Biological Sciences
Linkage
In genetics, linkage refers to the tendency of genes that are located close together on a chromosome to be inherited together. This occurs because these genes are physically linked and are less likely to be separated during the process of genetic recombination. Linkage plays a crucial role in understanding inheritance patterns and genetic diversity.
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9 Key excerpts on "Linkage"
eBook - PDF- Tomar, Arun Kumar(Authors)
- 2021(Publication Date)
- Daya Publishing House(Publisher)
The probability of crossing over between very closely linked loci is increased with higher numbers of progeny produced. Therefore, Linkage is not important in farm animals compared to that in fruit fly. This is one of the problems associated with Linkage studies of genes closely located. 5.7 CHROMOSOME MAPPING The genes are located on chromosomes in a linear arrangement having their fixed relative position on the chromosome. The genetic map (or chromosome map), known as chromosome mapping, is the graphical representation of genes on the chromosome indicating distance of genes between loci and their relative position from each other in each Linkage group. The distance of genes indicates the map distance that how far the two genes are located on the chromosome while the relative position of genes indicates the gene order (sequence of genes) on the chromosome. The map distance (distance between genes) is represented in percentage of cross over (recombination) between loci along the chromosome. This is because the amount of crossing over, (percentage of crossover progeny produced), is proportional to the distance between two loci on a chromosome. This is based on the hypothesis formulated by Sturtevant (1913) that each gene has a definite position (locus) on its chromosome and the place for occurrence of chiasma (synapsis or pairing of chromosome for occurrence of crossing over) is a matter of chance and hence the frequency of crossover is proportional to the linear distance between genes on the chromosome. He thus suggested that the percentage of crossover can be used as a quantitative index of the gene distance on the chromosome. This helped in chromosome This ebook is exclusively for this university only. Cannot be resold/distributed. mapping. Thus, map distance is measured from the frequency of crossovers obtained either from test cross or F 2 data. The map distance is measured in map units (anti Morgan).
eBook - PDFStatistical Genetics
Gene Mapping Through Linkage and Association
- Benjamin Neale, Manuel Ferreira, Sarah Medland, Danielle Posthuma, Benjamin Neale, Manuel Ferreira, Sarah Medland, Danielle Posthuma(Authors)
- 2007(Publication Date)
- Taylor & Francis(Publisher)
Principles of Linkage analysis Dale R. Nyholt Variation in most human traits and diseases is now viewed as having some genetic component, and considerable effort is being made to find and study the genes involved. However, in most human inherited diseases, the biochemical defects are unknown. In other words, the gene or genes causing the disease as well as their location are not known. This situation requires genomic screening to localize the gene of interest, a process known as positional cloning, a type of gene mapping, and has been used to isolate genes for many diseases, including Huntington’s disease (Gusella et al., 1980, 1983), Duchenne muscular dystrophy (Koenig et al., 1987), cystic fibrosis (Kerem et al., 1989; Riordan et al., 1989; Rommens et al., 1989) and neurofibromatosis type -1 (Xu et al., 1990). These disorders are known as Mendelian diseases and largely stem from a single, highly penetrant gene effect resulting in characteristic and well-defined transmission. This chapter begins with a conceptual introduction to Linkage analysis (Section 7.1). Following this, we focus on the two major groups of Linkage statistics, ‘model-based’ (also termed ‘parametric’, in Section 7.2) and ‘model-free’ (also termed ‘nonparametric’, in Section 7.3) methods for the analysis of affection traits. Specific model-free methods for quantitative traits are detailed in subsequent chapters (see Chapters 9-12). The final section (7.4) of this chapter provides a brief overview of how to estimate Linkage significance empirically, rather then relying on asymptotic theory for which the underlying assumptions are often not met in Linkage analysis. 7.1 Gene Mapping The goal of gene mapping is to localize and identify genetic vari ants that regulate a trait of interest. Initial localization of genetic variants can be achieved by genetic Linkage studies, whereas iden tification typically relies on association and functional analyses.
