The Impact of Recessive Deleterious Variation on Signals of Adaptive Introgression in Human Populations

Admixture with archaic hominins has altered the landscape of genomic variation in modern human populations. Several gene regions have been identified previously as candidates of adaptive introgression (AI) that facilitated human adaptation to specific environments. However, simulation-based studies have suggested that population genetic processes other than adaptive mutations, such as heterosis from recessive deleterious variants private to populations before admixture, can also lead to patterns in genomic data that resemble AI. The extent to which the presence of deleterious variants affect the false-positive rate and the power of current methods to detect AI has not been fully assessed. Here, we used extensive simulations under parameters relevant for human evolution to show that recessive deleterious mutations can increase the false positive rates of tests for AI compared to models without deleterious variants, especially when the recombination rates are low. We next examined candidates of AI in modern humans identified from previous studies, and show that 24 out of 26 candidate regions remain significant, even when deleterious variants are included in the null model. However, two AI candidate genes, HYAL2 and HLA, are particularly susceptible to high false positive signals of AI due to recessive deleterious mutations. These genes are located in regions of the human genome with high exon density together with low recombination rate, factors that we show increase the rate of false-positives due to recessive deleterious mutations. Although the combination of such parameters is rare in the human genome, caution is warranted in such regions, as well as in other species with more compact genomes and/or lower recombination rates. In sum, our results suggest that recessive deleterious mutations cannot account for the signals of AI in most, but not all, of the top candidates for AI in humans, suggesting they may be genuine signals of adaptation.

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Recessive deleterious variation has a limited impact on signals of adaptive introgression in human populations

10.1101/2020.01.13.905174 ◽

2020 ◽

Author(s):

Xinjun Zhang ◽

Bernard Kim ◽

Kirk E. Lohmueller ◽

Emilia Huerta-Sánchez

Keyword(s):

False Positive ◽

False Positive Rate ◽

Genomic Variation ◽

Human Populations ◽

Deleterious Mutations ◽

Modern Humans ◽

Recombination Rates ◽

Limited Impact ◽

Adaptive Mutations ◽

Adaptive Introgression

AbstractAdmixture with archaic hominins has altered the landscape of genomic variation in modern human populations. Several gene regions have been previously identified as candidates of adaptive introgression (AI) that facilitated human adaptation to specific environments. However, simulation-based studies have suggested that population genetics processes other than adaptive mutations, such as heterosis from recessive deleterious variants private to populations before admixture, can also lead to patterns in genomic data that resemble adaptive introgression. The extent to which the presence of deleterious variants affect the false-positive rate and the power of current methods to detect AI has not been fully assessed. Here, we used extensive simulations to show that recessive deleterious mutations can increase the false positive rates of tests for AI compared to models without deleterious variants. We further examined candidates of AI in modern humans identified from previous studies and show that, although deleterious variants may hinder the performance of AI detection in modern humans, most signals remained robust when deleterious variants are included in the null model. While deleterious variants may have a limited impact on detecting signals of adaptive introgression in humans, we found that at least two AI candidate genes, HYAL2 and HLA, are particularly susceptible to high false positive rates due to the recessive deleterious mutations. By quantifying parameters that affect heterosis, we show that the high false positives are largely attributed to the high exon densities together with low recombination rates in the genomic regions, which can further be exaggerated by the population growth in recent human evolution. Although the combination of such parameters is rare in the human genome, caution is still warranted in other species with different genomic composition and demographic histories.

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Genome-Wide Mutagenesis of Hepatitis C Virus Reveals Ability of Genome To Overcome Detrimental Mutations

Journal of Virology ◽

10.1128/jvi.01327-19 ◽

2019 ◽

Vol 94 (3) ◽

Cited By ~ 1

Author(s):

Deepak Singh ◽

Shalini Soni ◽

Shaheen Khan ◽

Aditya N. Sarangi ◽

Ragothaman M. Yennamalli ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Cell Protein ◽

