-
Nature Reviews. Genetics Aug 2018Advancing from statistical associations of complex traits with genetic markers to understanding the functional genetic variants that influence traits is often a complex... (Review)
Review
Advancing from statistical associations of complex traits with genetic markers to understanding the functional genetic variants that influence traits is often a complex process. Fine-mapping can select and prioritize genetic variants for further study, yet the multitude of analytical strategies and study designs makes it challenging to choose an optimal approach. We review the strengths and weaknesses of different fine-mapping approaches, emphasizing the main factors that affect performance. Topics include interpreting results from genome-wide association studies (GWAS), the role of linkage disequilibrium, statistical fine-mapping approaches, trans-ethnic studies, genomic annotation and data integration, and other analysis and design issues.
Topics: Alleles; Chromosome Mapping; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Polymorphism, Single Nucleotide
PubMed: 29844615
DOI: 10.1038/s41576-018-0016-z -
Genes Dec 2021In recent years, optical genome mapping (OGM) has developed into a highly promising method of detecting large-scale structural variants in human genomes. It is capable...
In recent years, optical genome mapping (OGM) has developed into a highly promising method of detecting large-scale structural variants in human genomes. It is capable of detecting structural variants considered difficult to detect by other current methods. Hence, it promises to be feasible as a first-line diagnostic tool, permitting insight into a new realm of previously unknown variants. However, due to its novelty, little experience with OGM is available to infer best practices for its application or to clarify which features cannot be detected. In this study, we used the Saphyr system (Bionano Genomics, San Diego, CA, USA), to explore its capabilities in human genetic diagnostics. To this end, we tested 14 DNA samples to confirm a total of 14 different structural or numerical chromosomal variants originally detected by other means, namely, deletions, duplications, inversions, trisomies, and a translocation. Overall, 12 variants could be confirmed; one deletion and one inversion could not. The prerequisites for detection of similar variants were explored by reviewing the OGM data of 54 samples analyzed in our laboratory. Limitations, some owing to the novelty of the method and some inherent to it, were described. Finally, we tested the successful application of OGM in routine diagnostics and described some of the challenges that merit consideration when utilizing OGM as a diagnostic tool.
Topics: Chromosome Aberrations; Chromosome Disorders; Chromosome Mapping; DNA Copy Number Variations; Female; Genome, Human; Humans; Karyotyping; Male
PubMed: 34946907
DOI: 10.3390/genes12121958 -
Nature Neuroscience Dec 2015Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many... (Review)
Review
Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many common variants located primarily in regulatory regions of the genome. Understanding precisely how these variants contribute to disease will require a deeper appreciation for the mechanisms of gene regulation in the developing and adult human brain. The PsychENCODE project aims to produce a public resource of multidimensional genomic data using tissue- and cell type–specific samples from approximately 1,000 phenotypically well-characterized, high-quality healthy and disease-affected human post-mortem brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems. We are beginning with a focus on autism spectrum disorder, bipolar disorder and schizophrenia, and expect that this knowledge will apply to a wide variety of psychiatric disorders. This paper outlines the motivation and design of PsychENCODE.
Topics: Animals; Brain; Chromosome Mapping; Epigenesis, Genetic; Genetic Code; Humans; Mental Disorders; Transcriptome
PubMed: 26605881
DOI: 10.1038/nn.4156 -
GigaScience 2015Optical Mapping is an established single-molecule, whole-genome analysis system, which has been used to gain a comprehensive understanding of genomic structure and to... (Review)
Review
Optical Mapping is an established single-molecule, whole-genome analysis system, which has been used to gain a comprehensive understanding of genomic structure and to study structural variation of complex genomes. A critical component of Optical Mapping system is the image processing module, which extracts single molecule restriction maps from image datasets of immobilized, restriction digested and fluorescently stained large DNA molecules. In this review, we describe robust and efficient image processing techniques to process these massive datasets and extract accurate restriction maps in the presence of noise, ambiguity and confounding artifacts. We also highlight a few applications of the Optical Mapping system.
