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Short tandem repeats (STRs) and variable number tandem repeats (VNTRs) are important sources of natural and disease-causing variation, yet they have been problematic to resolve in reference genomes and genotype with short-read technology. We created a framework tomodel the evolution and instability of STRs and VNTRs in apes. We phased and assembled 3 ape genomes (chimpanzee, gorilla, and orangutan) using long-read and 10x Genomics linkedread sequence data for 21,442 human tandem repeats discovered in 6 haplotype-resolved assemblies of Yoruban, Chinese, and Puerto Rican origin. We define a set of 1,584 STRs/VNTRs expanded specifically in humans, including large tandem repeats affecting coding and noncoding portions of genes (e.g., MUC3A, CACNA1C). We show that short interspersed nuclear element–VNTR–Alu (SVA) retrotransposition is the main mechanism for distributing GC-rich human-specific tandem repeat expansions throughout the genome but with a bias against genes. In contrast, we observe that VNTRs not originating from retrotransposons have a propensity to cluster near genes, especially in the subtelomere. Using tissuespecific expression from human and chimpanzee brains, we identify genes where transcript isoform usage differs significantly, likely caused by cryptic splicing variation within VNTRs. Using single-cell expression from cerebral organoids, we observe a strong effect for genes associated with transcription profiles analogous to intermediate progenitor cells. Finally, we compare the sequence composition of some of the largest human-specific repeat expansions and identify 52 STRs/VNTRs with at least 40 uninterrupted pure tracts as candidates for genetically unstable regions associated with disease.

Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are diseases caused by the interaction of genetic and non-genetic factors. Therefore, the aim of our study was to investigate the association between six common genetic polymorphisms and T2DM and MetS in males. A total of 120 T2DM, 75 MetS, and 120 healthy controls (HC) were included in the study. ID, 4a/b, A1166C, (A>G), +35A/C, -21A/T gene polymorphisms were genotyped by PCR or PCR-RFLP techniques. T2DM was diagnosed at an earlier age compared to MetS (54 vs 55 years old, p=0.0003) and the difference was greater in carriers of the G allele (54 vs 56 years old, p=0.0002) or both G and b alleles (54 vs 56, p=0.00016). The AA genotype (O.R.=0.11, p=0.0006) and the presence of both I and A (O.R.=0.39, p=0.0005) alleles revealed to be protective for T2DM. AA and AC genotypes were protective factors for triglyceride (p=0.0002 and p=0.0005, respectively) and HDL cholesterol (p=0.0002 and p=0.0004, respectively) levels in T2DM patients. DD was identified more frequently in hypertensive T2DM patients (O.R.=3.77, p=0.0005) and in those who reported drinking alcohol (p=0.0001) comparing to HC and T2DM patients who did not drink alcohol, respectively. We observed that T2DM patients who reported drinking alcohol had an increased frequency of DD and bb (p<0.0001), or DD and G (p<0.0001) compared to non-drinkers. No gene polymorphisms were associated with MetS.

Genome-wide association studies (GWAS) originally identified ATP-binding cassette, sub-family A, member 7 (ABCA7), as a novel risk gene of Alzheimer’s disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human-based studies has corroborated and extended this association, promoting ABCA7 as one of the most important risk genes of both early-onset and late-onset AD, harboring both common and rare risk variants with relatively large effect on AD risk. Within this review, we provide a comprehensive assessment of the literature on ABCA7, with a focus on AD-related human -omics studies (e.g. genomics, transcriptomics, and methylomics). In European and African American populations, indirect ABCA7 GWAS associations are explained by expansion of an ABCA7 variable number tandem repeat (VNTR), and a common premature termination codon (PTC) variant, respectively. Rare ABCA7 PTC variants are strongly enriched in AD patients, and some of these have displayed inheritance patterns resembling autosomal dominant AD. In addition, rare missense variants are more frequent in AD patients than healthy controls, whereas a common ABCA7 missense variant may protect from disease. Methylation at several CpG sites in the ABCA7 locus is significantly associated with AD. Furthermore, ABCA7 contains many different isoforms and ABCA7 splicing has been shown to associate with AD. Besides associations with disease status, these genetic and epigenetic ABCA7 markers also showed significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human-based –omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism, and future studies should make clear if interventions on ABCA7 expression can serve as a valuable therapeutic target for AD.

Background Several models and algorithms have been proposed to build pangenomes from multiple input assemblies, but their impact on variant representation, and consequently downstream analyses, is largely unknown. Results We create multi-species super-pangenomes using pggb, cactus, and minigraph with the Bos taurus taurus reference sequence and eleven haplotype-resolved assemblies from taurine and indicine cattle, bison, yak, and gaur. We recover 221 k nonredundant structural variations (SVs) from the pangenomes, of which 135 k (61%) are common to all three. SVs derived from assembly-based calling show high agreement with the consensus calls from the pangenomes (96%), but validate only a small proportion of variations private to each graph. Pggb and cactus, which also incorporate base-level variation, have approximately 95% exact matches with assembly-derived small variant calls, which significantly improves the edit rate when realigning assemblies compared to minigraph. We use the three pangenomes to investigate 9566 variable number tandem repeats (VNTRs), finding 63% have identical predicted repeat counts in the three graphs, while minigraph can over or underestimate the count given its approximate coordinate system. We examine a highly variable VNTR locus and show that repeat unit copy number impacts the expression of proximal genes and non-coding RNA. Conclusions Our findings indicate good consensus between the three pangenome methods but also show their individual strengths and weaknesses that need to be considered when analysing different types of variants from multiple input assemblies.

