Genetic drift | EPFL Graph Search

Genetic drift, also known as random genetic drift, allelic drift or the Wright effect, is the change in the frequency of an existing gene variant (allele) in a population due to random chance. Genetic drift may cause gene variants to disappear completely and thereby reduce genetic variation. It can also cause initially rare alleles to become much more frequent and even fixed. When few copies of an allele exist, the effect of genetic drift is more notable, and when many copies exist, the effect is less notable. In the middle of the 20th century, vigorous debates occurred over the relative importance of natural selection versus neutral processes, including genetic drift. Ronald Fisher, who explained natural selection using Mendelian genetics, held the view that genetic drift plays at most a minor role in evolution, and this remained the dominant view for several decades. In 1968, population geneticist Motoo Kimura rekindled the debate with his neutral theory of molecular evolution, whi

Notch Signaling - a Booster of Chronic Lymphocytic Leukemia During Initiation and Disease Progression

Delphine Maude Tardivon

Chronic lymphocytic leukemia (CLL) is a B cell malignancy and represents the most common leukemia in adults within the Western world. This disease mainly affects the elderly, with a median age of diagnosis over 70. The disease course is highly variable among patients; some experience rapidly progressing leukemia which becomes resistant to treatment, while others bear indolent disease and will die from other causes. Morbidity correlates with the chromosomal aberration and mutational burdens observed in patients. NOTCH1 gain-of-function mutations are among the most frequently observed mutations in patients. They are found in 10-15% of CLL patients at diagnosis and their prevalence increases up to 30% in late-stage disease. Many correlative studies have shown that patients harboring NOTCH1 mutations exhibit a reduced survival compared to those with unmutated NOTCH1. Although the presence of NOTCH1 mutations is associated with poor prognosis, it remains unclear by which mechanisms NOTCH signaling might influence disease development. Here, we assessed the role of Notch signaling in CLL using genetic loss- and gain-of-function studies in a transgenic mouse model (IgH.TEµ) that faithfully recapitulates human disease phenotypes. We found that B cell specific knock-out of RBP-J significantly decreased prevalence of CLL induction in RBP-J depleted mice compared to control animals. Reciprocal Notch gain-of-function experiments revealed that mice with enforced Notch1 signaling had an earlier CLL onset compared to controls. Recipients of sorted CLL-like cells over-expressing Notch1 had reduced survival compared to control infusion. Taken together, these genetic studies strongly suggest a role for Notch signaling in disease initiation. To study the molecular mechanisms by which Notch1 signaling enhanced CLL aggressiveness, global gene expression as well as global epigenetic analyses were performed on sorted CLL-like cells from Notch1 gain-of-function and control animals. Cell cycle related pathways in gene set enrichment analysis were the most significantly induced signature in the Notch1 gain-of function CLL-like cells compared to control CLL-like cells. This result was further confirmed by functional cell cycle assays in vivo, strongly suggesting that Notch signaling accelerates CLL initiation by promoting proliferation.

EPFL2020

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Jacques Fellay, Amalio Telenti

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 D32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4) were homozygous for CCR5 32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

Oxford University Press2013

Inferring the age and strength of mutations evolving under positive selection

Nicky Louise Ormond

A fundamental goal of population genetics is to determine and quantify the interplay of mutation, natural selection, genetic drift and migration in shaping allelic frequency changes that underpin evolution-ary change. In this dissertation, I present computational, empirical and experimental approaches to address this goal. In the first chapter, I develop an approximate Bayesian computation (ABC) approach that co-estimates the selection strength and age of fixed beneficial mutations in single populations, by integrating a range of existing diversity, site frequency spectrum, haplotype and linkage disequilibrium based summary statistics. This approach is then extended to models of selection on standing variation in order to co-infer the frequency at which positive selection began to act upon the mutation. In the second chapter, I apply this method to an empirical study of convergent adaptation of blanched dorsal phenotypes in two lizard species to the newly formed White Sands system of New Mexico. Estimates of the age of the beneficial mutations underpinning the evolution of cryptic coloration are younger than the related geological shift and support a model of adaptation from de novo mutation. In the third chapter, I analyze the experimental evolution of H1N1 influenza virus populations under a combined protocol of two drugs with different modes of action: oseltamivir and favipiravir. Results indicate a complex interplay of mutation, selection and genetic drift, where selective sweeps around oseltamivir resistance mutations hitchhike deleterious mutations owing to the mutagenic effect of favipiravir to fixation. This effect reduces viral fitness and ac-celerates extinction via Mullerâs ratchet, but at the risk of spreading both established and newly emerging oseltamivir resistance mutations.

EPFL2017

Notch Signaling - a Booster of Chronic Lymphocytic Leukemia During Initiation and Disease Progression

Delphine Maude Tardivon

EPFL2020