eBook - PDF- William K. Scott, Marylyn D. Ritchie, William K. Scott, Marylyn D. Ritchie(Authors)
- 2021(Publication Date)
- Wiley-Blackwell(Publisher)
105 Genetic Analysis of Complex Diseases , Third Edition. Edited by William K. Scott and Marylyn D. Ritchie. © 2022 John Wiley & Sons, Inc. Published 2022 by John Wiley & Sons, Inc. 6 As discussed in Chapter 2, genes located near each other tend to be transmitted together to offspring. When there is variation at both of the genes, i.e. at least one parent is heterozygous at both loci (a double heterozygote), it is possible to track the cosegregation of the specific alleles through the pedigree. If we know the location of one of the genes, we can use this to determine the location (or map) the other gene; this latter gene is typically one that gives rise to a disease pheno-type. This concept is known as Linkage analysis. While disease gene mapping in humans is rela-tively recent, T. H. Morgan mapped several phenotypes in Drosophila melanogaster as early as 1911 (Morgan 1911). The possibility of a genetic map was first formally investigated by A. H. Sturtevant, who ordered five markers on the X chromosome in Drosophila and then estimated the relative spacing among them (Sturtevant 1921). In its simplest form, Linkage analysis involves the counting of the number of recombinant and nonrecombinant chromosomes and comparing the distribution to that expected under random assortment (Table 6.1). In experimental organisms, the mating types can be dictated, which allows for greater control. When studying diseases in humans, this is, of course, not possible. Therefore, maps of markers in humans have been developed by means of one of several statistical algorithms used in computer programs such as CRIMAP and MAPMAKER (Lander and Green 1987), CLinkage and MULTIMAP (Matise et al. 1994), and MAP-O-MAT (Matise and Gitlin 1999).
eBook - PDF- Srinivas Aluru(Author)
- 2005(Publication Date)
- Chapman and Hall/CRC(Publisher)
There is a an edge i → m from individual i to mating m , if i is one of the two participants in the mating. There is an edge m → c , if c is a child produced by the mating. Marriage graphs are often drawn with the directions on edges implicit from top to bottom because the undirected version has some utility as well. Genetic Linkage analysis attempts to compute statistical measures of cosegregation of known marker alleles and putative disease alleles, inferred from the phenotype and pen-etrance function. As explained in the next section, when such cosegregation is deemed significant, then one may conclude that the putative disease gene is close to the cosegregat-ing marker. Therefore, if one knows the precise chromosomal location of the marker, one may infer an approximate location for the nearby disease gene. In general, one may use more than a single marker within a Linkage analysis calculation. Using multiple markers simultaneously can lead to more convincing statistical proof of Linkage and in some cases to proof that the gene is likely to lie in between two markers. The first major distinction between Linkage analysis and association analysis is illustrated by the multiple founders with the allele 1 in Figure 17.1. Linkage analysis looks for the co-inheritance of the allele along paths, while association analysis looks for co-occurrence of the allele. The second major distinction between Linkage analysis and association analysis can be understood intuitively by imagining that one has two pedigrees with the structure of Figure 17.1, except that in the second copy the alleles 1 and 2 are swapped. In Linkage analysis, one treats the separate pedigrees separately, so that if marker alleles 1 and 2 were swapped in the second pedigree, both pedigrees would still be indicative of Linkage. In association analysis, one is interested in the co-occurrence of a specific marker allele with the disease allele across affected individuals.
eBook - PDFAn Introduction to Genetics for Language Scientists
Current Concepts, Methods, and Findings
- Dan Dediu(Author)
- 2015(Publication Date)
- Cambridge University Press(Publisher)
chromosome for the second locus and allele b on the other, but not necessarily that alleles A and B are on the same chromosome and a and b on the other (i.e., the two-locus genotype AaBb can correspond to AB ab or Ab aB ) where first row denotes the maternal and the second the paternal chromosomes. 5.2 Using Linkage disequilibrium 93 By studying the probability of recombination between pairs of loci it is pos- sible to build genetic maps representing the linear relationships between loci on the same chromosome. Moreover, by using physical landmarks on the chromo- some (such as bands visible under a microscope), one can place loci in actual physical space, ultimately pinpointing the precise location of a gene on the chromosome in terms of the number of nucleotides (or basepairs, bp, and mul- tiples such as thousand basepairs, kb, and millions of basepairs, Mb) from a conventional landmark (such as one end of the chromosome; for details see, for example, Snustad and Simmons, 2010, pp. 146–156). From this discussion it should be clear that there is a close relationship between Linkage (probability of recombination) and physical distance between two loci on the same chromosome. However, this relationship is far from sim- ple and linear: on average, 1 cM corresponds to about 1 Mb (one million basepairs) in humans, but there is huge variation in the actual relationship along the chromosomes. There are “hot” and “cold” spots which represent regions on the chromosomes where recombination happens orders of mag- nitude more (or less) often than the average (Hey, 2004). Interestingly, the location of these hotspots is partly under genetic control and a recently iden- tified gene, PRDM9, seems to be involved in the sense that the protein it produces binds to patterns of DNA nucleotides and marks that location as a hotspot (Berg et al., 2010; Parvanov et al., 2010; Baudat et al., 2010).
