Simultaneous Viral Exposure and Protection from Neanderthal Introgression.

In this issue, Enard and Petrov present intriguing results on the possibility of genetic traces left behind in our genomes from adaptation to past viral epidemics that may have been initiated by interaction with Neanderthal archaic hominins. The work highlights how powerful infectious agents can act as a selective force to shape our genetic makeup.

Leveraging shared ancestral variation to detect local introgression.

Introgression is a common evolutionary phenomenon that results in shared genetic material across non-sister taxa. Existing statistical methods such as Patterson's D statistic can detect introgression by measuring an excess of shared derived alleles between populations. The D statistic is effective to detect genome-wide patterns of introgression but can give spurious inferences of introgression when applied to local regions. We propose a new statistic, D+, that leverages both shared ancestral and derived alleles to infer local introgressed regions. Incorporating both shared derived and ancestral alleles increases the number of informative sites per region, improving our ability to identify local introgression. We use a coalescent framework to derive the expected value of this statistic as a function of different demographic parameters under an instantaneous admixture model and use coalescent simulations to compute the power and precision of D+. While the power of D and D+ is comparable, D+ has better precision than D. We apply D+ to empirical data from the 1000 Genome Project and Heliconius butterflies to infer local targets of introgression in humans and in butterflies.

Integrating sex-bias into studies of archaic introgression on chromosome X.

Evidence of interbreeding between archaic hominins and humans comes from methods that infer the locations of segments of archaic haplotypes, or 'archaic coverage' using the genomes of people living today. As more estimates of archaic coverage have emerged, it has become clear that most of this coverage is found on the autosomes- very little is retained on chromosome X. Here, we summarize published estimates of archaic coverage on autosomes and chromosome X from extant human samples. We find on average 7 times more archaic coverage on autosomes than chromosome X, and identify broad continental patterns in this ratio: greatest in European samples, and least in South Asian samples. We also perform extensive simulation studies to investigate how the amount of archaic coverage, lengths of coverage, and rates of purging of archaic coverage are affected by sex-bias caused by an unequal sex ratio within the archaic introgressors. Our results generally confirm that, with increasing male sex-bias, less archaic coverage is retained on chromosome X. Ours is the first study to explicitly model such sex-bias and its potential role in creating the dearth of archaic coverage on chromosome X.

Associations between forensic loci and expression levels of neighboring genes may compromise medical privacy.

A set of 20 short tandem repeats (STRs) is used by the US criminal justice system to identify suspects and to maintain a database of genetic profiles for individuals who have been previously convicted or arrested. Some of these STRs were identified in the 1990s, with a preference for markers in putative gene deserts to avoid forensic profiles revealing protected medical information. We revisit that assumption, investigating whether forensic genetic profiles reveal information about gene-expression variation or potential medical information. We find six significant correlations (false discovery rate = 0.23) between the forensic STRs and the expression levels of neighboring genes in lymphoblastoid cell lines. We explore possible mechanisms for these associations, showing evidence compatible with forensic STRs causing expression variation or being in linkage disequilibrium with a causal locus in three cases and weaker or potentially spurious associations in the other three cases. Together, these results suggest that forensic genetic loci may reveal expression levels and, perhaps, medical information.

The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans.

Recent studies suggest that admixture with archaic hominins played an important role in facilitating biological adaptations to new environments. For example, interbreeding with Denisovans facilitated the adaptation to high-altitude environments on the Tibetan Plateau. Specifically, the EPAS1 gene, a transcription factor that regulates the response to hypoxia, exhibits strong signatures of both positive selection and introgression from Denisovans in Tibetan individuals. Interestingly, despite being geographically closer to the Denisova Cave, East Asian populations do not harbor as much Denisovan ancestry as populations from Melanesia. Recently, two studies have suggested two independent waves of Denisovan admixture into East Asians, one of which is shared with South Asians and Oceanians. Here, we leverage data from EPAS1 in 78 Tibetan individuals to interrogate which of these two introgression events introduced the EPAS1 beneficial sequence into the ancestral population of Tibetans, and we use the distribution of introgressed segment lengths at this locus to infer the timing of the introgression and selection event. We find that the introgression event unique to East Asians most likely introduced the beneficial haplotype into the ancestral population of Tibetans around 48,700 (16,000-59,500) y ago, and selection started around 9,000 (2,500-42,000) y ago. Our estimates suggest that one of the most convincing examples of adaptive introgression is in fact selection acting on standing archaic variation.

Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells.

