Publications by authors named "Nádia Pinto"

27 Publications

  • Page 1 of 1

Risk Variants in Three Alzheimer's Disease Genes Show Association with EEG Endophenotypes.

J Alzheimers Dis 2021 ;80(1):209-223

IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.

Background: Dementia due to Alzheimer's disease (AD) is a complex neurodegenerative disorder, which much of heritability remains unexplained. At the clinical level, one of the most common physiological alterations is the slowing of oscillatory brain activity, measurable by electroencephalography (EEG). Relative power (RP) at the conventional frequency bands (i.e., delta, theta, alpha, beta-1, and beta-2) can be considered as AD endophenotypes.

Objective: The aim of this work is to analyze the association between sixteen genes previously related with AD: APOE, PICALM, CLU, BCHE, CETP, CR1, SLC6A3, GRIN2 β, SORL1, TOMM40, GSK3 β, UNC5C, OPRD1, NAV2, HOMER2, and IL1RAP, and the slowing of the brain activity, assessed by means of RP at the aforementioned frequency bands.

Methods: An Iberian cohort of 45 elderly controls, 45 individuals with mild cognitive impairment, and 109 AD patients in the three stages of the disease was considered. Genomic information and brain activity of each subject were analyzed.

Results: The slowing of brain activity was observed in carriers of risk alleles in IL1RAP (rs10212109, rs9823517, rs4687150), UNC5C (rs17024131), and NAV2 (rs1425227, rs862785) genes, regardless of the disease status and situation towards the strongest risk factors: age, sex, and APOE ɛ4 presence.

Conclusion: Endophenotypes reduce the complexity of the general phenotype and genetic variants with a major effect on those specific traits may be then identified. The found associations in this work are novel and may contribute to the comprehension of AD pathogenesis, each with a different biological role, and influencing multiple factors involved in brain physiology.
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http://dx.doi.org/10.3233/JAD-200963DOI Listing
January 2021

4SpecID: Reference DNA Libraries Auditing and Annotation System for Forensic Applications.

Genes (Basel) 2021 Jan 2;12(1). Epub 2021 Jan 2.

Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal.

Forensic genetics is a fast-growing field that frequently requires DNA-based taxonomy, namely, when evidence are parts of specimens, often highly processed in food, potions, or ointments. Reference DNA-sequences libraries, such as BOLD or GenBank, are imperative tools for taxonomic assignment, particularly when morphology is inadequate for classification. The auditing and curation of these datasets require reliable mechanisms, preferably with automated data preprocessing. Software tools were developed to grade these datasets considering as primary criterion the number of records, which is not compliant with forensic standards, where the priority is validation from independent sources. Moreover, 4SpecID is an efficient software tool developed to audit and annotate reference libraries, specifically designed for forensic applications. Its intuitive user-friendly interface virtually accesses any database and includes specific data mining functions tuned for the widespread BOLD repositories. The built tool was evaluated in laptop MacBook and a dual-Xeon server with a large BOLD dataset ( 36,115 records), and the best execution time to grade the dataset on the laptop was 0.28 s. Datasets of and families were used to evaluate the quality of the tool and the relevance of independent sources validation.
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http://dx.doi.org/10.3390/genes12010061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824288PMC
January 2021

Variants in an Iberian Alzheimer Cohort Detected through an Optimized Sanger Sequencing Protocol.

Genes (Basel) 2020 Dec 22;12(1). Epub 2020 Dec 22.

IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal.

The primary genetic risk factor for late onset Alzheimer's disease (LOAD) is the allele of () gene. The three most common variants of are determined by single nucleotide polymorphisms (SNPs) rs429358 and rs7412. Our aim was to estimate allele and genotype frequencies of variants in an Iberian cohort, thus helping to understand differences in -related LOAD risk observed across populations. We analyzed saliva or buccal swab samples from 229 LOAD patients and 89 healthy elderly controls (≥68 years old) from Northern Portugal and Castile and León region, Spain. The genotyping was performed by Sanger sequencing, optimized to overcome GC content drawbacks. Results obtained in our Iberian LOAD and control cohorts are in line with previous large meta-analyses on frequencies in Caucasian populations; however, we found differences in allele frequencies between our Portuguese and Spanish subgroups of AD patients. Moreover, when comparing studies from Iberian and other Caucasian cohorts, differences in and frequencies and subsequent different -related LOAD risks must be clarified. These results show the importance of studying genetic variation at the gene in different populations (including analyses at a regional level) to increase our knowledge about its clinical significance.
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http://dx.doi.org/10.3390/genes12010004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822120PMC
December 2020

Genome-Wide Scan for Five Brain Oscillatory Phenotypes Identifies a New QTL Associated with Theta EEG Band.

Brain Sci 2020 Nov 18;10(11). Epub 2020 Nov 18.

IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-135 Porto, Portugal.