Virus Protein ◽

Reproduction Rate ◽

Full Genome ◽

Deleterious Mutations ◽

Adaptive Mutations ◽

Random Substitutions ◽

The Impact

ABSTRACT To gain insight into the impact of mutations on the viability of the hepatitis C virus (HCV) genome, we created a set of full-genome mutant libraries, differing from the parent sequence as well as each other, by using a random mutagenesis approach; the proportion of mutations increased across these libraries with declining template amount or dATP concentration. The replication efficiencies of full-genome mutant libraries ranged between 71 and 329 focus-forming units (FFU) per 105 Huh7.5 cells. Mutant libraries with low proportions of mutations demonstrated low replication capabilities, whereas those with high proportions of mutations had their replication capabilities restored. Hepatoma cells transfected with selected mutant libraries, with low (4 mutations per 10,000 bp copied), moderate (33 mutations), and high (66 mutations) proportions of mutations, and their progeny were subjected to serial passage. Predominant virus variants (mutants) from these mutant libraries (Mutantl, Mutantm, and Mutanth, respectively) were evaluated for changes in growth kinetics and particle-to-FFU unit ratio, virus protein expression, and modulation of host cell protein synthesis. Mutantm and Mutantl variants produced >3.0-log-higher extracellular progeny per ml than the parent, and Mutanth produced progeny at a rate 1.0-log lower. More than 80% of the mutations were in a nonstructural part of the mutant genomes, the majority were nonsynonymous, and a moderate to large proportion were in the conserved regions. Our results suggest that the HCV genome has the ability to overcome lethal/deleterious mutations because of the high reproduction rate but highly selects for random, beneficial mutations. IMPORTANCE Hepatitis C virus (HCV) in vivo displays high genetic heterogeneity, which is partly due to the high reproduction and random substitutions during error-prone genome replication. It is difficult to introduce random substitutions in vitro because of limitations in inducing mutagenesis from the 5′ end to the 3′ end of the genome. Our study has overcome this limitation. We synthesized full-length genomes with few to several random mutations in the background of an HCV clone that can recapitulate all steps of the life cycle. Our study provides evidence of the capability of the HCV genome to overcome deleterious mutations and remain viable. Mutants that emerged from the libraries had diverse phenotype profiles compared to the parent, and putative adaptive mutations mapped to segments of the conserved nonstructural genome. We demonstrate the potential utility of our system for the study of sequence variation that ensures the survival and adaptation of HCV.

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A novel machine learning algorithm has the potential to reduce by 1/3 the quantity of ILR episodes needing review

European Heart Journal ◽

10.1093/eurheartj/ehab724.0316 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

A Rosier ◽

E Crespin ◽

A Lazarus ◽

G Laurent ◽

A Menet ◽

...

Keyword(s):

Machine Learning ◽

False Positive ◽

Learning Algorithm ◽

False Positive Rate ◽

Machine Learning Algorithm ◽

The Novel ◽

Funding Sources ◽

High Workload ◽

Positive Rate ◽

The Impact

Abstract Background Implantable Loop Recorders (ILRs) are increasingly used and generate a high workload for timely adjudication of ECG recordings. In particular, the excessive false positive rate leads to a significant review burden. Purpose A novel machine learning algorithm was developed to reclassify ILR episodes in order to decrease by 80% the False Positive rate while maintaining 99% sensitivity. This study aims to evaluate the impact of this algorithm to reduce the number of abnormal episodes reported in Medtronic ILRs. Methods Among 20 European centers, all Medtronic ILR patients were enrolled during the 2nd semester of 2020. Using a remote monitoring platform, every ILR transmitted episode was collected and anonymised. For every ILR detected episode with a transmitted ECG, the new algorithm reclassified it applying the same labels as the ILR (asystole, brady, AT/AF, VT, artifact, normal). We measured the number of episodes identified as false positive and reclassified as normal by the algorithm, and their proportion among all episodes. Results In 370 patients, ILRs recorded 3755 episodes including 305 patient-triggered and 629 with no ECG transmitted. 2821 episodes were analyzed by the novel algorithm, which reclassified 1227 episodes as normal rhythm. These reclassified episodes accounted for 43% of analyzed episodes and 32.6% of all episodes recorded. Conclusion A novel machine learning algorithm significantly reduces the quantity of episodes flagged as abnormal and typically reviewed by healthcare professionals. FUNDunding Acknowledgement Type of funding sources: None. Figure 1. ILR episodes analysis

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The impact of P-hacking on "Redefine statistical significance"

10.31234/osf.io/bp2z4 ◽

2017 ◽

Author(s):

Harry Crane

Keyword(s):

