Whole-genome sequencing reveals a complex African population demographic history and signatures of local adaptation.

We conduct high coverage (>30×) whole-genome sequencing of 180 individuals from 12 indigenous African populations. We identify millions of unreported variants, many predicted to be functionally important. We observe that the ancestors of southern African San and central African rainforest hunter-gatherers (RHG) diverged from other populations >200 kya and maintained a large effective population size. We observe evidence for ancient population structure in Africa and for multiple introgression events from "ghost" populations with highly diverged genetic lineages. Although currently geographically isolated, we observe evidence for gene flow between eastern and southern Khoesan-speaking hunter-gatherer populations lasting until ∼12 kya. We identify signatures of local adaptation for traits related to skin color, immune response, height, and metabolic processes. We identify a positively selected variant in the lightly pigmented San that influences pigmentation in vitro by regulating the enhancer activity and gene expression of PDPK1.

NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.

PGG.SV: a whole-genome-sequencing-based structural variant resource and data analysis platform.

Structural variations (SVs) play important roles in human evolution and diseases, but there is a lack of data resources concerning representative samples, especially for East Asians. Taking advantage of both next-generation sequencing and third-generation sequencing data at the whole-genome level, we developed the database PGG.SV to provide a practical platform for both regionally and globally representative structural variants. In its current version, PGG.SV archives 584 277 SVs obtained from whole-genome sequencing data of 6048 samples, including 1030 long-read sequencing genomes representing 177 global populations. PGG.SV provides (i) high-quality SVs with fine-scale and precise genomic locations in both GRCh37 and GRCh38, covering underrepresented SVs in existing sequencing and microarray data; (ii) hierarchical estimation of SV prevalence in geographical populations; (iii) informative annotations of SV-related genes, potential functions and clinical effects; (iv) an analysis platform to facilitate SV-based case-control association studies and (v) various visualization tools for understanding the SV structures in the human genome. Taken together, PGG.SV provides a user-friendly online interface, easy-to-use analysis tools and a detailed presentation of results. PGG.SV is freely accessible via https://www.biosino.org/pggsv.

Unveiling novel genetic variants in 370 challenging medically relevant genes using the long read sequencing data of 41 samples from 19 global populations.

BACKGROUND: A large number of challenging medically relevant genes (CMRGs) are situated in complex or highly repetitive regions of the human genome, hindering comprehensive characterization of genetic variants using next-generation sequencing technologies. In this study, we employed long-read sequencing technology, extensively utilized in studying complex genomic regions, to characterize genetic alterations, including short variants (single nucleotide variants and short insertions and deletions) and copy number variations, in 370 CMRGs across 41 individuals from 19 global populations. RESULTS: Our analysis revealed high levels of genetic variants in CMRGs, with 68.73% exhibiting copy number variations and 65.20% containing short variants that may disrupt protein function across individuals. Such variants can influence pharmacogenomics, genetic disease susceptibility, and other clinical outcomes. We observed significant differences in CMRG variation across populations, with individuals of African ancestry harboring the highest number of copy number variants and short variants compared to samples from other continents. Notably, 15.79% to 33.96% of short variants were exclusively detectable through long-read sequencing. While the T2T-CHM13 reference genome significantly improved the assembly of CMRG regions, thereby facilitating variant detection in these regions, some regions still lacked resolution. CONCLUSION: Our results provide an important reference for future clinical and pharmacogenetic studies, highlighting the need for a comprehensive representation of global genetic diversity in the reference genome and improved variant calling techniques to fully resolve medically relevant genes.

Systematic review and meta-analysis of single-stage vs two-stage revision for periprosthetic joint infection: a call for a prospective randomized trial.

