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Genetic Disorders
Published in Jeremy R. Jass, Understanding Pathology, 2020
This process of crossing-over is now termed recombination, and accounts for much of the variability within species. Further studies have shown that inherited characteristics that are linked must be close together on the chromosome and therefore unlikely to be parted during the process of recombination. The distance between genetic loci on a chromosome is proportional to the recombination frequency expressed as a percentage (known as a centimorgan—named after the discoverer). These insights, for which Morgan received the Nobel prize in physiology and medicine, form the basis of modern gene mapping or positional cloning. Once the position of one gene is known the position of another can be calculated from linkage data. It is interesting to note that this work preceded our understanding of the molecular structure of the gene by five decades.
Human Genetic Variability and Susceptibility to Infectious Diseases
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
In the analysis of complex traits such as infectious diseases, linkage studies designed to locate chromosomal regions containing genes of interest may focus on a few candidate regions or use a genome-wide search. The whole genome approach ensures that all major loci involved in the control of a phenotype are identified and provides the opportunity to discover new major genes (and, consequently, pathophysiologic pathways) that were not previously suspected of contributing to a phenotype. Unlike the analysis of simple monogenic diseases, fine mapping of genes of interest for complex infectious phenotypes cannot be expected from linkage studies. When successful, linkage analyses generally identify regions of about 10–20 centiMorgans (a centiMorgan is a unit of genetic distance that corresponds to about 1,000,000 bases on the human genome) that may contain hundreds of genes. Linkage studies, which are performed on familial data, are classically divided into parametric and nonparametric approaches (8,13).
Molecular Genetic Diagnosis of Human Malignant Hyperthermia
Published in S. Tsuyoshi Ohnishi, Tomoko Ohnishi, Malignant Hyperthermia, 1994
So long as transmission of MH susceptibility in the pedigree is compatible with a single gene disorder, inheritance of the phenotype of interest may be linked to co-inheritance of specific markers. The central concept of linkage analysis is that during meiosis reciprocal exchanges of segments occur between pairs of homologous parental chromosomes (Figure 2). The likelihood of segment exchange, termed recombination or crossing over, increases in correlation to the distance between two loci on a chromosome. The closer together a pair of loci are on the same chromosome, the less will be the chance of crossing over between them. One to six recombinations per chromosome take place during each meiotic division so that the chromosome of the gamete is a hybrid of paternal and maternal segments, each consisting of many genes. The rate of crossing over, measured by the fraction of offspring with recombination between two loci along a chromosome divided by the total number of offspring, is an index of the intervening distance. A recombination fraction (θ) of 0.01 indicates that recombination takes place l% of the time between the two loci. On average a l% chance of a recombination between two loci during a meiotic event represents separation of the two by approximately 1 million base pairs. Referred to as the centiMorgan or cM, this is the standard unit of genetic distance.
Genetic substructure and admixture of Mongolians and Kazakhs inferred from genome-wide array genotyping
Published in Annals of Human Biology, 2020
Jing Zhao, Jin Sun, Ziyang Xia, Guanglin He, Xiaomin Yang, Jianxin Guo, Hui-Zhen Cheng, Yingxiang Li, Song Lin, Tie-Lin Yang, Xi Hu, Hua Du, Peng Cheng, Rong Hu, Gang Chen, Haibing Yuan, Xiu-Fang Zhang, Lan-Hai Wei, Hu-Qin Zhang, Chuan-Chao Wang
We inferred pairwise identity-by-descent (IBD) segments between the individuals using Refined IBD (Browning and Browning 2013). Refined IBD utilises a haplotype dictionary to detect exact short matches between phased haplotypes among individuals and then expands these matches to identify long, nearly identical IBD segments between these individuals (Browning and Browning 2013). Refined IBD then evaluates candidate IBD segments with a probabilistic approach to assess the strength of evidence for IBD and reports the segment above a threshold as IBD segments. We first used PLINK (version 1.90b3w) (Chang et al. 2015) to filtrate genotypes with the missing rate greater than 0.1 and performed shapeit to generate one VCF file per chromosome with a threshold of 10 cM to achieve a very low false-positive rate. We then used the Refined IBD function implemented in Beagle (version 4.1) to phase these genotypes and calculate IBD segments with default parameters except for applying a minimum log odds (LOD) score of 0.5 and a minimum IBD segment length of 1 cM. The length of the IBD segment in centimorgans was computed using recombination maps from HapMap II (build GRCh37/hg19) (provided on the Beagle website: https://faculty.washington.edu/browning/beagle/b4_1.html).