False Positive ◽

Statistical Significance ◽

False Positive Rate ◽

Perceived Benefits ◽

Replication Rate ◽

Recent Proposal ◽

Positive Rate ◽

Replication Crisis ◽

The Impact ◽

Lower Cutoff

A recent proposal to "redefine statistical significance" (Benjamin, et al. Nature Human Behaviour, 2017) claims that false positive rates "would immediately improve" by factors greater than two and replication rates would double simply by changing the conventional cutoff for 'statistical significance' from P<0.05 to P<0.005. I analyze the veracity of these claims, focusing especially on how Benjamin, et al neglect the effects of P-hacking in assessing the impact of their proposal. My analysis shows that once P-hacking is accounted for the perceived benefits of the lower threshold all but disappear, prompting two main conclusions: (i) The claimed improvements to false positive rate and replication rate in Benjamin, et al (2017) are exaggerated and misleading. (ii) There are plausible scenarios under which the lower cutoff will make the replication crisis worse.

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Ethnic-specific reference range affects the efficacy of quadruple test as a universal screening for Down syndrome in a developing country

PLoS ONE ◽

10.1371/journal.pone.0251381 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0251381

Author(s):

Savitree Pranpanus ◽

Ounjai Kor-anantakul ◽

Thitima Suntharasaj ◽

Chitkasaem Suwanrath ◽

Tharangrut Hanprasertpong ◽

...

Keyword(s):

Down Syndrome ◽

Gestational Age ◽

False Positive ◽

Detection Rate ◽

Reference Range ◽

Risk Estimation ◽

False Positive Rate ◽

Specific Reference ◽

The Impact ◽

Ethnic Factor

Objective To evaluate the efficacy of the quadruple test for potential use as a Thai national policy for Down syndrome (DS) screening and establish an accurate equation for risk estimation of Down syndrome based on gestational age, weight and the ethnic-specific reference range of our population. Methods A prospective study was conducted on singleton pregnancies at 14 to 21 weeks of gestation to evaluate the efficacy of quadruple DS screening using the automatically calculated Western European descent factor (WF) in our population and the impact of screening using a specific Thai ethnic factor as well as to establish an equation for the risk estimation of DS based on gestational age, weight and a local Thai ethnic factor to correct for the impact of ethnic factor on the screening efficacy. Results Of a total of 5,515 women, 12 cases of DS and 8 cases of other aneuploidies were found. The detection rate, false positive rate and specificity were 75.0%, 9.1% and 90.9%, respectively, by automatic calculation with the widely used WF; the screening efficacy was lower when used in Asian populations than in other studies. The best-fitted regression equation of serum quadruple screening of AFP, free β-hCG, uE3 and inhibin A was established by adjustment for gestational age (GA) in days, maternal weight and our Thai-specific ethnic reference range which was created for this study. Calculations with our Thai-specific ethnic model gave a better detection rate of 83.3%, a false positive rate of 9.6% and specificity of 90.4%. Conclusion The serum quadruple test had a lower detection rate than expected when the risk estimation was based on the WF reference range. The serum quadruple test using WF had significantly different levels when corrected with our ethnic-specific factor. Using our local ethnic specific model could increase the detection rate of DS screening in Thailand with a minimal increase in false positive rates. Our findings indicate that DS screening should be adjusted with an appropriate individual ethnic factor when used for national screening.

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Deleterious variation mimics signatures of genomic incompatibility and adaptive introgression

10.1101/221705 ◽

2017 ◽

Cited By ~ 1

Author(s):

Bernard Y. Kim ◽

Christian D. Huber ◽

Kirk E. Lohmueller

Keyword(s):

Population Genetic ◽

Natural Populations ◽

Genetic Load ◽

Population Admixture ◽

Population Differences ◽

Deleterious Mutations ◽

Recombination Rates ◽

Adaptive Introgression ◽

Fitness Effects ◽

New Mutations

AbstractWhile it is appreciated that population size changes can impact patterns of deleterious variation in natural populations, less attention has been paid to how population admixture affects the dynamics of deleterious variation. Here we use population genetic simulations to examine how admixture impacts deleterious variation under a variety of demographic scenarios, dominance coefficients, and recombination rates. Our results show that gene flow between populations can temporarily reduce the genetic load of smaller populations, especially if deleterious mutations are recessive. Additionally, when fitness effects of new mutations are recessive, between-population differences in the sites at which deleterious variants exist creates heterosis in hybrid individuals. This can lead to an increase in introgressed ancestry, particularly when recombination rates are low. Under certain scenarios, introgressed ancestry can increase from an initial frequency of 5% to 30-75% and fix at many loci, even in the absence of beneficial mutations. Further, deleterious variation and admixture can generate correlations between the frequency of introgressed ancestry and recombination rate or exon density, even in the absence of other types of selection. The direction of these correlations is determined by the specific demography and whether mutations are additive or recessive. Therefore, it is essential that null models include both demography and deleterious variation before invoking reproductive incompatibilities or adaptive introgression to explain unusual patterns of genetic variation.