Brain waves, measured by electroencephalography (EEG), are a powerful tool in the investigation of neurophysiological traits and a noninvasive and cost-effective alternative in the diagnostic of some neurological diseases. In order to identify novel Quantitative Trait Loci (QTLs) for brain wave relative power (RP), we collected resting state EEG data in five frequency bands (δ, θ, α, β1, and β2) and genome-wide data in a cohort of 105 patients with late onset Alzheimer's disease (LOAD), 41 individuals with mild cognitive impairment and 45 controls from Iberia, correcting for disease status. One novel association was found with an interesting candidate for a role in brain wave biology, (C-type lectin domain family 16), with a variant at this locus passing the adjusted genome-wide significance threshold after Bonferroni correction. This finding reinforces the importance of immune regulation in brain function. Additionally, at a significance cutoff value of 5 × 10, 18 independent association signals were detected. These signals comprise brain expression Quantitative Loci (eQTLs) in caudate basal ganglia, spinal cord, anterior cingulate cortex and hypothalamus, as well as chromatin interactions in adult and fetal cortex, neural progenitor cells and hippocampus. Moreover, in the set of genes showing signals of association with brain wave RP in our dataset, there is an overrepresentation of loci previously associated with neurological traits and pathologies, evidencing the pleiotropy of the genetic variation modulating brain function.
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http://dx.doi.org/10.3390/brainsci10110870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698967PMC
November 2020

Twenty Years Later: A Comprehensive Review of the X Chromosome Use in Forensic Genetics.

Front Genet 2020 17;11:926. Epub 2020 Sep 17.

Institute for Research and Innovation in Health Sciences (i3S), University of Porto, Porto, Portugal.

The unique structure of the X chromosome shaped by evolution has led to the present gender-specific genetic differences, which are not shared by its counterpart, the Y chromosome, and neither by the autosomes. In males, recombination between the X and Y chromosomes is limited to the pseudoautosomal regions, PAR1 and PAR2; therefore, in males, the X chromosome is (almost) entirely transmitted to female offspring. On the other hand, the X chromosome is present in females with two copies that recombine along the whole chromosome during female meiosis and that is transmitted to both female and male descendants. These transmission characteristics, besides the obvious clinical impact (sex chromosome aneuploidies are extremely frequent), make the X chromosome an irreplaceable genetic tool for population genetic-based studies as well as for kinship and forensic investigations. In the early 2000s, the number of publications using X-chromosomal polymorphisms in forensic and population genetic applications increased steadily. However, nearly 20 years later, we observe a conspicuous decrease in the rate of these publications. In light of this observation, the main aim of this article is to provide a comprehensive review of the advances and applications of X-chromosomal markers in population and forensic genetics over the last two decades. The foremost relevant topics are addressed as: (i) developments concerning the number and types of markers available, with special emphasis on short tandem repeat (STR) polymorphisms (STR nomenclatures and practical concerns); (ii) overview of worldwide population (frequency) data; (iii) the use of X-chromosomal markers in (complex) kinship testing and the forensic statistical evaluation of evidence; (iv) segregation and mutation studies; and (v) current weaknesses and future prospects.
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http://dx.doi.org/10.3389/fgene.2020.00926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527635PMC
September 2020

Relationship between the Presence of the 4 Allele and EEG Complexity along the Alzheimer's Disease Continuum.

Sensors (Basel) 2020 Jul 10;20(14). Epub 2020 Jul 10.

Biomedical Engineering Group, E.T.S.I. de Telecomunicación, Universidad de Valladolid, 47011 Valladolid, Spain.

Alzheimer's disease (AD) is the most prevalent cause of dementia, being considered a major health problem, especially in developed countries. Late-onset AD is the most common form of the disease, with symptoms appearing after 65 years old. Genetic determinants of AD risk are vastly unknown, though, ε 4 allele of the gene has been reported as the strongest genetic risk factor for AD. The objective of this study was to analyze the relationship between brain complexity and the presence of ε 4 alleles along the AD continuum. For this purpose, resting-state electroencephalography (EEG) activity was analyzed by computing Lempel-Ziv complexity (LZC) from 46 healthy control subjects, 49 mild cognitive impairment subjects, 45 mild AD patients, 44 moderate AD patients and 33 severe AD patients, subdivided by status. Subjects with one or more ε 4 alleles were included in the carriers subgroups, whereas the ε 4 non-carriers subgroups were formed by subjects without any ε 4 allele. Our results showed that AD continuum is characterized by a progressive complexity loss. No differences were observed between AD ε 4 carriers and non-carriers. However, brain activity from healthy subjects with ε 4 allele (carriers subgroup) is more complex than from non-carriers, mainly in left temporal, frontal and posterior regions (-values < 0.05, FDR-corrected Mann-Whitney -test). These results suggest that the presence of ε 4 allele could modify the EEG complexity patterns in different brain regions, as the temporal lobes. These alterations might be related to anatomical changes associated to neurodegeneration, increasing the risk of suffering dementia due to AD before its clinical onset. This interesting finding might help to advance in the development of new tools for early AD diagnosis.
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http://dx.doi.org/10.3390/s20143849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411888PMC
July 2020

Paternal and maternal mutations in X-STRs: A GHEP-ISFG collaborative study.