BACKGROUND: Periprosthetic joint infection (PJI) is a severe complication of joint arthroplasty that causes significant pain and economic loss. This study aimed to determine whether the current evidence supports single-stage revision for PJI based on reinfection and reoperation rates. METHODS: We searched the PubMed, EBSCO, Medline, and Cochrane Library databases from inception to 30 May 2023 to identify studies that compared single-stage revision and two-stage revision for PJI. Data on reinfection and reoperation rates were pooled. RESULTS: This meta-analysis included a total of 40 studies with 8711 patients. Overall, there was no significant difference between single- and two-stage revision regarding the postoperative reinfection rate and reoperation rate. Subgroup analysis by surgery period and different surgical sites revealed no difference between the two groups in the reinfection and reoperation rates. CONCLUSIONS: Based on the available evidence, our study did not identify a significant difference in reinfection and reoperation rates between single- and two-stage revision for PJI. Given the limitations in inclusion/exclusion criteria and the observed heterogeneity, we acknowledge the complexity of drawing strong conclusions. Therefore, we suggest that the choice between single- and two-stage revision should be carefully considered on an individual basis, taking into account patient-specific factors and further research developments.

Signatures of Convergent Evolution and Natural Selection at the Alcohol Dehydrogenase Gene Region are Correlated with Agriculture in Ethnically Diverse Africans.

The alcohol dehydrogenase (ADH) family of genes encodes enzymes that catalyze the metabolism of ethanol into acetaldehyde. Nucleotide variation in ADH genes can affect the catalytic properties of these enzymes and is associated with a variety of traits, including alcoholism and cancer. Some ADH variants, including the ADH1B*48His (rs1229984) mutation in the ADH1B gene, reduce the risk of alcoholism and are under positive selection in multiple human populations. The advent of Neolithic agriculture and associated increase in fermented foods and beverages is hypothesized to have been a selective force acting on such variants. However, this hypothesis has not been tested in populations outside of Asia. Here, we use genome-wide selection scans to show that the ADH gene region is enriched for variants showing strong signals of positive selection in multiple Afroasiatic-speaking, agriculturalist populations from Ethiopia, and that this signal is unique among sub-Saharan Africans. We also observe strong selection signals at putatively functional variants in nearby lipid metabolism genes, which may influence evolutionary dynamics at the ADH region. Finally, we show that haplotypes carrying these selected variants were introduced into Northeast Africa from a West-Eurasian source within the last ∼2,000 years and experienced positive selection following admixture. These selection signals are not evident in nearby, genetically similar populations that practice hunting/gathering or pastoralist subsistence lifestyles, supporting the hypothesis that the emergence of agriculture shapes patterns of selection at ADH genes. Together, these results enhance our understanding of how adaptations to diverse environments and diets have influenced the African genomic landscape.

Comprehensive evaluation of structural variant genotyping methods based on long-read sequencing data.

BACKGROUND: Structural variants (SVs) play a crucial role in gene regulation, trait association, and disease in humans. SV genotyping has been extensively applied in genomics research and clinical diagnosis. Although a growing number of SV genotyping methods for long reads have been developed, a comprehensive performance assessment of these methods has yet to be done. RESULTS: Based on one simulated and three real SV datasets, we performed an in-depth evaluation of five SV genotyping methods, including cuteSV, LRcaller, Sniffles, SVJedi, and VaPoR. The results show that for insertions and deletions, cuteSV and LRcaller have similar F1 scores (cuteSV, insertions: 0.69-0.90, deletions: 0.77-0.90 and LRcaller, insertions: 0.67-0.87, deletions: 0.74-0.91) and are superior to other methods. For duplications, inversions, and translocations, LRcaller yields the most accurate genotyping results (0.84, 0.68, and 0.47, respectively). When genotyping SVs located in tandem repeat region or with imprecise breakpoints, cuteSV (insertions and deletions) and LRcaller (duplications, inversions, and translocations) are better than other methods. In addition, we observed a decrease in F1 scores when the SV size increased. Finally, our analyses suggest that the F1 scores of these methods reach the point of diminishing returns at 20× depth of coverage. CONCLUSIONS: We present an in-depth benchmark study of long-read SV genotyping methods. Our results highlight the advantages and disadvantages of each genotyping method, which provide practical guidance for optimal application selection and prospective directions for tool improvement.