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VolcanoFinder: genomic scans for adaptive introgression

10.1101/697987 ◽

2019 ◽

Cited By ~ 6

Author(s):

Derek Setter ◽

Sylvain Mousset ◽

Xiaoheng Cheng ◽

Rasmus Nielsen ◽

Michael DeGiorgio ◽

...

Keyword(s):

Related Species ◽

Genomic Data ◽

Composite Likelihood ◽

Genomic Variation ◽

Human Populations ◽

Closely Related Species ◽

Adaptive Introgression ◽

A Genome ◽

Wide Range ◽

Donor Species

AbstractRecent research shows that introgression between closely-related species is an important source of adaptive alleles for a wide range of taxa. Typically, detection of adaptive introgression from genomic data relies on comparative analyses that require sequence data from both the recipient and the donor species. However, in many cases, the donor is unknown or the data is not currently available. Here, we introduce a genome-scan method—VolcanoFinder—to detect recent events of adaptive introgression using polymorphism data from the recipient species only.VolcanoFinder detects adaptive introgression sweeps from the pattern of excess intermediate-frequency polymorphism they produce in the flanking region of the genome, a pattern which appears as a volcano-shape in pairwise genetic diversity.Using coalescent theory, we derive analytical predictions for these patterns. Based on these results, we develop a composite-likelihood test to detect signatures of adaptive introgression relative to the genomic background. Simulation results show that VolcanoFinder has high statistical power to detect these signatures, even for older sweeps and for soft sweeps initiated by multiple migrant haplotypes. Finally, we implement VolcanoFinder to detect archaic introgression in European and sub-Saharan African human populations, and uncovered interesting candidates in both populations, such as TSHR in Europeans and TCHH-RPTN in Africans. We discuss their biological implications and provide guidelines for identifying and circumventing artifactual signals during empirical applications of VolcanoFinder.Author summaryThe process by which beneficial alleles are introduced into a species from a closely-related species is termed adaptive introgression. We present an analytically-tractable model for the effects of adaptive introgression on non-adaptive genetic variation in the genomic region surrounding the beneficial allele. The result we describe is a characteristic volcano-shaped pattern of increased variability that arises around the positively-selected site, and we introduce an open-source method VolcanoFinder to detect this signal in genomic data. Importantly, VolcanoFinder is a population-genetic likelihood-based approach, rather than a comparative-genomic approach, and can therefore probe genomic variation data from a single population for footprints of adaptive introgression, even from a priori unknown and possibly extinct donor species.

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The impact of natural selection on the evolution and function of placentally expressed galectins

10.1101/505339 ◽

2018 ◽

Cited By ~ 1

Author(s):

Zackery A. Ely ◽

Jiyun M. Moon ◽

Gregory R. Sliwoski ◽

Amandeep K. Sangha ◽

Xing-Xing Shen ◽

...

Keyword(s):