eBook - PDF- W Paul Vogt(Author)
- 2011(Publication Date)
- SAGE Publications Ltd(Publisher)
Thus, at a funda-mental level, associations studies are a sort of Linkage analysis performed on one or more huge pedigrees. Figure 11 illustrates the origin of Linkage disequilibrium. In the figure, the original mutation is indicated in black and the rest of the ancestral chro-mosome is indicated in grey. The putative allele first appeared in a population through mutation or migration. Over generations, the Linkage disequilibrium in the ancestral chromosome tends to decay; that is, the flanking stretches of ancestral haplotypes tend to become shorter and shorter. The rate of the decay in Linkage disequilibrium is a function of generation t and recombination rate r between markers as described in the equation D = (1 − r ) t D 0 . The con-temporary individuals who carry the mutant alleles (Figure 11) will also carry segments of the ancestral chromosome (grey) that is adjacent to the mutant alleles. However, the DNA segments tend to be small. It is generally accepted that the segments do not extend beyond tens to hundreds of kilo-bases (kb; thousands of base pairs) as compared with the much wider seg-ments of DNA (thousands of kb) considered in Linkage analysis. Association studies are often considered more attractive than Linkage analy-sis for mapping complex phenotypes in recent years because of superior statis-tical power. Association studies are thought particularly promising for detecting Guo and Adkins Linking Human Outcomes and Genetic Variants 261 Figure 11: Origin of Linkage disequilibrium associations between common genetic variants and common diseases (Cardon and Abecasis 2003; Risch and Merikangas 1996). More recently, whole genomewide association studies have increasingly become the focus of attention. Genomewide association studies aim at a near “thorough” survey of all known human genetic variants.
- Cavan Reilly(Author)
- 2009(Publication Date)
- Chapman and Hall/CRC(Publisher)
CHAPTER 4 Basic Linkage Analysis 4.1 Production of gametes and data for genetic mapping In order to understand the basis for genetic mapping of disease, we need to consider the events that take place during meiosis , the formation of sex cells, also referred to as gametes . Sex cells (i.e. egg and sperm cells), unlike other cells in the body (referred to as somatic cells ) only carry one copy of each chromosome, either the mother’s or father’s. Meiosis starts when a cell carrying 2 copies of each gene duplicates all of the chromosomes in the genome. Once the chromosomes have been duplicated, the cell divides into 2 cells with 2 copies of each chromosome. Then these 2 cells both divide one more time, resulting in 4 cells with 1 copy of each chromosome. Each of these 4 cells has a mix of chromosomes from the 2 parental sources so that each chromosome is equally likely to be found in the resulting 4 cells. When 2 sex cells fuse, the result then has a pair of chromosomes. During meiosis, after all the DNA is duplicated, the chromosomes with the same number but from the different parental sources pair up and at certain random loca-tions on the chromosomes contact one another. When the chromosomes touch (which is known as a crossover ), they exchange segments of DNA, thereby creating a pair of chromosomes which are distinct from either of the progenitor chromosomes. This process is called recombination , and was first observed in the early twentieth century. The process of recombination is thought to be driven by chromosomal breakage: a break in one chromosome is repaired by using the other chromosome in the pair as a template, and this results in copying DNA from one chromosome to the other in a pair.