Although some variation introgressed from Neanderthals has undergone selective sweeps, little is known about its functional significance. We used a Massively Parallel Reporter Assay (MPRA) to assay 5,353 high-frequency introgressed variants for their ability to modulate the gene expression within 170 bp of endogenous sequence. We identified 2,548 variants in active putative cis-regulatory elements (CREs) and 292 expression-modulating variants (emVars). These emVars are predicted to alter the binding motifs of important immune transcription factors, are enriched for associations with neutrophil and white blood cell count, and are associated with the expression of genes that function in innate immune pathways including inflammatory response and antiviral defense. We combined the MPRA data with other data sets to identify strong candidates to be driver variants of positive selection including an emVar that may contribute to protection against severe COVID-19 response. We endogenously deleted two CREs containing expression-modulation variants linked to immune function, rs11624425 and rs80317430, identifying their primary genic targets as ELMSAN1, and PAN2 and STAT2, respectively, three genes differentially expressed during influenza infection. Overall, we present the first database of experimentally identified expression-modulating Neanderthal-introgressed alleles contributing to potential immune response in modern humans.

ABO Genetic Variation in Neanderthals and Denisovans.

Variation at the ABO locus was one of the earliest sources of data in the study of human population identity and history, and to this day remains widely genotyped due to its importance in blood and tissue transfusions. Here, we look at ABO blood type variants in our archaic relatives: Neanderthals and Denisovans. Our goal is to understand the genetic landscape of the ABO gene in archaic humans, and how it relates to modern human ABO variation. We found two Neanderthal variants of the O allele in the Siberian Neanderthals (O1 and O2), one of these variants is shared with an European Neanderthal, who is a heterozygote for this O1 variant and a rare cis-AB variant. The Denisovan individual is heterozygous for two variants of the O1 allele, functionally similar to variants found widely in modern humans. Perhaps more surprisingly, the O2 allele variant found in Siberian Neanderthals can be found at low frequencies in modern Europeans and Southeast Asians, and the O1 allele variant found in Siberian and European Neanderthal is also found at very low frequency in modern East Asians. Our genetic distance analyses suggest both alleles survive in modern humans due to inbreeding with Neanderthals. We find that the sequence backgrounds of the surviving Neanderthal-like O alleles in modern humans retain a higher sequence divergence than other surviving Neanderthal genome fragments, supporting a view of balancing selection operating in the Neanderthal ABO alleles by retaining highly diverse haplotypes compared with portions of the genome evolving neutrally.

Midterm postoperative results of mid-urethral slings. Role of ultrasound in explaining surgical failures.

INTRODUCTION: Surgical treatment for stress urinary incontinence (SUI) with mid-urethral sling (MUS) is considered to have a high success rate. However, between 5% and 20% of MUS fail, with inadequate surgical implantation being a possible cause of SUI persistence or recurrence. Misplacement of a MUS can be determined by pelvic floor ultrasound (PF-US). The aim of this study was to investigate the role of PF-US in patients with persistent or recurrent urinary incontinence (UI) symptoms after MUS surgery for SUI with a midterm follow-up. MATERIALS AND METHODS: A historical cohort study including women undergoing MUS surgery for SUI between 2013 and 2015 was designed. The primary outcome was to correlate the sonographic parameters of MUS with SUI cure (negative International Continence Society-Uniform Cough Stress Test, Incontinence Questionnaire-Short Form < 5 points and no symptoms of SUI), at 5 years postsurgery. Secondary outcomes were changes of maximum urethral closure pressure (MUCP) and symptoms of urgency urinary incontinence (UUI) at 1 and 5 years after surgery. RESULTS: Eighty-seven patients (80 transobturator-MUS, 7 retropubic-MUS) were included. At 5 years all patients referred improvement of UI and objective cure of SUI was demonstrated in 81.2%. The MUS was sonographically correct in 67 (98.5%) of the 68 patients with cure of SUI. The MUS was considered incorrectly placed in only 4 (28.6%) of the 14 patients with noncured SUI. MUCP decreased from 61.9 to 48.8 cmH2 O at 5 years of follow-up (p < 0.01) and up to 53% of women had UUI symptoms after surgery, with a nonsignificant decrease compared to baseline. CONCLUSION: Patients cured of SUI had sonographically correct MUS by PF-US. Less than one-third of cases of SUI persistence or recurrence after MUS surgery could be explained by a sonographically incorrect sling. Low urethral resistance and/or UUI symptoms could help to explain the remaining failures. Complete functional and anatomic studies, including urodynamics and PF-US, should be performed before deciding on the next management strategy in patients with SUI persistence or recurrence after MUS.

Mid-term results of the Remeex® readjustable sling for female complex stress urinary incontinence and sonographic hypomobile urethra.