Understanding regional molecular epidemiology allows for the development of more efficient tuberculosis prevention strategies in low-incidence settings. We analyzed 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem repeat (MIRU-VNTR) genotyping for 2290 Mycobacterium tuberculosis clinical isolates collected in the province of British Columbia (BC), Canada, in 2005-2014. Laboratory data for each isolate were linked to case-level clinical and demographic data. These data were used to describe the molecular epidemiology of tuberculosis across the province. We detected >1500 distinct genotypes across the 4 major M. tuberculosis lineages, reflecting BC's diverse population. Disease site and clustering rates varied across lineages, and MIRU-VNTR was used to group the 2290 isolates into 189 clusters (2-70 isolates per cluster), with an overall clustering rate of 42.4% and an estimated local transmission rate of 34.1%. Risk factors for clustering varied between Canadian-born and foreign-born individuals; the former had increased odds (odds ratio, 7.8; 95% confidence interval [CI], 6.2-9.6) of belonging to a genotypic cluster, although nearly one-quarter of clusters included both Canadian- and foreign-born persons. Large clusters (≥10 cases) occurred more frequently within the M. tuberculosis Euro-American lineage, and individual-level risk factors associated with belonging to a large cluster included being Canadian born (adjusted odds ratio, 3.3; 95% CI, 2.3-4.8), residing in a rural area (2.3; 1.2-4.5), and illicit drug use (2.0; 1.2-3.4). Although tuberculosis in BC largely arises through reactivation of latent tuberculosis in foreign-born persons, locally transmitted infections occur in discrete populations with distinct disease and risk factor profiles, representing groups for targeted interventions.

Technological limitations have hindered the large-scale genetic investigation of tandem repeats in disease. We show that long-read sequencing with a single Oxford Nanopore Technologies PromethION flow cell per individual achieves 30× human genome coverage and enables accurate assessment of tandem repeats including the 10,000-bp Alzheimer’s disease-associated ABCA7 VNTR. The Guppy “flip-flop” base caller and tandem-genotypes tandem repeat caller are efficient for large-scale tandem repeat assessment, but base calling and alignment challenges persist. We present NanoSatellite, which analyzes tandem repeats directly on electric current data and improves calling of GC-rich tandem repeats, expanded alleles, and motif interruptions.

Abstract Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide polymorphisms (SNPs) with functional implications for the microRNA’s expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.

Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7’s identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode‐of‐action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain. Highlights Alzheimer's risk‐increasing variants in ABCA7 can be found in up to 7% of AD patients. We review the recently characterized protein structure of ABCA7. We present latest insights in genetics, expression patterns, and functions of ABCA7.

Purpose The aim of this study was to compare morning and evening time-trial performance, RPE and mood state of trained swimmers, taking into account chronotype, habitual training time-of-day and PERIOD3 (PER3) variable number tandem repeat genotype. Methods Twenty-six swimmers (18 males, age: 32.6 ± 5.7 years) swam 200 m time trials (TT) at 06h30 and 18h30 in a randomised order. Results There was no difference between morning and evening performance when the swimmers were considered as a single group (06h30: 158.8 ± 22.7 s, 18h30: 158.5 ± 22.0 s, p  = 0.611). However, grouping swimmers by chronotype and habitual training time-of-day allowed us to detect significant diurnal variation in performance, such that morning-type swimmers and those who habitually train in the morning were faster in the 06h30 TT ( p  = 0.036 and p  = 0.011, respectively). This was accompanied by lower ratings of perceived exertion (RPE) scores post-warm-up, higher vigour and lower fatigues scores prior to the 06h30 TT in morning-type swimmers or those who trained in the morning. Similarly, neither types and those who trained in the evenings had lower fatigue and higher vigour prior to the 18h30 TT. Conclusions It appears that both chronotype and habitual training time-of-day need to be considered when assessing diurnal variation in performance. From a practical point of view, athletes and coaches should be aware of the potentially powerful effect of training time on shifting time-of-day variation in performance.

Introduction: Tuberculosis (TB) is a re-emerging disease considered a public health concern. In the present study, we analyzed the epidemiology and drug resistance of Mycobacterium tuberculosis strains isolated from patients with pulmonary TB. Methodology: Mycobacterium tuberculosis isolates (n = 190) were obtained from patients with pulmonary TB admitted to Dr. José Eleuterio González University Hospital (UH). Each M. tuberculosis isolate was analyzed by spoligotyping (spacer oligonucleotide typing) and MIRU-VNTR (Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeat). Drug resistance was evaluated using the Anyplex™ II MTB/MDR/XDR assay. Results: The predominant spoligotypes observed were X1 (SIT 119, n = 46), T1 (SIT 53, n = 40), H3 (SIT 50, n = 13), Beijing (SIT 1, n = 11), and EAI2-Manila (SIT 19, n = 8). MIRU-VNTR analysis showed that the locus QUB-26 had the highest allelic variability. The observed drug resistance included monoresistance to rifampicin (2.6%; n = 5), isoniazid (3.2%; n = 6), and fluoroquinolones (1.6%; n = 3) as well as multidrug resistance (5.3%; n = 10). All of the Beijing strains were susceptible. Regarding comorbidities, 13.7% (26/190) of the patients were co-infected with TB and HIV (TB+HIV+), and 31.6% (55/190) had TB along with diabetes (TB + diabetes). Conclusions: The most prevalent lineages were X1 (SIT 119; 24.3%) and T1 (SIT 53; 21%). An alarming proportion (12.6%) of M. tuberculosis isolates presented drug resistance. To effectively manage TB, continuous surveillance of regional strain dissemination, drug resistance profiles, and TB-associated comorbidities is crucial.