online survey focused on the intent to vaccinate and the reasons for their choice. 39% of adolescents intended to take the COVID-19 vaccination and significant factors for this decision include: having at least one parent vaccinated, knowing somebody diagnosed with COVID-19 and receiving the influenza vaccine. Adolescents' major concerns were either the safety and efficacy of the vaccine or the risk of infection. This study has proved that even in adolescents the vaccine hesitancy model is prominent with adolescents' intentions highly related to confidence in the vaccine and perception of disease risk. Future interventions should target these specific concerns to ensure adolescents are well educated to overcome vaccine hesitancy.

Effective detection of abnormal gait patterns in Parkinson's disease patients using kinematics, nonlinear, and stability gait features.

BACKGROUND AND OBJECTIVES: Parkinson's disease (PD) is a neurodegenerative disease that produces movement disorders and it is the second most common neurodegenerative disease after Alzheimer's. Among other symptoms, PD affects gait patterns and produces bradykinesia, abnormal changes in posture, and shortened strides. In this study we present a comprehensive analysis of three different feature sets to model those abnormal gait patterns. The proposed approach is evaluated upon three groups of subjects: PD patients, young healthy controls (YHC), and elderly healthy controls (EHC). METHODS: Three feature sets are created: (1) kinematic measures including those that allow modeling time, distance and velocity of the strides, (2) nonlinear dynamics including different measures extracted from embedded attractors resulting from the time-series of the gait signals, and (3) different stability measures extracted in the time and frequency-domains. Support Vector Machine, Random Forest and XGBoost classifiers are trained to automatically discriminate between PD patients and healthy subjects. RESULTS: Among the considered feature sets, three individual measures emerge as the ones that yield accurate detection of PD and could potentially be used in clinical practice. Accuracies of up to 87.0% and 90.0% are found for the classification between PD vs. YHC and PD vs. EHC, respectively, considering individual measures. CONCLUSIONS: This study contributes to a better understanding of abnormal gait patterns observed in PD patients. Particularly the introduced approach shows good results that could be potentially used in clinical practice as a tool to support the diagnosis and follow-up of the patients.

A genome-wide association study identifies novel gene associations with facial skin wrinkling and mole count in Latin Americans.

BACKGROUND: Genome-wide association studies (GWASs) have identified genes influencing skin ageing and mole count in Europeans, but little is known about the relevance of these (or other genes) in non-Europeans. OBJECTIVES: To conduct a GWAS for facial skin ageing and mole count in adults < 40 years old, of mixed European, Native American and African ancestry, recruited in Latin America. METHODS: Skin ageing and mole count scores were obtained from facial photographs of over 6000 individuals. After quality control checks, three wrinkling traits and mole count were retained for genetic analyses. DNA samples were genotyped with Illumina's HumanOmniExpress chip. Association testing was performed on around 8 703 729 single-nucleotide polymorphisms (SNPs) across the autosomal genome. RESULTS: Genome-wide significant association was observed at four genome regions: two were associated with wrinkling (in 1p13·3 and 21q21·2), one with mole count (in 1q32·3) and one with both wrinkling and mole count (in 5p13·2). Associated SNPs in 5p13·2 and in 1p13·3 are intronic within SLC45A2 and VAV3, respectively, while SNPs in 1q32·3 are near the SLC30A1 gene, and those in 21q21·2 occur in a gene desert. Analyses of SNPs in IRF4 and MC1R are consistent with a role of these genes in skin ageing. CONCLUSIONS: We replicate the association of wrinkling with variants in SLC45A2, IRF4 and MC1R reported in Europeans. We identify VAV3 and SLC30A1 as two novel candidate genes impacting on wrinkling and mole count, respectively. We provide the first evidence that SLC45A2 influences mole count, in addition to variants in this gene affecting melanoma risk in Europeans.

A laboratory study of the scouting ability of two reciprocating glide path instruments in mesial root canals of extracted mandibular molars.

AIM: To evaluate in a laboratory setting the performance of two reciprocating glide path systems, WaveOne Gold Glider (WO) and R-Pilot (RP), to create a glide path in mesial root canals of mandibular molars and to assess the torsional resistance of instruments after performing the glide path. METHODOLOGY: A total of 60 mesial root canals of extracted human mandibular molars were divided into two groups (n = 30) according to the glide path system to be used. The data from the volume of each canal, acquired by microcomputed tomography (micro-CT), were validated statistically for the anatomical pairing of the groups. Preparation time, frequency in gaining apical patency, plastic deformation rate of instruments, and canal transportation and centring ability were recorded and compared statistically. The torsional fatigue of the instruments after use was also evaluated. Data were analysed using Fisher's exact test and Mann-Whitney U-test with a 5% significance level. RESULTS: No significant differences were found between groups regarding the time required to perform the glide path, the frequency distributions of the canals classified as patent and the instruments with plastic deformation after use (P > 0.05). No significant differences were found between groups regarding the degree of canal transportation and centring ability at the cervical, middle and apical thirds (P > 0.05). The RP groups had significantly greater maximum torsional strength values compared with the WO groups (P < 0.05). The used WO group had greater angular deflection to fracture when compared to the new WO group (P < 0.05). A significant difference was also found in the percentage of loss of angular deflection in a comparison of the WO group with the RP group (P < 0.05). CONCLUSIONS: The WO and RP instruments performed the same in terms of preparation time, plastic deformation, gaining apical patency, degree of canal transportation and centring ability. The RP instruments had greater torsional strength, less angular deflection and lower percentage of loss in angular deflection than the WO. The used WO group had the greatest angular deflection values.

Validity and reliability of the Child Perceptions Questionnaire 11-14 for Colombian school children.

PURPOSE: To evaluate the validity and reliability of the Child Perceptions Questionnaire 11-14 (CPQ11-14) for children attending public educational institutions in Floridablanca (Colombia). METHODS: An evaluation study of diagnostic technology was conducted. The questionnaire was completed by 500 students aged 11-14 years who were selected by simple random sampling. The test-retest reproducibility was evaluated in 36 students chosen at random from one of the schools; the questionnaire was completed a second time by these students, with an interval of two weeks between administrations. Internal consistency was estimated using the Cronbach's alpha coefficient, and test-retest reproducibility was determined with the intraclass correlation coefficient (ICC). The Rasch Rating Scale Model was used to perform the validation; the structure of the categories, the quality of the items, the invariance and the one-dimensionality were analyzed; invariance was confirmed using differential item functioning (DIF). Informed consent was obtained from the parents or guardians, and assent was obtained from the minors. RESULTS: The mean age was 12.7 ± 1.1 years, and 210 (42.0%) participants were female. The Cronbach's alpha and ICC values were 0.91 and 0.63, respectively. The 37 items fit the Rasch model, but a uniform DIF was observed for an item that was eliminated. The questionnaire was not one-dimensional, and the proportion of variance explained by the model was poor (26.3%). CONCLUSION: The CPQ11-14 showed unsatisfactory test-retest reproducibility and excellent internal consistency; no unidimensionality was observed, but the items fit the Rasch model.