Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

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

Genetics and analysis of quantitative traits

The recent successes of genome-wide expression profiling in biology tend to overlook the power of genetics. We here propose a merger of genomics and genetics into ‘genetical genomics’. This involves expression profiling and marker-based fingerprinting of each individual of a segregating population, and exploits all the statistical tools used in the analysis of quantitative trait loci. Genetical genomics will combine the power of two different worlds in a way that is likely to become instrumental in the further unravelling of metabolic, regulatory and developmental pathways.

Genetical genomics : the added value from segregation

The development of linkage maps with large numbers of molecular markers has stimulated the search for methods to map genes involved in quantitative traits (QTLs). A promising method, proposed by Lander and Botstein (1989), employs pairs of neighbouring markers to obtain maximum linkage information about the presence of a QTL within the enclosed chromosomal segment. In this paper the accuracy of this method was investigated by computer simulation. The results show that there is a reasonable probability of detecting QTLs that explain at least 5% of the total variance. For this purpose a minimum population of 200 backcross or F2 individuals is necessary. Both the number of individuals and the relative size of the genotypic effect of the QTL are important factors determining the mapping precision. On the average, a QTL with 5% or 10% explained variance is mapped on an interval of 40 or 20 centiMorgans, respectively. Of course, QTLs with a larger genotypic effect will be located more precisely. It must be noted, however, that the interval length is rather variable.

Accuracy of mapping quantitative trait loci in autogamous species.

Les strongles gastro-intestinaux, dont Haemonchus contortus constituent un probleme majeur pour l'elevage des ovins allaitants. Ils entrainent des pertes de production et le recours aux anthelminthiques est remis en question par l'apparition de souches de vers resistantes. La selection d'ovins plus resistants fait partie des strategies complementaires de lutte les plus serieuses. Cependant sa mise en oeuvre requiert une meilleure comprehension des mecanismes sous-jacents. Cette these vise a identifier les regions du genome ovin impliquees dans la resistance aux strongles gastro-intestinaux. Une analyse statistique d'association entre des marqueurs genetiques et des mesures de resistance d'un troupeau d'ovins croises Martinik Black-belly x Romane a mis en evidence un nombre limite de regions d'interet. Parmi celles-ci, un segment du chromosome 12 a ete choisi pour effectuer des accouplements raisonnes et valider son role dans la resistance a H. contortus. L'effet de cette region a ete valide chez les descendants issus d'accouplements assistes par marqueurs genetiques. Cette region semble limiter fertilite des vers femelles tout en contribuant a une reponse immunitaire plus forte. Le role d'une region du chromosome 21 dans la variation de concentration plasmatique en pepsinogene, un marqueur de lesions abomasales, a egalement ete confirme. Un gene candidat sous-jacent est en cours de sequencage et l'analyse des polymorphismes devrait contribuer a la validation de son role. Deux autres genes tres proches pourraient egalement etre impliques et meriteraient une consideration future. Ces travaux illustrent a la fois la variation genetique disponible pour les caracteres de resistance a H. contortus et la complexite des mecanismes mis en jeu. Des etudes complementaires de sequencage et d'etude d'expression par sequencage devrait contribuer a une meilleure comprehension des fonctions des genes impliques et de leurs interactions. ABSTRACT : Gastro-intestinal nematodes, among which Haemonchus contortus are a major threat to the meat sheep industry. They are responsible for production losses and the apparition of worm populations resistant to drugs limits their use as worm control strategy. Breeding more resistant sheep is among the most practicable alternative strategy. However its implementation requires a deeper understanding of underlying mechanisms. This PhD aims at identifying regions of the ovine genome affecting resistance to gastro-intestinal nematodes. A statistical analysis of existing associations between genetic markers and resistance traits of a Martinik Black-belly x Romane cross-bred sheep flock unraveled a limited number of key players. Among these, a fragment of the chromosome 12 was chosen to perform marker-assisted matings and to validate its role in resistance to H. contortus. The effect of this region was validated in the progenies born from matings. It seems this chromosomic fragment limits female worms fertility and is associated to a stronger immune response. The putative role played by a fragment of the chromosome 21 in plasmatic pepsinogen concentration (a biomarker of abomasal lesions) was also confirmed in this work. A candidate gene underlying this region has been sequenced and the analysis of the detected polymorphisms should confirm its role. Further, two other genes in its vicinity could also play a role in this biological phenomenon and they should also deserve future considerations. This work illustrated both the existing genetic variation for resistance to H. contortus and the associated complexity of underlying mechanisms. Additional sequencing and gene expression sequencing studies should help understanding gene functions and interactions.

Guillaume Sallé

Papers

Détection et validation fonctionnelle de régions du génome affectant la résistance aux strongles gastro-intestinaux chez le mouton