Natural Selection ◽

Protein Structure ◽

Genomic Variation ◽

Human Populations ◽

Carbohydrate Binding ◽

Sequence Evolution ◽

Placental Development ◽

Human Genetic Disease ◽

3D Protein Structure ◽

The Impact

AbstractImmunity genes have repeatedly experienced natural selection during mammalian evolution. Galectins are carbohydrate-binding proteins that regulate diverse immune responses, including maternal-fetal immune tolerance in placental pregnancy. Seven human galectins, four conserved across vertebrates and three specific to primates, are involved in placental development. To comprehensively study the molecular evolution of these galectins both across mammals and within humans, we conducted a series of between-and within-species evolutionary analyses. By examining patterns of sequence evolution between species, we found that primate-specific galectins showed uniformly high substitution rates, whereas two of the four other galectins experienced accelerated evolution in primates. By examining human population genomic variation, we found that galectin genes and variants, including variants previously linked to immune diseases, showed signatures of recent positive selection in specific human populations. By examining one nonsynonymous variant in Galectin-8 previously associated with autoimmune diseases, we further discovered that it is tightly linked to three other nonsynonymous variants; surprisingly, the global frequency of this four-variant haplotype is ∼50%. To begin understanding the impact of this major haplotype on Galectin-8 protein structure, we modeled its 3D protein structure and found that it differed substantially from the reference protein structure. These results suggest that placentally expressed galectins experienced both ancient and more recent selection in a lineage-and population-specific manner. Furthermore, our discovery that the major Galectin-8 haplotype is structurally distinct from and more commonly found than the reference haplotype illustrates the significance of understanding the evolutionary processes that sculpted variants associated with human genetic disease.

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A four-dimensional analysis of partitioned approximate filters

Proceedings of the VLDB Endowment ◽

10.14778/3476249.3476286 ◽

2021 ◽

Vol 14 (11) ◽

pp. 2355-2368

Author(s):

Tobias Schmidt ◽

Maximilian Bandle ◽

Jana Giceva

Keyword(s):

False Positive ◽

State Of The Art ◽

False Positive Rate ◽

Bloom Filters ◽

Use Case ◽

Positive Rate ◽

Key Dimensions ◽

The Many ◽

Data Disk ◽

The Impact

With today's data deluge, approximate filters are particularly attractive to avoid expensive operations like remote data/disk accesses. Among the many filter variants available, it is non-trivial to find the most suitable one and its optimal configuration for a specific use-case. We provide open-source implementations for the most relevant filters (Bloom, Cuckoo, Morton, and Xor filters) and compare them in four key dimensions: the false-positive rate, space consumption, build, and lookup throughput. We improve upon existing state-of-the-art implementations with a new optimization, radix partitioning, which boosts the build and lookup throughput for large filters by up to 9x and 5x. Our in-depth evaluation first studies the impact of all available optimizations separately before combining them to determine the optimal filter for specific use-cases. While register-blocked Bloom filters offer the highest throughput, the new Xor filters are best suited when optimizing for small filter sizes or low false-positive rates.

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The Impact of Natural Selection on the Evolution and Function of Placentally Expressed Galectins

Genome Biology and Evolution ◽

10.1093/gbe/evz183 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2574-2592 ◽

Cited By ~ 1

Author(s):

Zackery A Ely ◽

Jiyun M Moon ◽

Gregory R Sliwoski ◽

Amandeep K Sangha ◽

Xing-Xing Shen ◽

...

Keyword(s):

Natural Selection ◽

Protein Structure ◽

Genomic Variation ◽

Human Populations ◽

Carbohydrate Binding ◽

Sequence Evolution ◽

Placental Development ◽

Human Genetic Disease ◽

3D Protein Structure ◽

The Impact

Abstract Immunity genes have repeatedly experienced natural selection during mammalian evolution. Galectins are carbohydrate-binding proteins that regulate diverse immune responses, including maternal–fetal immune tolerance in placental pregnancy. Seven human galectins, four conserved across vertebrates and three specific to primates, are involved in placental development. To comprehensively study the molecular evolution of these galectins, both across mammals and within humans, we conducted a series of between- and within-species evolutionary analyses. By examining patterns of sequence evolution between species, we found that primate-specific galectins showed uniformly high substitution rates, whereas two of the four other galectins experienced accelerated evolution in primates. By examining human population genomic variation, we found that galectin genes and variants, including variants previously linked to immune diseases, showed signatures of recent positive selection in specific human populations. By examining one nonsynonymous variant in Galectin-8 previously associated with autoimmune diseases, we further discovered that it is tightly linked to three other nonsynonymous variants; surprisingly, the global frequency of this four-variant haplotype is ∼50%. To begin understanding the impact of this major haplotype on Galectin-8 protein structure, we modeled its 3D protein structure and found that it differed substantially from the reference protein structure. These results suggest that placentally expressed galectins experienced both ancient and more recent selection in a lineage- and population-specific manner. Furthermore, our discovery that the major Galectin-8 haplotype is structurally distinct from and more commonly found than the reference haplotype illustrates the significance of understanding the evolutionary processes that sculpted variants associated with human genetic disease.

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