Defining genetic changes associated with cutaneous malignant melanoma
J. K. Cowell in Molecular Genetics of Cancer, 2003
The purpose of linkage analysis is to evaluate the cosegregation of alleles at a particular locus with disease within families; that is, one examines the tendency for alleles, which are close to each other on the same chromosome to be transmitted together. Genetic linkage analysis requires identification and collection of individuals with histopathologically verified melanoma from melanoma-prone families and typing polymorphic markers at a chosen interval throughout the genome to identify the chromosomal locations of genes predisposing individuals to melanoma. The linkage of a putative disease locus and a marker locus is evaluated by measuring the number of recombination events between them with the recombination fraction (θ), which is the probability of an exchange of genetic material, i.e., cross-over between two loci. Linkage is often measured in terms of a LOD score, defined as the log10 of the ratio of two likelihoods: the (relative) probability of observing a given sibship at some particular recombination value relative to the probability of the family given no linkage.
Inflammatory bowel disease
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
To determine the IBD-associated susceptibility genes, investigators originally used two main types of genetic studies, namely, genetic linkage and candidate-gene association studies. Genetic linkage involves the study of the inheritance patterns of polymorphic genetic markers in families with multiple affected relatives. This approach led to the identification of at least nine disease loci designated IBD1–9 (Table 34.1); however, only five of these loci (IBD1, 2, and 4–6) showed significant linkage (LOD score >3.6 or P < 2.2 × 10−5), with little replication across the scans. Such linkage studies supported the polygenic basis of these disorders and predicted future observations—to be discussed later—showing that IBD probably results from the minor effects of a large number of genetic variants in a given individual. However, some genetic loci were unique and observed to contribute significant statistical risk for the development of IBD. One genetic locus that is worthy of being highlighted and was in fact the first genetic region to be identified was found within the pericentromeric region of chromosome 16. This locus was named IBD1 and was later shown to contain NOD2 (nucleotide-binding oligomerization domain-containing 2), also known as caspase recruitment domain protein 15 (CARD15), the first susceptibility gene for Crohn's disease, but not ulcerative colitis.
Introductory Remarks
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Linkage is the tendency for genes and other genetic markers to be inherited together in a nearby location on the same chromosome. Linkage analysis searches for chromosomal segments that cosegregate with the disease phenotype through families. In parametric (or model-based) linkage analysis (if the relationship between phenotypic and genetic similarity is known), the probability that a gene important for a disease is linked to a genetic marker is estimated through the LOD (logarithm [base 10] of odds) score, with a LOD score of 3 or more being an indicator that the two loci are linked and are close to one another. In non-parametric (model-free) linkage analysis, the probability of an allele being identical is evaluated without particular model assumptions. Both parametric and nonparametric linkage analyses are useful for detecting regions of the genome harboring high penetrance risk variants [12,13].
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
On the other hand, non-candidate gene approaches begin with a particular trait or phenotype and try to identify genes that are associated with it. Included in these approaches are genome-wide association studies (GWAS), genetic linkage analyses and so on. Genetic variants implicated by these studies are supported by robust statistical power and reproducibility. But most importantly, these studies enable the identification of previously unknown culprit genes [14]. A GWAS is a phenotype-first approach study where DNA of many individuals with and without a particular trait are analyzed and single-nucleotide polymorphisms (SNPs) that are associated with the trait are identified by statistical techniques [18]. Genetic linkage is phenomenon wherein genes physically located near each other on a chromosome are inherited together during meiosis. Linkage analyses are genetic association studies whereby culprit genes for a given condition are localized due to genetic linkage, i.e. due to their co-segregation with genes responsible for easily identifiable traits that tend to be inherited with the condition under consideration [19]. Like GWAS, these studies have been used to identify genes and DNA segments that were previously never implicated in the causation of a given condition. Beyond understanding the pathophysiology of arrhythmias, various genetic analyses have helped us unravel the molecular mechanisms of normal cardiac electrophysiologic function [14]. (Figure 1)
A diversity outbred F1 mouse model identifies host-intrinsic genetic regulators of response to immune checkpoint inhibitors
Published in OncoImmunology, 2022
Justin B. Hackett, James E. Glassbrook, Maria C. Muñiz, Madeline Bross, Abigail Fielder, Gregory Dyson, Nasrin Movahhedin, Jennifer McCasland, Claire McCarthy-Leo, Heather M. Gibson
To perform a GWAS, we selected tumor latency as the phenotype representing response to ICI. As described above, tumor latency is defined by the time (in days) for a tumor to reach a volume of 150 mm3 (Figure 2(a)). Genotyping was performed via GigaMUGA, and haplotype reconstruction and GWAS was performed using the R/qtl2 package.15,16 Genetic linkage analysis identifies peaks on Chr 2, 7, 13, and 14 with logarithm of odds (LOD) scores (an adjusted measurement of significance) greater than 6, with the strongest association in Chr13 (Figure 3(a)). Importantly, we did not detect a correlation of the proportion of host B6 genome to tumor latency (Figure 3(b)), suggesting variation in response does not result from “degree of foreignness” of the tumor. Similarly, the proportion of the other seven contributing host founder strains also lacked correlation to tumor latency (Fig. S3).
A family of fuchs endothelial corneal dystrophy and anterior polar cataract with an analysis of whole exome sequencing
Published in Ophthalmic Genetics, 2020
Xue Jiang, Xin Jin, Nan Zhang, Hong Zhang
Based on the above analysis, it was speculated that this rare phenotype was caused by the common variation shared by two sub-pedigrees. The intersection of 01, 02, and 03 was the key genes, which had 83 genes in total in this family. WES data were shown on Supplementary data. No interval with LOD greater than 2 was found in genome-wide linkage analysis (Multipoint parametric or nonparametric linkage analysis) (Supplementary data).After further data filtering, 2 rare genes (2 variants) were shared in six patients (Table 5). The remaining members of the family (II-1, II-11, II-12, II-13, III-1, III-2, III-3, III-5, III-6, IV-1, IV-2, IV-3, IV-5, V-1) went through Sanger sequencing after PCR. However, it was not found that the variations were co-segregated with the rare clinical phenotype. The sequence chromatograms were shown in Figure 1h. According to the results, no TMCO3 (Chen P et al.) or other known genes leading to FECD were found, indicating that there may be a new gene or locus leading to this rare phenotype in the non-coding sequence of the genome.
Related Knowledge Centers
- Chromatid
- Chromosomal Crossover
- Genetic Marker
- Penetrance
- Sexual Reproduction
- Meiosis
- Genetic Recombination
- Nucleic Acid Sequence
- Chromosome
- Gene