Genomics of Normal Human Variation

The Human Transition Project
(Youssef Idaghdour, Graduate Student)

A new and exciting direction for the lab is examining the structure of human gene expression variation within and among populations.  We are particularly interested in differences associated with lifestyle, such as the transition from nomadic or pastoralist societies to modern urban settings.  Since so much of complex human disease (starting with diabetes, asthma, and depression) is due to an interaction between genotype and environment, we reason that we need to know how genes are differentially utilized between populations and environments.  The first project was carried out in Morocco in Deecember of 2006, with the assistance of the International Foundation for the Conservation and Development of Wildlife (IFCDW).  Blood samples were collected from Bedouins in the Sahara Desert, and from genetically similar villages and the city of Agadir, and are being compared for expression variation throughout the genome.  Over the next few years, we intend to extend the project to other human transitions around the globe.

The Duke Memory Project
(Priscilla Hunt and Ana Patricia Wagoner, Research Technicians, with Anna Need and David Goldstein, Duke University Institute for Genome Science and Policy)

The objective of this project is to perform a whole genome scan for short term recall memory performance in a large cohort of over one thousand students.  The study is funded and coordinated by the Duke IGSP, and our role is to conduct memory tests and collect blood samples from 500 NC State students.  Illumina BeadChips are used to type each person at over 500,000 different SNPs, and various statistical tools will be used to search for associations between particular genes and memory performance.  In a preliminary analysis of the data, we demonstrated complete failure to replicate a recently reported association between a gene called KIBRA and verbal memory recall.  Anyone interested in participating in the project is encouraged to email Priscilla Hunt at memorygenes@ncsu.edu .

Canine Biomedical Genomics

Canine Epilepsy Pharmacogenomics
(Youssef Idaghdour and Erin Kennerly, Graduate Students, with Natasha Olby and Karen Munana, NCSU CVM, and the EpilK9 Foundation)

Epilepsy is a neurological disorder that results in recurrent seizures. It is estimated that up to 5% of dogs from all breeds including mixed breeds are affected and some breeds have a higher incidence of the disease. Phenobarbital is an effective antiepileptic drug and is the most commonly used therapy in dogs. However, approximately one-quarter of dogs continue to have seizures at an unacceptable level when treated with Phenobarbital alone. The purpose of this project is to see how the genetic makeup of dogs influences response to Phenobarbital. Our primary objective is to look for association between genotypes at candidate genes and pharmacological response. We designed an Illumina genotyping array with 384 single nucleotide polymorphisms, representing 30 candidate genes at an average of 13 tagging SNPs per gene. These will be used to type 192 dogs, one half of which will be known to be refractory to Phenobarbital, and one half responsive.  Successful identification of variants that influence drug response may lead to more effective treatment, or might be used by breeders to help reduce the incidence of refractoriness to the drugs.  Please visit http://www.carolinacanineepilepsy.org .

Gene Expression Profiling and Canine Disease
(Erin Kennerly, Graduate Student, with Prema Arasu, Matthew Breen, Natasha Olby, Thierry Olivry, and Michael Stoskopf, NCSU CVM)

Dogs are emerging as an important biomedical model for complex disease.   They share many aspects of the human environment, disease etiology, and display fascinating population structure.   We are interested in gene expression differences within and among diseases and across environments.  For example, we have carried out studies of expression in diverse brain regions of five dogs, of canine meningiomas, and in the blood after infection with hookworm.   A side project in collaboration with the Red Wolf Conservation project in eastern North Carolina found a suite of stress responses in captive versus free range wolves.  Future plans call for comprehensive measurement of the effects of breed structure on the heritability of gene expression in the blood, and its effect on the incidence and severity of atopy (allergic skin disease).  

Drosophila Quantitative Genomics

A Drosophila model of Metabolic Syndrome
(Laura Reed, Postdoc, with Julie Brown, Undergraduate)

Metabolic Syndrome refers to the predisposition to a suite of related diseases – obesity, diabetes, hypertension, atherosclerosis, liver disease – that affects as many as one third of all Americans.  We are asking whether a similar syndrome may exist in flies, noting that there is considerable genetic variation for weight gain on different diets, as well as for age-dependent heart failure, and that insulin regulates the longevity of healthy heart function (work performed with Rolf Bodmer’s group at the Burnham Institute in San Diego).  Laura is using a combination of quantitative genetics, metabolomic profiling by Mass Spectrometry, and gene expression profiling, to dissect the genetic basis of the obesity in flies, as a model for understanding how genotype-by-environment interactions impact common disease. 

Evolutionary Genetics of Early Embryogenesis  
(Lisa Goering, Postdoc, with Cassandra Heighington, Research Technician)

It used to be thought that the earliest stages of development would be devoid of genetic variation, because any disruption at the beginning of embryogenesis would presumably amplify into gross abnormalities.   However, interspecific comparisons have revealed surprising lability of pattern formation, suggesting that there may be considerable additive genetic variation for A-P and D-V axis determination.   We are finding that the spatial domains of expression of the gap genes – for example, hunchback, giant, orthodentical - in the early embryo show highly heritable differences, and are searching for regulatory polymorphisms that may explain the expression variation.  One particularly promising polymorphism in a bicoid binding site upstream of one of the genes seems to be under strong selection in Drosophila melanogaster and is associated with variable spatial expression.  We are thus engaged in the identification of a network of polymorphisms that function together in a homeostatic network to guide development.

Quantitative Genetics of Wing Shape
(Ian Dworkin, Postdoc)

One of the major challenges for quantitative genetics in the genomic era continues to be fine-scale mapping of genotype onto phenotype.   An extra twist is that we can add transcript abundance to the studies: how does genotype predict expression profile and in turn phenotype?   Our primary trait for addressing this problem is the shape of the Drosophila melanogaster wing.   Having recently shown that a particular SNP in the Egfr promoter explains just 1% of wing shape variation in natural populations, we are now scanning the regulatory regions of 50 candidate genes involved in the placement and differentiation of wing veins, for SNPs that may associate with morphometric descriptors of wing shape.   Ian has also constructed a custom Illumina Sentrix BeadArray for interrogating the expression of 1400 wing development genes in a variety of mutant backgrounds.  Comparison of expression in Scalloped mutants shows that genes like vestigial are differentially expressed between genetic backgrounds, probably contributing to the variable morphological response among backgrounds.   Comparison of wild-type variation and weak mutant phenotypes will allow us to assess how cryptic variation affects the architecture of this complex morphological trait.