Prediction Model of Photodegradation for PBAT/PLA Mulch Films: Strategy to Fast Evaluate Service Life.

Eco-friendly biodegradable PBAT/PLA mulch films are attracting increasing interest in sustainable agricultural production. However, currently, little is known about the service life for the PBAT/PLA mulch films. Herein, PBAT/PLA mulch films are subjected to indoor UV-accelerated degradation (UAD) experiments and field cultivation environment degradation (CED) experiments to systematically investigate the relationship between UAD and CED processes. Results demonstrate that 10 days of indoor UAD treatment corresponds to around 120 days aging under outdoor CED conditions. Using eight PBAT/PLA evaluation indicators (haze, elongation at break, tensile strength, gel content, light transmittance, polydispersity index, Mn, Mw), we established a service life prediction model for PBAT/PLA mulch films based on short-term indoor UAD experiments, which could accurately estimate the long-term service life of the mulch films in the field. In particular, using the haze value, near-perfect correlation (R2 = 0.995 for eq. 1 and R2 = 0.993 for eq. 2) was found between CED days and UAD days. The establishment of these reliable predictive models for the service lifetime of PBAT/PLA mulch films will avoid the undesirable premature breakdown during crop growth, thus fostering end-user confidence in eco-friendly biodegradable mulch films.

The seahorse genome and the evolution of its specialized morphology.

Seahorses have a specialized morphology that includes a toothless tubular mouth, a body covered with bony plates, a male brood pouch, and the absence of caudal and pelvic fins. Here we report the sequencing and de novo assembly of the genome of the tiger tail seahorse, Hippocampus comes. Comparative genomic analysis identifies higher protein and nucleotide evolutionary rates in H. comes compared with other teleost fish genomes. We identified an astacin metalloprotease gene family that has undergone expansion and is highly expressed in the male brood pouch. We also find that the H. comes genome lacks enamel matrix protein-coding proline/glutamine-rich secretory calcium-binding phosphoprotein genes, which might have led to the loss of mineralized teeth. tbx4, a regulator of hindlimb development, is also not found in H. comes genome. Knockout of tbx4 in zebrafish showed a 'pelvic fin-loss' phenotype similar to that of seahorses.

Glucagon-like peptide-1 attenuates cardiac hypertrophy via the AngII/AT1R/ACE2 and AMPK/mTOR/p70S6K pathways.

Glucagon-like peptide-1 (GLP-1), a novel type of glucose-lowering agent, has been reported to exert cardioprotective effects. However, the cardioprotective mechanism of GLP-1 on spontaneous hypertension-induced cardiac hypertrophy has not been fully elucidated. In this study, we revealed that liraglutide or alogliptin treatment ameliorated spontaneous hypertension-induced cardiac hypertrophy, as evidenced by decreased levels of cardiac hypertrophic markers (atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain), as well as systolic blood pressure, diastolic blood pressure, mean arterial pressure, and histological changes. Both drugs significantly reduced the levels of angiotensin II (AngII) and AngII type 1 receptor (AT1R) and upregulated the levels of AngII type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2), as indicated by a reduced AT1R/AT2R ratio. Simultaneously, treatment with liraglutide or alogliptin significantly increased GLP-1 receptor expression and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and downregulated the phosphorylation of mammalian target of rapamycin (mTOR), p70 ribosomal S6 protein kinase, and eukaryotic translation initiation factor 4E binding protein 1 in spontaneous hypertension rats. Furthermore, our data demonstrated that the AMPK inhibitor compound C or mTOR activator MHY1485 inhibited the anti-hypertrophic effect of GLP-1. In summary, our study suggests that liraglutide or alogliptin protects the heart against cardiac hypertrophy by regulating the expression of AngII/AT1R/ACE2 and activating the AMPK/mTOR pathway, and GLP-1 agonist can be used in the treatment of patients with cardiac hypertrophy.