INTRODUCTION AND HYPOTHESIS: We aimed to evaluate the results of a readjustable sling (Remeex® system) among a selected group of women with complex stress urinary incontinence (SUI) with sonographic hypomobile urethra and assessing failure-related risk factors. METHODS: Observational, longitudinal, prospective cohort study, including patients who underwent surgery with the Remeex® system. The primary outcome was a binary outcome in change of one level or more of the severity of urinary incontinence symptoms according to the intervals of the Incontinence Questionnaire-Short Form (ICIQ-UI-SF) score (mild, moderate, severe and very severe). Secondary outcomes were postsurgical complications, absolute ICIQ-UI-SF, 24-h pad weight test (24-h PT), urodynamic SUI and Patient Global Impression of Improvement (PGI-I) score to evaluate subjective success. RESULTS: Among 120 women included, after surgery we found a 70% subjective success rate, a 76.7% decrease of urinary incontinence severity and a mean reduction of the 24-h PT of 109.6 ± 291.4 g. Women with post-surgical decreased severity of incontinence had lower mean body mass index (BMI) and 24-h PT than those without incontinence severity changes with statistically significant differences (p = 0.028 and p = 0.027, respectively). A logistic regression model demonstrated that a 1-point increase of BMI increased the risk of persistence of incontinence severity after surgery by 19% (OR = 1.19; 95% CI: 1.01-1.41; p = 0.040), and an increase of 10 g in the pre-surgical 24-h PT represented a 3% rise of the aforementioned risk (OR = 1.03; 95% CI: 1.01-1.06; p = 0.034). CONCLUSIONS: In patients with complex SUI and sonographic hypomobile urethra, use of a readjustable sling (Remeex® system) led to improvement of SUI. Patients with a greater BMI and pre-surgical 24-h PT showed worse results after surgery.

Readjustable Sling in Women With Stress Urinary Incontinence and Hypomobile Urethra: Understanding the Mechanisms of Closure by Transperineal Ultrasound.

OBJECTIVES: To assess the postsurgical sonographic parameters of a readjustable sling (RAS) according to urinary incontinence (UI) symptoms after surgery and compare this RAS sonographic pattern with mid-urethral slings (MUS). METHODS: Observational, prospective multicenter study, including women undergoing stress urinary incontinence (SUI) surgery with RAS (Remeex®). The primary outcome was the association between UI symptoms and sonographic parameters measured by two-dimensional transperineal and high-frequency endovaginal ultrasound. We measured static parameters (bladder neck funneling, RAS position, symmetry, distance to the urethral lumen), and the movement of the sling on Valsalva. UI symptoms were measured with the postsurgical Incontinence Questionnaire-Short Form (ICIQ-UI-SF) questionnaire. We created two control groups including patients with transobturator-MUS (TOT-MUS) and retropubic-MUS (RT-MUS) to compare postsurgical sonographic parameters of RAS with MUS. RESULTS: Among the 55 women with RAS included, the postoperative ICIQ-UI-SF scores were significantly higher in patients with bladder neck funneling (15.0 (3.9) vs 10.6 (6.7); P = .020) and in those with discordant movement of RAS on Valsalva (14.6 (5.7) vs 10.3 (6.7); P = .045). Compared with the 109 women with TOT-MUS and the 55 with RT-MUS, RAS was more often located in the proximal urethra and farther from the urethral lumen. CONCLUSIONS: Postsurgical pelvic floor ultrasound demonstrated that in women with complex SUI and hypomobile urethra who underwent RAS (Remeex®) surgery, the presence of bladder neck funneling and discordant movement on Valsalva correlate with the persistence of UI symptoms. In these women, RAS is more often located in the proximal urethra and farther from the urethral lumen at rest in comparison with MUS.

Evidence for archaic adaptive introgression in humans.

As modern and ancient DNA sequence data from diverse human populations accumulate, evidence is increasing in support of the existence of beneficial variants acquired from archaic humans that may have accelerated adaptation and improved survival in new environments - a process known as adaptive introgression. Within the past few years, a series of studies have identified genomic regions that show strong evidence for archaic adaptive introgression. Here, we provide an overview of the statistical methods developed to identify archaic introgressed fragments in the genome sequences of modern humans and to determine whether positive selection has acted on these fragments. We review recently reported examples of adaptive introgression, grouped by selection pressure, and consider the level of supporting evidence for each. Finally, we discuss challenges and recommendations for inferring selection on introgressed regions.