Forensic Sci Int Genet 2020 05 5;46:102258. Epub 2020 Feb 5.

Laboratório de Diagnóstico por DNA (LDD), Universidade do Estado do Rio de Janeiro, Brazil.

The GHEP-ISFG organized a collaborative study to estimate mutation rates for the markers included in the Investigator Argus X-12 QS kit Qiagen. A total of 16 laboratories gathered data from 1,612 father/mother/daughter trios, which were used to estimate both maternal and paternal mutation rates, when pooled together with other already published data. Data on fathers and mothers' age at the time of birth of the daughter were also available for ∼93 % of the cases. Population analyses were computed considering the genetic information of a subset of 1,327 unrelated daughters, corresponding to 2,654 haplotypes from residents in several regions of five countries: Argentina, Brazil, Ecuador, Portugal and Spain. Genetic differentiation analyses between the population samples from the same country did not reveal signs of significant stratification, although results from Hardy-Weinberg and linkage disequilibrium tests indicated the need of larger studies for Ecuador and Brazilian populations. The high genetic diversity of the markers resulted in a large number of haplotype combinations, showing the need of huge databases for reliable estimates of their frequencies. It should also be noted the high number of new alleles found, many of them not included in the allelic ladders provided with the kit, as very diverse populations were analyzed. The overall estimates for locus specific average mutation rates varied between 7.5E-04 (for DXS7423) and 1.1E-02 (for DXS10135), the latter being a troublesome figure for kinship analyses. Most of the found mutations (∼92 %) are compatible with the gain or loss of a single repeat. Paternal mutation rates showed to be 5.2 times higher than maternal ones. We also found that older fathers were more prone to transmit mutated alleles, having this trend not been observed in the case of the mothers.
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http://dx.doi.org/10.1016/j.fsigen.2020.102258DOI Listing
May 2020

Computational modeling of the effects of EEG volume conduction on functional connectivity metrics. Application to Alzheimer's disease continuum.

J Neural Eng 2019 10 29;16(6):066019. Epub 2019 Oct 29.

Biomedical Engineering Group, University of Valladolid, Valladolid, Spain.

Objective: The aim of this study was to evaluate the effect of electroencephalographic (EEG) volume conduction in different measures of functional connectivity and to characterize the EEG coupling alterations at the different stages of dementia due to Alzheimer's disease (AD).

Approach: Magnitude squared coherence (MSCOH), imaginary part of coherence (iCOH), lagged coherence (lagCOH), amplitude envelope correlation (AEC), synchronization likelihood (SL), phase lag index (PLI), phase locking value (PLV), and corrected imaginary PLV (ciPLV) were applied to: (i) synthetic signals generated with a Kuramoto-based model of several coupled oscillators; and (ii) a resting-state EEG database of real recordings from 51 cognitively healthy controls, 51 mild cognitive impairment (MCI) subjects, 51 mild AD (AD ) patients, 50 moderate AD (AD ) patients, and 50 severe AD (AD ) patients.

Main Results: Our results using synthetic signals showed that PLI was the least affected parameter by spurious influences in a simulated volume conduction environment. Results using real EEG recordings showed that spontaneous activity of MCI patients is characterized by a significant coupling increase in the [Formula: see text] band. As dementia progresses, this increase in the [Formula: see text] band became more pronounced, and a significant widespread decrease in [Formula: see text] band appeared at the last stage of dementia.

Significance: Our results revealed that the estimation of functional EEG connectivity using PLI could reduce the bias introduced by the spurious influence of volume conduction, and it could increase the insight into the underlying brain dynamics at different stages of the AD continuum.
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http://dx.doi.org/10.1088/1741-2552/ab4024DOI Listing
October 2019

EEG Characterization of the Alzheimer's Disease Continuum by Means of Multiscale Entropies.

Entropy (Basel) 2019 May 28;21(6). Epub 2019 May 28.

Biomedical Engineering Group, E.T.S.I. de Telecomunicación, Universidad de Valladolid, 47011 Valladolid, Spain.

Alzheimer's disease (AD) is a neurodegenerative disorder with high prevalence, known for its highly disabling symptoms. The aim of this study was to characterize the alterations in the irregularity and the complexity of the brain activity along the AD continuum. Both irregularity and complexity can be studied applying entropy-based measures throughout multiple temporal scales. In this regard, multiscale sample entropy (MSE) and refined multiscale spectral entropy (rMSSE) were calculated from electroencephalographic (EEG) data. Five minutes of resting-state EEG activity were recorded from 51 healthy controls, 51 mild cognitive impaired (MCI) subjects, 51 mild AD patients (AD), 50 moderate AD patients (AD), and 50 severe AD patients (AD). Our results show statistically significant differences (-values < 0.05, FDR-corrected Kruskal-Wallis test) between the five groups at each temporal scale. Additionally, average slope values and areas under MSE and rMSSE curves revealed significant changes in complexity mainly for controls vs. MCI, MCI vs. AD and AD vs. AD comparisons (-values < 0.05, FDR-corrected Mann-Whitney -test). These findings indicate that MSE and rMSSE reflect the neuronal disturbances associated with the development of dementia, and may contribute to the development of new tools to track the AD progression.
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http://dx.doi.org/10.3390/e21060544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515033PMC
May 2019