Learning to collaborate: bringing together behavior and quantitative genomics
Published in Journal of Neurogenetics, 2020
Patricka A. Williams-Simon, Mathangi Ganesan, Elizabeth G. King
Mapping the genetic variants contributing to complex traits in general has presented a major challenge due to the difficulty of characterizing the effect of a single variant when there are many other variants also affecting a phenotype and the effects at individual loci are subtle (Boyle, Li, & Pritchard, 2017; Rockman, 2012). If trait categories are viewed as a hierarchy, Garland and Kelly (2006) have argued that behavior is expected to be one of the most complex, because it will be influenced by physiology, morphology, etc. at the lower hierarchical levels, leading to the expectation that the genetic basis of most behaviors will be highly complex. In addition, the processes of learning and memory are themselves the products of many other processes, such as sensory and motor functions, which further argues for their expected complexity (Schultzhaus, Saleem, Iftikhar, & Carney, 2017; Dolan et al., 2019). Early quantitative genetic approaches to map genetic variants used two-way quantitative trait loci (QTL) mapping, in which two parental strains are crossed to create an F1, then the F1s are either crossed to themselves or backcrossed to one of the parents to create an F2 generation. This creates a population with recombination breakpoints at different positions throughout the genome, allowing one to identify the association between the genotype at a given position and the phenotype of interest. However, because the individuals are only crossed for just a few generations, resulting in large haplotype blocks, the resolution for identifying individual genes, rather than regions of the genome is low (Mackay, 2001; Slate, 2004), with mapping regions typically wider than 10 cM (centiMorgans) and encompassing hundreds of genes. This has made it difficult to hone in on candidate genes that are influencing a particular phenotype.
Association of the selenoprotein 15-kDa (SEP15) polymorphisms with cancer risk: a meta-analysis
Published in Nutrition and Cancer, 2020
Noel Pabalan, Phuntila Tharabenjasin, Sitakan Natphopsuk, Niramai Ekaratcharoenchai, Hamdi Jarjanazi
Cancer development has been attributed to genetic and environmental factors in which oxidative stress plays an important role (1). To prevent damage from reactive oxygen species (ROS), cells have developed a defense mechanism where antioxidants restore injuries caused by ROS and control redox-sensitive signaling pathways (2). The role of selenoproteins (SEP) in maintaining redox balance has been investigated (3). SEP has demonstrated antioxidant activity that reduces ROS (2). There are 17 SEP families in humans (4, 5). Some of them have been functionally characterized and correlated to cancer development and/or progression. Evidence for SEP genotype-specific effects in cancer implicates several SEPs that include SEP15, a 15-kDa selenoprotein. The SEP15 protein is found in the endoplasmic reticulum and protects the cell against damages by ROS (6, 7). Evidence suggests that SEP15 is required for apoptosis and that its loss is associated with malignancy (4). The gene for SEP15 (SEP15) is located on human chromosome 1 at 117–123 centiMorgans, consisting of five exons and four introns and found in a locus commonly deleted or mutated in human cancers (8). The polymorphic SEP15 gene exists as two allelic variants differing at positions 811 (rs5845) and 1125 (rs5859) in the cDNA sequence (7) which are in linkage disequilibrium (LD) (3). In these positions, the single nucleotide polymorphisms (SNP) cause a CT and GA substitutions, respectively. The SEP15 gene shows organ-specific expression patterns, high in normal tissue (e.g., liver/prostate) but reduced in the corresponding malignant tissues (9). The polymorphisms of SEP15 gene are related with malignant tumors (10, 11) and shown to correlate with race and cancer type (12). Moreover, the SEP15 gene affects the ability of selenium (at high doses) to induce apoptosis and inhibit uncontrolled cellular proliferation (13). In particular, SNPs in SEP15 genes, alone or together with the selenium status, may influence risk or progression of cancers (3). The rs5845 and rs5859 polymorphisms have been hypothesized to be associated with cancer. This hypothesis has been examined at the primary study level but the outcomes have been inconsistent. Therefore, we test this hypothesis at the meta-analysis level; facilitated by the sufficient number of association studies so that we could obtain a more precise estimate.