Patient-reported outcomes in the setting of a randomized control trial on the efficacy of transcutaneous stimulation of the posterior tibial nerve compared to percutaneous stimulation in idiopathic overactive bladder syndrome.

AIM: To compare the efficacy of transcutaneous tibial nerve stimulation (TTNS) with percutaneous tibial nerve stimulation (PTNS) regarding patient-reported outcomes measures, specifically quality-of-life (QoL) improvement and patient's treatment benefit, on symptoms associated with overactive bladder (OAB). METHODS: Patients with refractory OAB symptoms and detrusor overactivity were randomized to receive TTNS or PTNS for 12 weeks. Data from self-report OAB questionnaire short form (q-SF) and incontinence (I)-QoL questionnaires were collected pretreatment and at Weeks 6 and 12. Patients' self-perceived benefits on symptoms (treatment benefit scale, TBS) were also gathered. Mean change in scores within and between groups were estimated. RESULTS: Sixty-eight adult patients (67.6% women) were included in the intention to treat analysis. Of those, 61 completed all questionnaires and were analyzed as per protocol. Statistically significant improvements in OAB-q-SF and I-QoL between baseline and end-of-treatment scores were observed in both TTNS and PTNS groups (p < .001), being the differences much higher than the minimal important difference in both questionnaires. The scores of the OAB-q-SF scales (symptoms bother and health-related QoL) showed no statistically significant differences between the two groups. Similarly, the differences regarding the I-QoL questionnaire were statistically nonsignificant either (p = .607). When assessing the treatment benefit on symptoms, TBS responses between groups showed no statistical differences. CONCLUSION: A significant improvement of QoL was observed in both TTNS and PTNS groups. However, no patient-reported outcomes measures scores support a difference between the two groups. Therefore, these findings along with TTNS ease of application and less invasiveness may lead to an increased indication of this technique for OAB.

Weight-adapted fixed-dose combined adult antiretroviral tablets for HIV-infected children.

WHAT IS KNOWN AND OBJECTIVE: Therapeutic alternatives to simplify antiretroviral therapy (ART) in HIV-infected children are needed. We report our experience with abacavir(ABC)/lamivudine(3TC) individualized dose compounded capsules (IDCC). COMMENT: We present a prospective case series of HIV-infected children who did not weigh enough to receive the adult fixed-dose combination including ABC/3TC 600mg/300mg, and were treated with weight-adapted ABC/3TC IDCC in Barcelona, Spain. Thirteen patients (12 girls) received ABC/3TC IDCC for a median(IQR) time of 30(17-54) months. No significant changes were observed in CD4 cell counts, weight or height z-scores over time. Suppression of viral replication was maintained in 7 patients with undetectable viremia at baseline. Another 5 patients achieved viral suppression with ABC/3TC IDCC-based ART, while one non-adherent girl did not. No adverse events related to ABC/3TC IDCC were observed. WHAT IS NEW AND CONCLUSION: Despite small numbers, the long-term use of ABC/3TC IDCC was feasible, safe, and effective in the treatment of HIV-infected children.

Facts and Challenges about Asthma and COVID-19 among the Paediatric Population: A Systematic Literature Review.

A systematic review of the literature was conducted to analyse the factors that affect the probability of the paediatric asthma population suffering from COVID-19 or SARS-CoV-2, such as asthma phenotypes, inhaled corticosteroids, and the effects of lockdown. This systematic review was based on PRISMA guidelines. A bibliographic search was conducted using BNE, BVS (LILAC), CSIC (IME, ISOC), IBECS, Scielo, Scopus, Medline, and PubMed, using the following search profile: (COVID-19 or 2019-NCOV or SARS-CoV-2 or COV-19) AND asthma AND (children or adolescents or youths or children or teenagers). The results were limited to those articles published between December 2019 and December 2020, selecting only articles published in Spanish, English and French that included the study population (children aged 0-18 years). Among the 1066 results of the bibliographic search and seven articles selected from a manual search, only 19 articles were found to fit our eligibility criteria. Most of the articles highlight the effects of lockdown on the paediatric asthma population, increased therapeutic compliance, and the role of inhaled corticosteroids and intrinsic factors such as ACE2 receptors as causes of the decreased prevalence of COVID-19 among the paediatric asthma population. This population has unique characteristics that serve as protective factors against COVID-19. The safety measures implemented during the lockdown period along with inhaled corticosteroid treatment also contributed to this protection.

Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA.

As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.

Population genetics of wild Macaca fascicularis with low-coverage shotgun sequencing of museum specimens.