Assessment of EEG Connectivity Patterns in Mild Cognitive Impairment Using Phase Slope Index.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:263-266

Mild cognitive impairment (MCI) is a pathology characterized by an abnormal cognitive state. MCI patients are considered to be at high risk for developing dementia. The aim of this study is to characterize the changes that MCI causes in the patterns of brain information flow. For this purpose, spontaneous EEG activity from 41 MCI patients and 37 healthy controls was analyzed by means of an effective connectivity measure: the phase slope index (PSl). Our results showed statistically significant decreases in PSI values mainly at delta and alpha frequency bands for MCI patients, compared to the control group. These abnormal patterns may be due to the structural changes in the brain suffered by patients: decreased hippocampal volume, atrophy of the medial temporal lobe, or loss of gray matter volume. This study suggests the usefulness of PSI to provide further insights into the underlying brain dynamics associated with MCI.
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http://dx.doi.org/10.1109/EMBC.2018.8512270DOI Listing
July 2018

Big data in forensic genetics.

Forensic Sci Int Genet 2018 11 2;37:102-105. Epub 2018 Aug 2.

Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; Instituto de Investigação e Inovação em Saúde (i3s), Universidade do Porto, Porto, Portugal; CMUP, Centro de Matemática da Universidade do Porto, Porto, Portugal. Electronic address:

The potential and difficulties of the application of genome wide data in forensics are analyzed. We argue that, besides statistical, computational, ethical, economic and technical validation problems, the state of the art of population genetics theory is insufficient to deal with the forensic use of this type of data. In order to keep the current standards of quantifying and reporting genetic evidence, namely in kinship analyses and identification, substantial improvement in the theoretical framework should be reached, since to obtain genome-wide results is to provide the experts with data that they cannot quantify the corresponding evidentiary value. Therefore, while a satisfactory, generalized theoretical and biostatistical modelling is not achieved, it may well be wiser to improve the already established approaches to a limited, pre-defined number of validated genetic markers, amenable to a consensual handling and reporting. Whole genome population analyses will prove extremely useful in selecting the best suited and most efficient of those markers.
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http://dx.doi.org/10.1016/j.fsigen.2018.08.001DOI Listing
November 2018

Forensic genetics and genomics: Much more than just a human affair.

PLoS Genet 2017 Sep 21;13(9):e1006960. Epub 2017 Sep 21.

Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal.

While traditional forensic genetics has been oriented towards using human DNA in criminal investigation and civil court cases, it currently presents a much wider application range, including not only legal situations sensu stricto but also and, increasingly often, to preemptively avoid judicial processes. Despite some difficulties, current forensic genetics is progressively incorporating the analysis of nonhuman genetic material to a greater extent. The analysis of this material-including other animal species, plants, or microorganisms-is now broadly used, providing ancillary evidence in criminalistics in cases such as animal attacks, trafficking of species, bioterrorism and biocrimes, and identification of fraudulent food composition, among many others. Here, we explore how nonhuman forensic genetics is being revolutionized by the increasing variety of genetic markers, the establishment of faster, less error-burdened and cheaper sequencing technologies, and the emergence and improvement of models, methods, and bioinformatics facilities.
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http://dx.doi.org/10.1371/journal.pgen.1006960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608170PMC
September 2017

Exact likelihood ratio calculations for pairwise cases.

Forensic Sci Int Genet 2017 07 27;29:218-224. Epub 2017 Apr 27.

Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; Instituto de Investigação e Inovação em Saúde (i3s), Universidade do Porto, Porto, Portugal; Faculdade de Ciências, Universidade do Porto, Porto, Portugal.

Some practical and theoretical aspects of evaluation of evidence based on the likelihood ratio (LR) in kinship cases are discussed. If relationships are complex or if complicating factors like mutation, correction for population structure or silent alleles need to be accounted for, available software may fail. We present an explicit general formula for non-inbred pairwise cases. Equipped with this formula it is possible to evaluate, say, how strongly a shared rare allele, points towards a specific relationship. Moreover, a general expression as the one presented, adds to the understanding of models and the underlying biological mechanisms. It is also useful for checking software and defining the limitations of programs. Some ideas for improving software may also be generated by the derivation of exact expressions. We argue that a proportional mutation model is well suited from a pragmatic point of view and derive some theoretical properties of this model. Several examples based on the general pairwise formula and its implementation in the freely available R package mut are presented.
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http://dx.doi.org/10.1016/j.fsigen.2017.04.018DOI Listing
July 2017

Key individuals for discerning pedigrees belonging to the same autosomal kinship class.

Forensic Sci Int Genet 2017 07 19;29:71-79. Epub 2017 Mar 19.

Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; Instituto de Investigação e Inovação em Saúde (i3s), Universidade do Porto, Porto, Portugal; CMUP, Centro de Matemática da Universidade do Porto, Porto, Portugal. Electronic address:

The existence of pedigrees belonging to the same kinship class (i.e. indistinguishable through independent markers) is well known in the forensic community, and theoretical frameworks for autosomal and X-chromosomal markers were already developed for a pair of individuals. Nevertheless, studies for the cases where a greater number of individuals is available for testing are still lacking. With this work, we intend to pave the way for a theoretical and general framework, identifying the individuals/relatives that should be chosen to distinguish autosomal analyses between such pedigrees. In this work we identify the individuals/relatives that are non-informative for calculations (the pedigrees under discussion remaining indistinguishable independently of their genetic profile), as well as those that will likely be very informative, influencing the statistical outcome. For example, given the respective genotypes, to compare the likelihoods of the father of the individual B to be: (a.) the father, or (b.) a full-brother, of the individual A, the hypotheses H: "The individual A is paternal half-sibling of the individual B", and H: "The individual A is paternal uncle/aunt of the individual B" are considered. It is proved that considering just individuals A and B the hypotheses are equally likely. In this work we show that the same is also true for the case where the mother of B is available for testing, notwithstanding the hypotheses being differently weighted if the mother of A is considered. Similar considerations are done for other kinship hypotheses and/or individuals/relatives. Irrelevance of the genetic profile of some specific relatives are mathematically demonstrated, and data obtained from 20,000 simulated families are presented for the other cases.
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http://dx.doi.org/10.1016/j.fsigen.2017.03.018DOI Listing
July 2017

Formulation and communication of evaluative forensic science expert opinion-A GHEP-ISFG contribution to the establishment of standards.

Forensic Sci Int Genet 2016 11 7;25:210-213. Epub 2016 Sep 7.

Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; Instituto de Investigação e Inovação em Saúde (i3s), Universidade do Porto, Porto, Portugal; CMUP Centro de Matemática da Universidade do Porto, Porto, Portugal. Electronic address:

Communicating and interpreting genetic evidence in the administration of justice is currently a matter of great concern, due to the theoretical and technical complexity of the evaluative reporting and large difference in expertise between forensic experts and law professionals. A large number of initiatives have been taken trying to bridge this gap, contributing to the education of both parties. Results however have not been very encouraging, as most of these initiatives try to cope globally with the problem, addressing simultaneously theoretical and technical approaches which are in a quite heterogeneous state of development and validation. In consequence, the extension and complexity of the resulting documents disheartens their study by professionals (both jurists and geneticists) and makes a consensus very hard to reach even among the genetic experts' community. Here we propose a 'back-to-basics', example-driven approach, in which a model report for the two most common situations faced by forensic laboratories is presented. We do hope that this strategy will provide a solid basis for a stepwise generalisation.
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http://dx.doi.org/10.1016/j.fsigen.2016.09.003DOI Listing
November 2016

Mutation and mutation rates at Y chromosome specific Short Tandem Repeat Polymorphisms (STRs): a reappraisal.

Forensic Sci Int Genet 2014 Mar 31;9:20-4. Epub 2013 Oct 31.

IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal; Faculty of Sciences, University of Porto, Porto, Portugal. Electronic address:

Mutation is a topic of intense research and raises important problems in forensics. Since the markers of choice in current forensic genetics analyses are microsatellites or Short Tandem Repeat Polymorphisms (STRs), mutation is sufficiently common to cause difficulties in evaluating DNA evidence in a significant proportion of cases but at the same time rare enough to turn the estimation of the corresponding probability of occurrence into a hard task. We address these issues using the simplest model of transmission: the Y chromosome specific STRs. Within this model, and under an explicit set of definitions and involved assumptions, we developed the theoretical framework required for the study of allelic transitions in gametogenesis, identifying the required parameters and associated probabilities and finally we discuss the estimation of these parameters and their application in forensics. We conclude that (i) for forensic casework the relevant parameter for incorporation in a likelihood ratio is biallelic specific (i.e. the mutation rate estimate corresponds to the probability of the specific allelic transition observed) and (ii) for these estimates as well as in order to provide data for testing mutation models the absolute frequency of mutated and non-mutated transmissions per allele, along with the description of the observed mutations should be reported.
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http://dx.doi.org/10.1016/j.fsigen.2013.10.008DOI Listing
March 2014

A general approach to power calculation for relationship testing.

Forensic Sci Int Genet 2014 Mar 28;9:186-90. Epub 2013 Jun 28.

Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

This paper is motivated by power considerations in connection with relationship testing. Given the true relationship between a set of individuals, a claimed relationship between the same individuals, and a set of genetic markers, we compute the power of exclusion, i.e., the probability that the genotypes will be incompatible with the claimed relationship. If exclusion is impossible, as will be the case if it is required for instance to distinguish between sibs and half sibs, we rather obtain the distribution of the likelihood ratio. The problem we are addressing can also be seen as a standard way of measuring the ability of a battery of tests to resolve claimed family relationships. In particular, simple exclusion probabilities are regularly calculated worldwide as a part of designing forensic marker sets. Our approach to these problems is guided by a natural way of calculating exclusion probabilities on a computer. We present a user friendly implementation for this as part of the R package paramlink, originally designed by one of the authors (MDV) for pedigree manipulations and likelihood computations. By doing so we are able to handle problems more challenging than we have seen in the literature. Specifically, we deal with complex pedigrees with arbitrary inbreeding and conditioning. We present examples for autosomal as well as X-linked markers and some formulae to validate the results. The examples indicate a wide range of applications. Details are presented for an immigration case where previously reported calculations are extended to account for possible inbreeding and known genotypes. The supplementary material includes a tutorial on how to perform these calculations in paramlink.
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http://dx.doi.org/10.1016/j.fsigen.2013.05.001DOI Listing
March 2014

Paternity exclusion power: comparative behaviour of autosomal and X-chromosomal markers in standard and deficient cases with inbreeding.

Forensic Sci Int Genet 2013 Feb 9;7(2):290-5. Epub 2013 Jan 9.

IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.

In paternity testing the informativeness of genetic markers is traditionally measured through the probability of finding, in randomly chosen individuals, inconsistencies with parent to child Mendelian rules of transmission. This statistic, called power of exclusion (PE), paternal exclusion chance or probability, can be defined for duos (mother not typed) or trios (random false fathers are matched against mother/child pairs) and performed both for autosomal and X-chromosomal markers (restricted to paternity testing involving daughters). PE is an a priori statistic, in the sense of not depending on the individual's genetic data of a case, being dependent however on the estimates of genetic markers allele (or haplotype) frequencies. We have studied the behaviour of this statistic in situations where the randomness assumption is not met, because either (a) the alleged - and false - father is related to the true one, or (b) there is a non-negligible level of background relatedness in the population. For the first case, we derived general (autosomal and X-chromosomal) PE formulas for duos and trios for any genealogy linking alleged father and child, highlighting that the PE of each marker only depends on a single kinship parameter associated with their pedigree. In this case we also estimate a lower bound for the number of extra markers needed to be analysed to achieve the same global power as for unrelated individuals. In the second situation, we demonstrate that for realistic values of the coancestry coefficient the decrease in PE due to population inbreeding is very moderate even when duos are analysed. In this work, beyond the aforementioned issues, we also discuss the suitability of assuming the pedigree father-daughter for calculating the X-PE, since X-markers are not the tool of choice in laboratorial routine when the alleged father is available for testing. Indeed, X-markers are particularly useful in situations where the alleged father is not available for testing but experts are able to type the mother or a daughter of his. Such increase of power is due to the paternal genealogies: half- and full-sisters, and grandmother-granddaughter, having a non-null X-PE even when only duos are analysed in contrast to what happens for autosomes. Algebraic expressions for these cases are also presented.
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http://dx.doi.org/10.1016/j.fsigen.2012.12.002DOI Listing
February 2013

Comparative evaluation of alternative batteries of genetic markers to complement autosomal STRs in kinship investigations: autosomal indels vs. X-chromosome STRs.

Int J Legal Med 2012 Nov 1;126(6):917-21. Epub 2012 Sep 1.

Institute of Molecular Pathology and Immunology, University of Porto, 4200-465, Porto, Portugal.

Kinship investigations such as paternity are currently solved using sets of (commercially available) highly polymorphic autosomal short tandem repeats (STRs), which lead to powerful likelihood ratios (LR). Still, some difficult cases arise whenever the kinship is much more remote or if the alternative hypotheses are not correctly formulated due to the lack of information (for e.g. there is an unknown relationship between the alleged and the true fathers). In these situations, beyond the routinely used marker set, laboratories usually enlarge the number and/or the type of markers analysed. Among these, autosomal indels and X-chromosome STRs have gained popularity. The aim of this study was to compare the results obtained after complementing an initial set of autosomal STRs with indels or with X-chromosome-specific STRs in simulated paternity cases where the alleged father is a close relative of the real one. Results show that in paternity cases where a low number of incompatibilities are observed, the best strategy is to increase the number of autosomal STRs under analysis. Nevertheless, if these are not available, our study globally shows that in father-daughter duos, a set of 12 X-STRs is more advantageous than 38 highly diverse autosomal biallelic markers. Additionally, the usefulness of X-STRs was also evaluated in cases where only a close relative of the alleged parent (father or mother) is available for testing. For those situations where these markers have the power to exclude, strong LR values are obtained. In the remaining cases, LRs are usually weak and sometimes the results are more likely under the wrong kinship hypothesis.
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http://dx.doi.org/10.1007/s00414-012-0768-5DOI Listing
November 2012

Assessing paternities with inconclusive STR results: The suitability of bi-allelic markers.

Forensic Sci Int Genet 2013 Jan 1;7(1):16-21. Epub 2012 Jun 1.

IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Portugal.