Topics: Animals; Chromosome Mapping; Genome; Humans; Image Processing, Computer-Assisted; Sensitivity and Specificity
PubMed: 26617984
DOI: 10.1186/s13742-015-0096-z -
Heredity Mar 2023Map distance is one of the key measures in genetics and indicates the expected number of crossovers between two loci. Map distance is estimated from the observed...
Map distance is one of the key measures in genetics and indicates the expected number of crossovers between two loci. Map distance is estimated from the observed recombination frequency using mapping functions, the most widely used of those, Haldane and Kosambi, being developed at the time when the number of markers was low and unobserved crossovers had a substantial effect on the recombination fractions. In contemporary high-density marker data, the probability of multiple crossovers between adjacent loci is negligible and different mapping functions yield the same result, that is, the recombination frequency between adjacent loci is equal to the map distance in Morgans. However, high-density linkage maps contain an interpretation problem: the map distance over a long interval is additive and its association with recombination frequency is not defined. Here, we demonstrate with high-density linkage maps from humans and stickleback fishes that the inverses of Haldane's and Kosambi's mapping functions systematically underpredict recombination frequencies from map distance. To remedy this, we formulate a piecewise function that yields more accurate predictions of recombination frequency from map distance. Our results demonstrate that the association between map distance and recombination frequency is context-dependent and without a universal solution.
Topics: Humans; Recombination, Genetic; Chromosome Mapping; Probability; Genetic Linkage
PubMed: 36566319
DOI: 10.1038/s41437-022-00585-3 -
PeerJ 2022Bulked segregant analysis implemented in MutMap and QTL-seq is a powerful and efficient method to identify loci contributing to important phenotypic traits. However, the...
SUMMARY
Bulked segregant analysis implemented in MutMap and QTL-seq is a powerful and efficient method to identify loci contributing to important phenotypic traits. However, the previous pipelines were not user-friendly to install and run. Here, we describe new pipelines for MutMap and QTL-seq. These updated pipelines are approximately 5-8 times faster than the previous pipeline, are easier for novice users to use, and can be easily installed through bioconda with all dependencies.
AVAILABILITY
The new pipelines of MutMap and QTL-seq are written in Python and can be installed via bioconda. The source code and manuals are available online (MutMap: https://github.com/YuSugihara/MutMap, QTL-seq: https://github.com/YuSugihara/QTL-seq).
Topics: Quantitative Trait Loci; Chromosome Mapping; Phenotype; Software
PubMed: 35321412
DOI: 10.7717/peerj.13170 -
Genome Research Dec 1995Random subcloning strategies are commonly employed for analyzing pieces of DNA that are too large for direct analysis. Such strategies are applicable to gene finding,...
Random subcloning strategies are commonly employed for analyzing pieces of DNA that are too large for direct analysis. Such strategies are applicable to gene finding, physical mapping, and DNA sequencing. Random subcloning refers to the generation of many small, directly analyzable fragments of DNA that represent random fragments of a larger whole, such as a genome. Following analysis of these fragments, a map or sequence of the original target may be reconstructed. Mathematical modeling is useful in planning such strategies and in providing a reference for their evaluation, both during execution and following completion. The statistical theory necessary for constructing these models has been developed independently over the last century. This paper brings this theory together into a statistical model for random subcloning strategies. This mathematical model retains its utility even at high subclone redundancies, which are necessary for project completion. The discussion here centers on shotgun sequencing, a random subcloning strategy envisioned as the method of choice for sequencing the human genome.
