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Determination of genetic relatedness from low-coverage human genome sequences using pedigree simulations.

ABSTRACT: We develop and evaluate methods for inferring relatedness among individuals from low-coverage DNA sequences of their genomes, with particular emphasis on sequences obtained from fossil remains. We suggest the major factors complicating the determination of relatedness among ancient individuals are sequencing depth, the number of overlapping sites, the sequencing error rate and the presence of contamination from present-day genetic sources. We develop a theoretical model that facilitates the exploration of these factors and their relative effects, via measurement of pairwise genetic distances, without calling genotypes, and determine the power to infer relatedness under various scenarios of varying sequencing depth, present-day contamination and sequencing error. The model is validated by a simulation study as well as the analysis of aligned sequences from present-day human genomes. We then apply the method to the recently published genome sequences of ancient Europeans, developing a statistical treatment to determine confidence in assigned relatedness that is, in some cases, more precise than previously reported. As the majority of ancient specimens are from animals, this method would be applicable to investigate kinship in nonhuman remains. The developed software grups (Genetic Relatedness Using Pedigree Simulations) is implemented in Python and freely available.

SUBMITTER: Martin MD

PROVIDER: S-EPMC6485253 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Determination of genetic relatedness from low-coverage human genome sequences using pedigree simulations.

Martin Michael D MD Jay Flora F Castellano Sergi S Slatkin Montgomery M

Molecular ecology 20170707 16

We develop and evaluate methods for inferring relatedness among individuals from low-coverage DNA sequences of their genomes, with particular emphasis on sequences obtained from fossil remains. We suggest the major factors complicating the determination of relatedness among ancient individuals are sequencing depth, the number of overlapping sites, the sequencing error rate and the presence of contamination from present-day genetic sources. We develop a theoretical model that facilitates the expl ...[more]

PMID: 28543951

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Project description:Animal models typically require a known genetic pedigree to estimate quantitative genetic parameters. Here we test whether animal models can alternatively be based on estimates of relatedness derived entirely from molecular marker data. Our case study is the morphology of a wild bird population, for which we report estimates of the genetic variance-covariance matrices (G) of six morphological traits using three methods: the traditional animal model; a molecular marker-based approach to estimate heritability based on Ritland's pairwise regression method; and a new approach using a molecular genealogy arranged in a relatedness matrix (R) to replace the pedigree in an animal model. Using the traditional animal model, we found significant genetic variance for all six traits and positive genetic covariance among traits. The pairwise regression method did not return reliable estimates of quantitative genetic parameters in this population, with estimates of genetic variance and covariance typically being very small or negative. In contrast, we found mixed evidence for the use of the pedigree-free animal model. Similar to the pairwise regression method, the pedigree-free approach performed poorly when the full-rank R matrix based on the molecular genealogy was employed. However, performance improved substantially when we reduced the dimensionality of the R matrix in order to maximize the signal to noise ratio. Using reduced-rank R matrices generated estimates of genetic variance that were much closer to those from the traditional model. Nevertheless, this method was less reliable at estimating covariances, which were often estimated to be negative. Taken together, these results suggest that pedigree-free animal models can recover quantitative genetic information, although the signal remains relatively weak. It remains to be determined whether this problem can be overcome by the use of a more powerful battery of molecular markers and improved methods for reconstructing genealogies.

Project description:Human identification of unknown samples following disaster and mass casualty events is essential, especially to bring closure to family and friends of the deceased. Unfortunately, victim identification is often challenging for forensic investigators as analysis becomes complicated when biological samples are degraded or of poor quality as a result of exposure to harsh environmental factors. Mitochondrial DNA becomes the ideal option for analysis, particularly for determining the origin of the samples. In such events, the estimation of genetic parameters plays an important role in modelling and predicting genetic relatedness and is useful in assigning unknown individuals to an ethnic group. Various techniques exist for the estimation of genetic relatedness, but the use of Machine learning (ML) algorithms are novel and presently the least used in forensic genetic studies. In this study, we investigated the ability of ML algorithms to predict genetic relatedness using hypervariable region I sequences; that were retrieved from the GenBank database for three race groups, namely African, Asian and Caucasian. Four ML classification algorithms; Support vector machines (SVM), Linear discriminant analysis (LDA), Quadratic discriminant analysis (QDA) and Random Forest (RF) were hybridised with one-hot encoding, Principal component analysis (PCA) and Bags of Words (BoW), and were compared for inferring genetic relatedness. The findings from this study on WEKA showed that genetic inferences based on PCA-SVM achieved an overall accuracy of 80-90% and consistently outperformed PCA-LDA, PCA-RF and PCA-QDA, while in Python BoW-PCA-RF achieved 94.4% accuracy which outperformed BoW-PCA-SVM, BoW-PCA-LDA and BoW-PCA-QDA respectively. ML results from the use of WEKA and Python software tools displayed higher accuracies as compared to the Analysis of molecular variance results. Given the results, SVM and RF algorithms are likely to also be useful in other sequence classification applications, making it a promising tool in genetics and forensic science. The study provides evidence that ML can be utilized as a supplementary tool for forensic genetics casework analysis.

Dataset Information

Determination of genetic relatedness from low-coverage human genome sequences using pedigree simulations.

Publications

Determination of genetic relatedness from low-coverage human genome sequences using pedigree simulations.

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