So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

It has been suggested that map information for molecular markers can be used to strengthen finterprinting analyses. The success of this strategy depends on the distribution of linkage disequilibrium over the genome. Using 451 mapped AFLP markers, we investigated the occurrence of linkage disequilibrium in nine sugar beet breeding lines. A low but significant level of linkage disequilibrium was found for unlinked markers. Only for very tigthly linked (<3 cM) markers was this level substantially higher. This implies that little is gained in utilising the map position of the markers in fingerprinting applications.

Linkage disequilibrium and fingerprinting in sugar beet

The detection of genes that control quantitative characters is a problem of great interest to the genetic mapping community. Methods for locating these quantitative trait loci (QTL) relative to maps of genetic markers are now widely used. This paper addresses an issue common to all QTL mapping methods, that of determining an appropriate threshold value for declaring significant QTL effects. An empirical method is described, based on the concept of a permutation test, for estimating threshold values that are tailored to the experimental data at hand. The method is demonstrated using two real data sets derived from F(2) and recombinant inbred plant populations. An example using simulated data from a backcross design illustrates the effect of marker density on threshold values.

/pdf/empirical-threshold-values-for-quantitative-trait-mapping-336xyasfa9.pdf

Empirical threshold values for quantitative trait mapping.

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Genetics have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits--describing the methods, limitations, and recent applications to biological problems.

https://focus.psychiatryonline.org/doi/pdf/10.1176/foc.4.3.442

Genetic dissection of complex traits

Genetics and analysis of quantitative traits

Summary
A computerized procedure to construct integrated genetic maps is presented. The computer program (Join Map) can handle raw data from F2s, backcrosses and recombinant inbred lines, as well as listed pair-wise recombination frequencies. The procedure is useful for combining linkage data that have been collected in different experiments; the result is a mathematical alignment of the distinct genetic maps. Data from single experiments can be dealt with as well. In view of the fast growing amount of linkage information for molecular markers, which is often being generated by different research groups, integrated maps provide useful information on the map position of genes and DNA markers.

The procedure performs a sequential build-up of the map and, at each step, a numerical search for the best fitting order of markers. Weighted least squares is used for the estimation of map distances.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-313X.1993.00739.x

Construction of integrated genetic linkage maps by means of a new computer package: JOINMAP.

A very general method is described for multiple linear regression of a quantitative phenotype on genotype [putative quantitative trait loci (QTLs) and markers] in segregating generations obtained from line crosses. The method exploits two features, (a) the use of additional parental and F1 data, which fixes the joint QTL effects and the environmental error, and (b) the use of markers as cofactors, which reduces the genetic background noise. As a result, a significant increase of QTL detection power is achieved in comparison with conventional QTL mapping. The core of the method is the completion of any missing genotypic (QTL and marker) observations, which is embedded in a general and simple expectation maximization (EM) algorithm to obtain maximum likelihood estimates of the model parameters. The method is described in detail for the analysis of an F2 generation. Because of the generality of the approach, it is easily applicable to other generations, such as backcross progenies and recombinant inbred lines. An example is presented in which multiple QTLs for plant height in tomato are mapped in an F2 progeny, using additional data from the parents and their F1 progeny.

https://www.genetics.org/content/genetics/136/4/1447.full.pdf

High Resolution of Quantitative Traits Into Multiple Loci via Interval Mapping

Associations between markers and complex quantitative traits were investigated in a collection of 146 modern two-row spring barley cultivars, representing the current commercial germ plasm in Europe. Using 236 AFLP markers, associations between markers were found for markers as far apart as 10 cM. Subsequently, for the 146 cultivars the complex traits mean yield, adaptability (Finlay-Wilkinson slope), and stability (deviations from regression) were estimated from the analysis of variety trial data. Regression of those traits on individual marker data disclosed marker-trait associations for mean yield and yield stability. Support for identified associations was obtained from association profiles, i.e., from plots of P-values against chromosome positions. In addition, many of the associated markers were located in regions where earlier QTL were found for yield and yield components. To study the oligogenic genetic base of the traits in more detail, multiple linear regression of the traits on markers was carried out, using stepwise selection. By this procedure, 18–20 markers that accounted for 40–58% of the variation were selected. Our results indicate that association mapping approaches can be a viable alternative to classical QTL approaches based on crosses between inbred lines, especially for complex traits with costly measurements.

https://www.genetics.org/content/genetics/168/1/435.full.pdf

Linkage disequilibrium mapping of yield and yield stability in modern spring barley cultivars.

For Arabidopsis thaliana (L.) Heynh. (2n = 10), 76 loci have now been assigned to five linkage groups, corresponding to the five chromosomes. From a large number of estimated recombination percentages Internally consistent linkage maps were con- structed, ranging in genetic length from 51 cM (chromosome 2) to 123 cM (chromosome 1). Map lengths and centromere positions agree well with cytological observations of pre-

Linkage map of Arabidopsis thaliana

A new method, REcombination Counting and ORDering (RECORD) is presented for the ordering of loci on genetic linkage maps. The method minimizes the total number of recombination events. The search algorithm is a heuristic procedure, combining elements of branch-and-bound with local reshuffling. Since the criterion we propose does not require intensive calculations, the algorithm rapidly produces an optimal ordering as well as a series of near-optimal ones. The latter provides insight into the local certainty of ordering along the map. A simulation study was performed to compare the performance of RECORD and JoinMap. RECORD is much faster and less sensitive to missing observations and scoring errors, since the optimisation criterion is less dependent on the position of the erroneous markers. In particular, RECORD performs better in regions of the map with high marker density. The implications of high marker densities on linkage map construction are discussed.

/pdf/record-a-novel-method-for-ordering-loci-on-a-genetic-linkage-4maiqxac7b.pdf

Piet Stam

Papers

Construction of integrated genetic linkage maps by means of a new computer package: JOINMAP.

High Resolution of Quantitative Traits Into Multiple Loci via Interval Mapping

Linkage disequilibrium mapping of yield and yield stability in modern spring barley cultivars.

Linkage map of Arabidopsis thaliana

RECORD: a novel method for ordering loci on a genetic linkage map