Topics: Chromosome Mapping; Cloning, Molecular; Computer Simulation; Models, Genetic; Models, Statistical; Monte Carlo Method; Sequence Analysis, DNA
PubMed: 8808467
DOI: 10.1101/gr.5.5.464 -
Journal of Genetics 2012Most traits of interest to medical, agricultural and animal scientists show continuous variation and complex mode of inheritance. DNA-based markers are being deployed to... (Review)
Review
Most traits of interest to medical, agricultural and animal scientists show continuous variation and complex mode of inheritance. DNA-based markers are being deployed to analyse such complex traits, that are known as quantitative trait loci (QTL). In conventional QTL analysis, F2, backcross populations, recombinant inbred lines, backcross inbred lines and double haploids from biparental crosses are commonly used. Introgression lines and near isogenic lines are also being used for QTL analysis. However, such populations have major limitations like predominantly relying on the recombination events taking place in the F1 generation and mapping of only the allelic pairs present in the two parents. The second generation mapping resources like association mapping, nested association mapping and multiparent intercross populations potentially address the major limitations of available mapping resources. The potential of multiparent intercross populations in gene mapping has been discussed here. In such populations both linkage and association analysis can be conductted without encountering the limitations of structured populations. In such populations, larger genetic variation in the germplasm is accessed and various allelic and cytoplasmic interactions are assessed. For all practical purposes, across crop species, use of eight founders and a fixed population of 1000 individuals are most appropriate. Limitations with multiparent intercross populations are that they require longer time and more resource to be generated and they are likely to show extensive segregation for developmental traits, limiting their use in the analysis of complex traits. However, multiparent intercross population resources are likely to bring a paradigm shift towards QTL analysis in plant species.
Topics: Chromosome Mapping; Crosses, Genetic; Genetic Linkage; Genetics, Population; Quantitative Trait, Heritable
PubMed: 22546834
DOI: 10.1007/s12041-012-0144-8 -
The Plant Cell Aug 2009The goal of many plant scientists' research is to explain natural phenotypic variation in terms of simple changes in DNA sequence. Traditionally, linkage mapping has... (Review)
Review
The goal of many plant scientists' research is to explain natural phenotypic variation in terms of simple changes in DNA sequence. Traditionally, linkage mapping has been the most commonly employed method to reach this goal: experimental crosses are made to generate a family with known relatedness, and attempts are made to identify cosegregation of genetic markers and phenotypes within this family. In vertebrate systems, association mapping (also known as linkage disequilibrium mapping) is increasingly being adopted as the mapping method of choice. Association mapping involves searching for genotype-phenotype correlations in unrelated individuals and often is more rapid and cost-effective than traditional linkage mapping. We emphasize here that linkage and association mapping are complementary approaches and are more similar than is often assumed. Unlike in vertebrates, where controlled crosses can be expensive or impossible (e.g., in humans), the plant scientific community can exploit the advantages of both controlled crosses and association mapping to increase statistical power and mapping resolution. While the time and money required for the collection of genotype data were critical considerations in the past, the increasing availability of inexpensive DNA sequencing and genotyping methods should prompt researchers to shift their attention to experimental design. This review provides thoughts on finding the optimal experimental mix of association mapping using unrelated individuals and controlled crosses to identify the genes underlying phenotypic variation.
Topics: Animals; Chromosome Mapping; Genotype; Humans; Phenotype; Research Design
PubMed: 19654263
DOI: 10.1105/tpc.109.068437 -
Arthritis Research & Therapy Feb 2011Genomewide association studies (GWAS) have proven a powerful hypothesis-free method to identify common disease-associated variants. Even quite large GWAS, however, have... (Review)
Review
Genomewide association studies (GWAS) have proven a powerful hypothesis-free method to identify common disease-associated variants. Even quite large GWAS, however, have only at best identified moderate proportions of the genetic variants contributing to disease heritability. To provide cost-effective genotyping of common and rare variants to map the remaining heritability and to fine-map established loci, the Immunochip Consortium has developed a 200,000 SNP chip that has been produced in very large numbers for a fraction of the cost of GWAS chips. This chip provides a powerful tool for immunogenetics gene mapping.
Topics: Chromosome Mapping; Genome-Wide Association Study; Humans; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide
PubMed: 21345260
DOI: 10.1186/ar3204