In paternity testing the genetic profiles of the individuals are used to compare the relative likelihoods of the alleged father and the child being related as father/offspring against, usually, being unrelated. In the great majority of the cases, analyses with the widely used sets of short tandem repeat markers (STRs) provide powerful statistical evidence favouring one of the alternative hypotheses. Nevertheless, there are situations where the final statistical result is ambiguous, mostly because the alleged father shows incompatible genotypes at a few loci along with a very high paternity index in the remaining systems. In these cases, the possibility that the alleged father is actually a close relative of the real one (son, father or brother) can reasonably be raised. In such cases, when the statistical evidence obtained is considered as insufficient, the common practice is to extend the set of analysed markers. In this context, many authors have suggested that bi-allelic markers, such as single nucleotide (SNP) or insertion/deletion (Indel) polymorphisms, are markers of choice, as they are incomparably less prone to mutation than STRs. In this work we address the soundness of this claim and the consequences of this strategy, analyzing the a priori odds both for (a) expected number of Mendelian incompatibilities, and (b) expected values for the final likelihood ratios. Moreover, one hundred real pairs of second degree relatives, typed for two sets of markers: 15 STRs plus 38 Indels, were used to simulate paternity testing. Our data show that, for the number of markers commonly considered, the results from an extended battery of SNPs or Indels should be interpreted with caution when relatives are possibly involved.
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http://dx.doi.org/10.1016/j.fsigen.2012.05.002DOI Listing
January 2013

Straightforward inference of ancestry and admixture proportions through ancestry-informative insertion deletion multiplexing.

PLoS One 2012 17;7(1):e29684. Epub 2012 Jan 17.

IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal.

Ancestry-informative markers (AIMs) show high allele frequency divergence between different ancestral or geographically distant populations. These genetic markers are especially useful in inferring the likely ancestral origin of an individual or estimating the apportionment of ancestry components in admixed individuals or populations. The study of AIMs is of great interest in clinical genetics research, particularly to detect and correct for population substructure effects in case-control association studies, but also in population and forensic genetics studies. This work presents a set of 46 ancestry-informative insertion deletion polymorphisms selected to efficiently measure population admixture proportions of four different origins (African, European, East Asian and Native American). All markers are analyzed in short fragments (under 230 basepairs) through a single PCR followed by capillary electrophoresis (CE) allowing a very simple one tube PCR-to-CE approach. HGDP-CEPH diversity panel samples from the four groups, together with Oceanians, were genotyped to evaluate the efficiency of the assay in clustering populations from different continental origins and to establish reference databases. In addition, other populations from diverse geographic origins were tested using the HGDP-CEPH samples as reference data. The results revealed that the AIM-INDEL set developed is highly efficient at inferring the ancestry of individuals and provides good estimates of ancestry proportions at the population level. In conclusion, we have optimized the multiplexed genotyping of 46 AIM-INDELs in a simple and informative assay, enabling a more straightforward alternative to the commonly available AIM-SNP typing methods dependent on complex, multi-step protocols or implementation of large-scale genotyping technologies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029684PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260179PMC
June 2012

A general method to assess the utility of the X-chromosomal markers in kinship testing.

Forensic Sci Int Genet 2012 Mar 17;6(2):198-207. Epub 2011 May 17.

Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Portugal.

In studies involving pedigree reconstruction and kinship estimation, it is acknowledged that some pedigrees have the same algebraic expressions for the joint genotypic probabilities and are, therefore, indistinguishable when considering only genetic information, no matter what the mode of transmission considered. Indeed, although standard forensic practice considers solely unlinked autosomal markers, the existence of pedigrees with the referred theoretical property (that are then said to belong to the same kinship class) is possible when considering any kind of genetic transmission. The research on genetic relatedness has always been linked to the root concept of identity-by-descent (IBD). However, although the basic theoretical core for autosomal transmission has been long formalised, a general method allowing the decision if two pedigrees linking two non-inbred individuals are distinguishable using unlinked autosomal markers along with the respective IBD partitions (and consequently the algebraic expressions for the joint genotypic probabilities) was only recently published. In this work X-chromosomal transmission will be at stake, considering that the analytical framework for X-chromosomal markers has been recently established and the importance of X-chromosome markers for these questions has been steadily growing, particularly in forensics, as a tool both to complement the information given by autosomes in complex kinship testing cases and to differentiate pedigrees belonging to the same autosomal kinship class. Therefore, here it will be presented a formal and mathematically well supported framework where a general counting rule is given, allowing a secure and expeditious decision on the usefulness of typing (unlinked) X-chromosomal markers on pairwise kinship testing involving two non-inbred individuals. Moreover the counting rule now presented allows the derivation of algebraic expressions for the joint genotypic probabilities associated with any pedigree.
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http://dx.doi.org/10.1016/j.fsigen.2011.04.014DOI Listing
March 2012

Identification of species by multiplex analysis of variable-length sequences.

Nucleic Acids Res 2010 Dec 4;38(22):e203. Epub 2010 Oct 4.

Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), R. Dr. Roberto Frias s/n, 4200-465 Porto, Portugal.

