Biology:Linkage based QTL mapping
Linkage based QTL mapping is a variant of QTL mapping.
Historical Introduction
Mendel’s experimental results on law of segregation and independent assortment ( presented in 1865 and published in 1866 in the Proceedings of the Brunn Society of Natural History) has led founding stone in genetical studies in plants and humans. The studies were much accelerated after 1900, when Mendel’s law was rediscovered by de Veries, Correns, and von Tschermak-Seysenegg. Morgan demonstrated phenomena of sex linkage in Drosophila in 1910. Subsequently, the idea of gene mapping was first proposed by a 19-year-old college student working in
Linkage Mapping of QTLs involves using linkage behaviour between QTL or major genes with the markers of interest.
Linkage mapping
Based on Morgan's observation that the recombination fraction between two loci increases with the distance between them, Alfred Sturtevant neglected his homework one evening and constructed the first genetic map covering six loci in Drosophila (Sturtevant, 1913).
The statistical foundations of gene mapping were subsequently laid by Haldane, Hogben, Fisher, Penrose, Smith, and Morton (Morton, 1955). Genetic dissection of simple Mendalian and Mendalian-like traits has been greatly enhanced by numerous pioneering contribution of Newton E. Morton over the decades. The same methods are widely used today for investigating and sometime determining genetic basic of complex traits. The lod score method (Morton, 1955), which constitutes the basis of most of linkage studies, has been recognized as pivotal contribution. Unfortunately, linkage analysis in humans, animals and plants languished for more than a half century after Sturtevant's discovery because of the lack of genetic markers and of adequate computing power. By the early 1970s, computing resources were sufficiently widely distributed to stimulate algorithmic breakthroughs in likelihood evaluation on human pedigree data (Elston and Stewart, 1971; Lange and Elston, 1975; Ott, 1976; Cannings et al., 1978). Armed with Ott's computer program LIPED, geneticists were well poised to embark on human linkage studies. Initially the mapping work was limited to some of morphological markers and the speed was quite low. Mapping efforts are speeded by development of DNA markers that provided virtually unlimited supply of genetic markers – an idea first conceived by Botstein and colleagues for yeast crosses (Petes and Botstein, 1977) and subsequently for human families (Botstein et al., 1980). The idea of using markers to map in such families is to trace inheritance of existing human pedigrees as if one had set up crosses in the laboratory. After a decade of first discovery of molecular markers, the very first genome map in plants was reported in maize and tomato (Helentjaris et al., 1986) using RFLP marker in a F2 population. The familial linkage methods were very popular for qualitatively inherited molecular markers and traits of interest in humans, animals and plants. Later on the focus was turned to more complex traits – quantitatively inherited traits with high environmental influence. Such complex traits are affected by both environment and genes.
Study designs for mapping: Experimental Population vs Natural Population
Natural populations include collection of individuals from a natural habitat connected with or without having pedigree. Pedigree data, if available are unmanipulated i.e. not crossed in experimenter’s interest. Pedigree can not be manipulated in human and some of animals and leaves no options of using natural populations including families whatever available in nature (for review: mapping in natural populations by Slate, 2005). QTL analysis in such population is challenging because the number of alleles segregating at the QTL is unknown, the marker phases may be unknown or only partially known, the marker and QTL allele frequencies must be estimated from the data, inbreeding loops may exist in the pedigree, and markers may be noninformative or ungenotyped. Although it is possible to simplify the analysis of complex pedigree data by fragmenting the pedigree into smaller component families, methods that fully account for complex relationships between individuals are expected to provide greater power to detect QTL (Almasy and Blangero 1998). General natural pedigree are analyzed using a mixed effects model in which components of variance (e.g. additive genetic variance, maternal effects, environmental variance) can be estimated from a pedigreed population of individuals of any structure (Slate, 2005. Variance components are usually estimated by restricted maximum-likelihood (REML). Natural population can be further classified into mapping populations consisting of related individuals (family pedigrees) or unrelated populations.
Experimental crosses
The traditional experimental crosses are based on single experimental cross, such as the backcross, F2 or full-sib family, initiated with two different lines. The principle behind genetic mapping that uses an experimental cross is the occurrence of recombination events between genetic loci (measured by the recombination fraction) when gametes are formed and transmitted from parents to offspring. By estimating the recombination fraction between markers and QTLs, the genomic location of the QTL of traits can be determined. QTL mapping in such experimental crosses in fixed effects modeling.
Linkage vs Association
Linkage and association analysis are primary tool for gene discovery, localization and functional analysis. While conceptual underpinning of these approaches have been long known, advances in recent decades in molecular genetics, development in efficient algorithms, and computing power have enabled the large scale application of these methods. While linkage studies seek to identify loci that cosegregate with the trait within families, association studies seek to identify particular variants that are associated with the phenotype at the population level. These are complementary methods that, together, provide means to probe the genome and describe etiology of complex human traits. In linkage studies, we seek to identify the loci that cosegregate with a specific genomic region, tagged by polymorphic markers, within families. In contrast, in association studies, we seek a correlation between a specific genetic variation and trait variation in sample of individuals, implicating a causal role of the variant. Linkage tests are powerful and specific for gene discovery, the localization of locus can be achieved only to a certain level of precision – on order of megabases – that potentially represents a region that potentially include hundreds of genes.
Linkage based QTL mapping software
- MapQTL
- R/qtl
- R/qtl2
- DOQTL
- WinQTL cartographer
See also
QTL mapping
Family based QTL mapping
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