OBJECTIVES: Long-tailed macaques (Macaca fascicularis) are widely distributed throughout the mainland and islands of Southeast Asia, making them a useful model for understanding the complex biogeographical history resulting from drastic changes in sea levels throughout the Pleistocene. Past studies based on mitochondrial genomes (mitogenomes) of long-tailed macaque museum specimens have traced their colonization patterns throughout the archipelago, but mitogenomes trace only the maternal history. Here, our objectives were to trace phylogeographic patterns of long-tailed macaques using low-coverage nuclear DNA (nDNA) data from museum specimens. METHODS: We performed population genetic analyses and phylogenetic reconstruction on nuclear single nucleotide polymorphisms (SNPs) from shotgun sequencing of 75 long-tailed macaque museum specimens from localities throughout Southeast Asia. RESULTS: We show that shotgun sequencing of museum specimens yields sufficient genome coverage (average ~1.7%) for reconstructing population relationships using SNP data. Contrary to expectations of divergent results between nuclear and mitochondrial genomes for a female philopatric species, phylogeographical patterns based on nuclear SNPs proved to be closely similar to those found using mitogenomes. In particular, population genetic analyses and phylogenetic reconstruction from the nDNA identify two major clades within M. fascicularis: Clade A includes all individuals from the mainland along with individuals from northern Sumatra, while Clade B consists of the remaining island-living individuals, including those from southern Sumatra. CONCLUSIONS: Overall, we demonstrate that low-coverage sequencing of nDNA from museum specimens provides enough data for examining broad phylogeographic patterns, although greater genome coverage and sequencing depth would be needed to distinguish between very closely related populations, such as those throughout the Philippines.

Efficacy of transcutaneous stimulation of the posterior tibial nerve compared to percutaneous stimulation in idiopathic overactive bladder syndrome: Randomized control trial.

AIM: To evaluate the non-inferiority of the transcutaneous electrical stimulation technique, as compared with the percutaneous therapy (PTNS), regarding the efficacy in symptoms and QoL improvement in patients with overactive bladder (iOAB). METHODS: Patients with overactive detrusor (DO) and persisting symptoms after first-line or second-line treatment were randomized to receive either transcutaneous therapy or PTNS 1 day a week (30 min at 20 Hz and 200 cycles/s) for 12 weeks. Data from a 3-day voiding diary and a self-reported QoL-questionnaire were collected pre-treatment and at week 12. Non-inferiority was analyzed by estimating the mean change (95% confidence interval) of daytime micturition frequency. Statistical significance level was set at P < 0.05. RESULTS: Sixty-eight patients were included (67.6% women), mean age 59.6 years (SD 16.1). According to ITT analysis, daytime frequency decreased in both groups without statistically significant differences between them at the end of the treatment (adjusted difference 0.8; 95%CI; -0.1; 1.7); nor were differences in symptoms improvement for the variables collected through the 3-day voiding diary. Both techniques lessened urgency incontinence episodes by more than 50% and greatly improved the QoL. There were no relevant side effects and overall adherence to the treatment was 89.7%. CONCLUSIONS: This is the first RCT that evaluates the efficacy of the transcutaneous technique compared to the PTNS, and demonstrates non-inferiority in decreasing daytime frequency. Reduction in urgency incontinence episodes and improvement of QoL were also observed. These results and ease of application of transcutaneous neuromodulation may lead to a greater prescribing of this technique.

Signatures of Archaic Adaptive Introgression in Present-Day Human Populations.

Comparisons of DNA from archaic and modern humans show that these groups interbred, and in some cases received an evolutionary advantage from doing so. This process-adaptive introgression-may lead to a faster rate of adaptation than is predicted from models with mutation and selection alone. Within the last couple of years, a series of studies have identified regions of the genome that are likely examples of adaptive introgression. In many cases, once a region was ascertained as being introgressed, commonly used statistics based on both haplotype as well as allele frequency information were employed to test for positive selection. Introgression by itself, however, changes both the haplotype structure and the distribution of allele frequencies, thus confounding traditional tests for detecting positive selection. Therefore, patterns generated by introgression alone may lead to false inferences of positive selection. Here we explore models involving both introgression and positive selection to investigate the behavior of various statistics under adaptive introgression. In particular, we find that the number and allelic frequencies of sites that are uniquely shared between archaic humans and specific present-day populations are particularly useful for detecting adaptive introgression. We then examine the 1000 Genomes dataset to characterize the landscape of uniquely shared archaic alleles in human populations. Finally, we identify regions that were likely subject to adaptive introgression and discuss some of the most promising candidate genes located in these regions.

Archaic Adaptive Introgression in TBX15/WARS2.

A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using single nucleotide polymorphism chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15.