The quest for a universal and efficient method of identifying species has been a longstanding challenge in biology. Here, we show that accurate identification of species in all domains of life can be accomplished by multiplex analysis of variable-length sequences containing multiple insertion/deletion variants. The new method, called SPInDel, is able to discriminate 93.3% of eukaryotic species from 18 taxonomic groups. We also demonstrate that the identification of prokaryotic and viral species with numeric profiles of fragment lengths is generally straightforward. A computational platform is presented to facilitate the planning of projects and includes a large data set with nearly 1800 numeric profiles for species in all domains of life (1556 for eukaryotes, 105 for prokaryotes and 130 for viruses). Finally, a SPInDel profiling kit for discrimination of 10 mammalian species was successfully validated on highly processed food products with species mixtures and proved to be easily adaptable to multiple screening procedures routinely used in molecular biology laboratories. These results suggest that SPInDel is a reliable and cost-effective method for broad-spectrum species identification that is appropriate for use in suboptimal samples and is amenable to different high-throughput genotyping platforms without the need for DNA sequencing.
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http://dx.doi.org/10.1093/nar/gkq865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001097PMC
December 2010

General derivation of the sets of pedigrees with the same kinship coefficients.

Hum Hered 2010 19;70(3):194-204. Epub 2010 Aug 19.

Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal. npinto @ ipatimup.pt

Quantification of kinships between two individuals using unlinked autosomal markers rests upon the identity-by-descent (IBD) probabilities among their four alleles at a locus because they determine the algebraic expressions of the joint genotypic probabilities. Nevertheless, some pedigrees share the same IBD probabilities and are therefore indistinguishable using those markers. Examples of these pedigrees were previously described, such as the case of half-siblings, grandparent-grandchild and avuncular, but a general analysis has not been attempted. The aim of this study is to present a systematic and mathematically supported framework where considering unlinked autosomal markers complete sets of indistinguishable pedigrees linking two non-inbred individuals are generally derived. In our work, complete sets of pedigrees with the same IBD partitions are formally established and mathematically treated, considering kinships linking any pair of non-inbred individuals, whether they are related just maternally or paternally, or both. Moreover, general expressions for IBD partitions, and consequently for joint genotypic probabilities, are derived considering a simple counting rule based on two 'atom' pedigrees: parent-child and full-siblings. Besides the theoretical formalization of the problem, the developed framework has potential applications in forensics as well as in breeding strategies design and in conservation studies.
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http://dx.doi.org/10.1159/000316390DOI Listing
January 2011

X-chromosome markers in kinship testing: a generalisation of the IBD approach identifying situations where their contribution is crucial.

Forensic Sci Int Genet 2011 Jan 18;5(1):27-32. Epub 2010 Feb 18.

IPATIMUP, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.

The standard practice of forensic kinship evaluation uses unlinked autosomal markers. However, X-chromosome markers have recently gained recognition as a powerful tool to complement the information provided by autosomes, particularly in complex cases. In this paper, the X-chromosome mode of transmission is addressed in the theoretical identity-by-descent framework. Formulas for the joint genotypic probabilities considering various pedigrees relating two inbred and/or non-inbred individuals are derived. Finally, the importance of X-chromosome markers is highlighted by the fact that, in addition to complementing the autosomal information, X-chromosome transmission allows differential weighting of certain hypotheses regarding pedigrees belonging to the same autosomal class, i.e., pedigrees that are indistinguishable by the use of unlinked autosomal markers. Illustrative examples of common kinship testing are shown.
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http://dx.doi.org/10.1016/j.fsigen.2010.01.011DOI Listing
January 2011

The Karimojong from Uganda: genetic characterization using an X-STR decaplex system.

Forensic Sci Int Genet 2009 Sep 19;3(4):e127-8. Epub 2008 Dec 19.

IPATIMUP, Institute of Pathology and Molecular Immunology, University of Porto, 4200-465 Porto, Portugal.

The Karimojong, an African group from the Karamoja region of Northeast Uganda, were genetically analysed using a decaplex system for X chromosome short tandem repeats (X-STRs). A total of 255 individuals (117 males and 138 females) were genotyped for the following loci: DXS8378, DXS9898, DXS7133, GATA31E08, GATA172D05, DXS7423, DXS6809, DXS7132, DXS9902 and DXS6789. Allele frequencies and parameters for forensic evaluation were calculated for each STR. No association was found between any pairs of loci studied. DXS6789 was the most polymorphic marker in this sample, followed by DXS6809, with gene diversities of 84.79% and 83.94%, respectively. The less discriminating locus observed was DXS7133, with a gene diversity of 39.79%. High overall values of power of discrimination were obtained for female (1 in 1.8 x 10(10)) and male samples (1 in 1.6 x 10(6)), as well as high power of exclusion in father/mother/daughter trios (99.9997%), in father daughter duos (99.9862%) and in half sisters with same father (99.0331%). These results confirm the potential of this 10-plex in parentage testing and in human identification.
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http://dx.doi.org/10.1016/j.fsigen.2008.10.009DOI Listing
September 2009