eBook - ePub- Milo Keynes, A. W. F. Edwards, Robert Peel(Authors)
- 2004(Publication Date)
- CRC Press(Publisher)
Success of major locus Linkage revolutionised human genetics. By localising genes to a small interval, typically no more than a few centimorgans (cM), it led to gene identification, cloning, and sequencing. This positional cloning underlies molecular biology and provides clinical genetics with precise tools for diagnosis of cases and carriers. Then, by creating the first connected maps of human chromosomes and demonstrating their utility, major locus Linkage led to the Human Genome Project, the goal of which is to sequence not only genes revealed by Linkage, but the whole genome. Although, at present, still in draft for most chromosomes, with thousands of gaps and sequence errors, the draft is evolving towards the final map that will guide the next century of Mendelism.Linkage of Oligogenes
Oligogenes, whether rare or common, have low penetrance and only microphenic effects on liability or a quantitative trait (i.e., less than 1 standard deviation). Identification is not hopeless, but the methods that have been so successful with major genes gave disappointing results until the end of the last century. Human geneticists disagree about whether the problem is with the methods or the way they have been applied. Computer programs for multilocus Linkage analysis assume that segregation parameters (frequency of the linked gene, dominance, penetrance in different liability classes, and residual variability due to other loci and family environment) have been determined by analysis that makes appropriate allowance for ascertainment. Given successful analysis, tests on major loci are robust to selection through multiple affected. Although feasible for major genes, prior segregation analysis gives ambiguous results for the small effects of oligogenes. Combined segregation and Linkage analysis is more promising, but so far it is limited to single markers and/or random ascertainment (Shields et al., 1994; Guo and Thompson, 1992). Until these limitations are overcome, human genetics is dependent on weakly parametric methods that summarise the genetic model by variance components and identity by descent (IBD) without separating gene frequency and effect and, therefore, with no possibility of modelling ascertainment through affection status. The current literature is full of controversy about whether means, variances, and correlations should be defined on random samples, selected families, or a medley, and the evidence comes from arbitrary simulation, unsupported by genetic probabilities under a realistic ascertainment model. In partial compensation, weakly parametric methods can be applied to extremely nonrandom sampling of affected relatives for which no ascertainment measure has been devised, although there are solutions when all unaffected sibs are included but not necessarily typed (Morton et al., 1991).
eBook - PDFIntroducing Genetics
From Mendel to Molecules
- Alison Thomas(Author)
- 2014(Publication Date)
- Garland Science(Publisher)
It is estimated that the human genome possesses approximately 21,000 genes. These are distributed between just 23 different chromosomes. A major goal of genetics during the early twenty-first century is to map (i.e. determine) the precise chromosomal position of all the human genes, as well as those of many other species. Mapping genes has become a sophisticated molecular process. However, traditional Mendelian analysis has been, and continues to be, a useful tool in the initial stages; the results of controlled genetic crosses are used to produce preliminary or outline maps . These show which of an organism’s genes are gathered together on a particular chromosome and their approximate positions relative to each other. Molecular analysis is then used to precisely locate these genes. This chapter describes the contribution made to chromosomal mapping by Mendelian genetics, in particular how: • Distinctive dihybrid phenotypic ratios can indicate when two genes are located on the same chromosome. Linkage and Chromosome Mapping 7 CHAPTER 94 CHAPTER 7 Linkage and Chromosome Mapping 7.1 Linkage and recombination In the late 1900s, Thomas Morgan (Box 7.1) was studying the inheritance of vestigial wings and purple eye color in the fruit fly, Drosophila melanogaster . The results of one of his crosses is shown in Figure 7.1. Morgan had used the standard Mendelian technique of crossing male and female flies that were pure breeding for the two pairs of contrasting characters (i.e. red-eyed, normal winged with purple-eyed, vestigial winged) to generate a F 1 generation (Figure 7.1). Among the various crosses that he then performed was a backcross of the F 1 flies to the double-mutant parent. Morgan obtained an unexpected result. He had expected to obtain all possible pairs of characters (i.e. red-eyed, normal; red-eyed, vesti-gial winged; purple-eyed, normal winged; and purple-eyed, vestigial winged) in equal proportions (this was a test cross, see Section 4.2).
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