[BBC] Job announcement: GIGA PhD and Postdoctoral Opportunities in Genomics

[marilou.ramospamplona at ulg.ac.be]

GIGA PhD and Postdoctoral Opportunities in Genomics

The GIGA-Genetics unit from the University of Liege (Belgium) seeks applicants for PhD and postdoctoral positions to join research projects in the areas of medical (CAUSIBD) and fundamental genomics (DAMONA). 

The successful applicants will have the motivation to make a strong contribution in the area of bioinformatics and statistical genetics, and will have a strong training in either biological, computer, engineering, physical or mathematical sciences.

Information about the GIGA institute and the Unit of Animal Genetics can be obtained from: http://www.giga.ulg.ac.be/jcms/c_5015/en/home and
http://www.giga.ulg.ac.be/jcms/prod_205624/unit-of-animal-genomics.

The fulltime positions are immediately available and will be for an initial period of two years with a possibility of renewal.

Applications or requests for further information should be sent to michel.georges at ulg.ac.be.

The advertisement will remain open until suitable candidates are selected, with a first round of selection to be done by 30 April 2013.


Description of projects

CAUSIBD

Inflammatory Bowel Disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), afflicts ~1/300 inhabitants of developed countries at one point during their lifetime. CD and UC are characterized by chronic and relapsing inflammation of the gastrointestinal tract associated with debilitating symptoms and tissue damage leading to complications and surgical resections of bowel segments. IBD strongly compromises life quality of the patients, and is a major burden to society due to the costs of treatment but also of unemployment and disability allowance. The incidence of IBD, as of other inflammatory pathologies, has increased dramatically during the 20-ies centuries in Western societies (particularly and worryingly in the young), pointing towards a major - as of yet unidentified - environmental or behavioral trigger.

However, all individuals are not equally susceptible to the effects of these environmental risk factors. Twin and familial studies indicate that the heritability of inherited predisposition to IBD (assuming a threshold model with underlying liability) is higher than 50%. Genome wide association studies have uncovered more than 100 “common” risk loci for IBD, including CD specific, UC-specific and CD/UC-shared risk loci, which jointly explain ~25% of inherited risk. Analysis of a subset of GWAS hits has revealed the importance of perturbed autophagy, innate immunity and IL23 signaling in determining inherited predisposition. Drug development targeting these pathways is ongoing. However, for the vast majority of risk loci (which typically encompass ~200 Kb, 500 DNA sequence variants and 5 genes) causative genes and variants remain unidentified. Moreover, the fact that identified loci only explain 25% of the heritability raises the question about the molecular nature of the 75% missing heritability.

The Belgian IBD consortium (BIBDC), comprising gastro-enterologists and geneticists from the ULg (E. Louis & M. Georges), ULB (D. Franchimont), KUL (S. Vermeire), and RUG (M. De Vos), has assembled one of the largest IBD case-control cohorts in the world. This has allowed BIBDC to make important contributions to recent studies into the genetics of IBD (f.i. Libioulle et al., PLoS Genetics 3:e58 (2007); Barrett et al., Nature Genetics 40:955-962 (2008); Imielinski et al. Nature Genetics 41:1335-1340 (2009); Franke et al., Nature Genetics 42:1118-1125 (2010); Momozawa et al., Nature Genetics 43:43-47 (2011); Anderson et al., Nature Genetics 43: 246-252 (2011)), and to be a major partner in the International IBD Genetics Consortium (IIBDGC), providing the Belgian IBD community with privileged access to meta-data.

The objectives of the CAUSIBD project are:

1. To identify causative genes and variants in known IBD risk loci using an integrated genomic, epigenomic, transcriptomic and endo-phenotypic approach.

2. To study the effect of host genotype on gut microbiome composition in relation to inherited predisposition to IBD.

3. To analyze the contribution of rare and low frequency risk variants, quasi-infinitesimal architecture, and epistatic interactions to the missing heritability for IBD predisposition.

4. To study the potential diagnostic utility of quasi-infinitesimal modeling of IBD predisposition, disease-progression, co-morbidity and differential diagnosis.


DAMONA

Mutation and recombination are fundamental biological processes that determine the adaptability of populations in changing environments. The mutation rate that prevails in a population reflects the equilibrium between the need to be adaptable, the burden of the mutation load, the resources invested in reducing the error rate (cost of fidelity), and random drift that determines a lower limit in achievable fidelity. Recombination fulfills an essential mechanistic role during meiosis and is exquisitely regulated to ensure proper chromosomal segregation. Recombination affects the rate of creation and loss of haplotypes with cis configured favorable alleles, imposing second order selection pressure on local and global modifiers of recombination.

It is becoming increasingly apparent that recombination and mutation rates vary between individuals, and that these differences are in part inherited. Both processes are therefore evolvable themselves, and hence amenable to genomic analysis. Identifying genetic determinants underlying these differences would provide novel insights in the molecular mechanisms regulating mutation and recombination. The mutational load, and in particular the number of lethal equivalents per average individual, remains poorly defined as epidemiological and molecular data yield estimates that differ by one order of magnitude. A relationship between recombination and fertility has been reported in Icelandic women but awaits confirmation.

Population structure (small effective population size; large harems), phenotypic data collection (systematic recording of > 50 traits on millions of cows), and large-scale SNP genotyping (for genomic selection), make cattle populations uniquely suited for genetic analyses.

Damona proposes to exploit these unique resources, combined with recent advances in next generation sequencing and genotyping, to:

1. Quantify and characterize inter-individual variation in male and female mutation and recombination rates,

2. Map, fine-map and identify causative genes and variants underlying QTL influencing these four phenotypes,

3. Test the effect of loss-of-function variants in protein-coding genes on >50 phenotypes including fertility, and study the effect of variation in recombination on fertility.