Introduction to SNP's and Haplotypes
Dr Ross McManus (Institute of Molecular Medicine, Trinity College Dublin)

Polymorphic variation within genomes is the cornerstone of genetics and accounts for common differences in phenotype such as pigmentation and height, but also is associated with genetic predisposition to disease. The most common form of genetic variation are Single Nucleotide Polymorphisms (SNPs) 10 – 20 million of which are thought to occur in the human genome. The frequency of such variants range from single instances to variants which occur commonly across populations. SNPs are found at high density in the genome and thus can be used for genetic mapping on the basis that all populations share genetic ancestry. As such populations can be used as large families once markers are present at a high enough density. SNPs of course occur on chromosomes and the sequence of DNA on a single chromosome is called a haplotype. Haplotypes from the maternal and paternal sources will differ according to the genetic variation present on each and they can be distinguished by typing the genetic variants on homolgous chromosomes. On closer inspection it is found that chromosomes are in fact composed of blocks of relatively stable sequences undisturbed by recombination (haplotype blocks), separated by regions of DNA where recombination occurs at high rates – recombination hotspots. Since haplotypes blocks are spared recombination, relationships between SNPS persist over long periods of time and are non-random; in other words, knowing the identity of one SNP on a block allows one to predict the identities of other SNPs within the block at a defined probability (a phenomenon called linkage disequilibrium). Another implication of this is that not all possible combinations of SNPs occur on a haplotype block– and thus for most populations, only a small number of different haplotypes exist for a given genomic region in a population. Thus it is possible to map an entire human genome using only a small proportion of the SNPs found – currently between 500k and 1M SNPs are used. This has been employed to map the genetic causes of common inherited diseases ranging from heart disease to asthma.

Genome-Wide Association Study Design
Prof Denis Shields (UCD Conway Institute of Biomolecular & Biomedical Research)

Genome-Wide Association Studies (GWAS) of e.g. 1 million SNPs in thousands of patients provide the opportunity to systematically discover the common variant components of diseases with a genetic basis. However, the large number of SNPs tested mean that very large samples are required in order to detect an appreciable fraction of the truly risk causing variants that confer a modest risk of disease, against a background of false positive findings. Secondly, data needs to be carefully screened to remove potential errors. The typical steps involved in GWAS will be outlined. Examples of results from GWAS studies will be shown. The interpretation of GWAS SNP findings and the potential role of the observed versus nearby associated SNPs (in "linkage disequilibrium") will be discusssed.

Following-Up Genome-Wide Association Studies
Dr Ric Anney (Institute of Molecular Medicine, St James's Hospital, TCD)

The GWA study provides a means to perform a systematic assessment of common variation across the whole genome to identify loci that may influence the trait under investigation. Single study association signals exceeding p<10e-8 are sometimes perceived to determine success and failure of the GWA approach. However, most analyses are essentially first-pass analyses looking for "low-hanging fruit". There is considerable wealth of data within the GWA resources. This talk will examine some of the appoaches available to enrich the data and follow-up the primary GWA analyses to gather additional insight into the genes and variation involved in the trait.

Copy Number Variation and Structural Rearrangements
Dr Sean Ennis (Our Lady's Hospital for Sick Children and School of Medicine & Medical Science, UCD)

This lecture will concentrate on recent and emerging technologies in the field of genomic structure and their application to the study of complex diseases.
Genetic studies have concentrated on the contribution of genetic variation to phenotype and genetic disease. Advances in molecular cytogenetic technologies are revealing the level of structural variation within the genome, both in terms of copy number variation (CNV) and structural rearrangements. The extent that this structural variation contributes to our phenotypic diversity remains as yet unknown, as does the contribution to diseases.
The application of these genomic structural approaches to the study of complex disease pathologies will be discussed. The state of the art of molecular cytogenetic technologies, future directions and emerging technologies in field of genomic structure will be discussed.

454 Sequencing: Applications in Human Disease Research
Andrew Livingston (Key Account Manager Sequencing Applications Roche Diagnostics Ltd.)

Next-generation sequencing is a rapidly evolving technology which is driving biological research on many fronts. This lecture will look at 454 sequencing by reviewing the latest in technology developments and how they are being utilised by the wider scientific community. In particular the significance of the long read ability of the 454 will be discussed and examples reviewed demonstrating its application in the context of SNP discovery and GWAS.

Using Next-Generation Sequencing to Interrogate the Genome
Prof Brendan Loftus (UCD Conway Institute of Biomolecular & Biomedical Research)

Since the completion of the first human genome anticipation had shifted towards a 'post-genome' era in which there would be a straightforward and predictive relationship between identifying the protein coding genes and the interpretation of their function. However as studies have delved deeper into the genome by more sensitive methodologies largely driven by advances in sequencing we have discovered a world of hitherto unseen complexity at the level of the types and functions of RNA produced by the genome which provide complexity and context to the transcriptional programs encoded by the genome. Rather than being in the post-genome era it appears that the genome is still in many respects a barely explored territory with much yet to discover and sequencing is likely to be to the fore in this regard.

Using Next-Generation Sequencing to Identify Rare Variants: Applications in Schizophrenia Research
Dr Derek Morris (Institute of Molecular Medicine, St James's Hospital, TCD)

This presentation will describe an important addition to the protocols available for next-generation sequencing, specifically targeted DNA resequencing. The ability to combine DNA samples prior to target enrichment is crucial for scaling up to large studies, e.g. rare variant detection in large clinical samples. We address this problem by first indexing multiple DNA samples and then combining them into one sequencing library that is target enriched using a single enrichment reaction. By indexing prior to enrichment, this method (i) dramatically reduces the costs associated with target enrichment and (ii) introduces significant flexibility into the design of targeted next-generation sequencing studies.

SNPs and Next-Generation Sequencing in the Study of Single Gene Disorders: Applications in Study of Sensory Phenotypes
Dr Sean Ennis (Our Lady's Hospital for Sick Children and School of Medicine & Medical Science, UCD)

This lecture will concentrate on the use of recent technologies and their application to the study of single gene disorders. Over 6,000 human diseases are caused by single-gene disorders. These single gene disorders are usually individually very rare however they affect about 1 in every 200 births. Because only a single gene is involved, these diseases generally have simple inheritance patterns (dominant, recessive, X-linked) which can be traced through family pedigrees.
Approaches to the study of rare single gene disorders will be discussed with particular reference to the study of sensory phenotypes.

How we can use modern transcriptomic methodologies to gain insights into cancer
Dr. Adrian Bracken (Smurfit Institute of Genetics, TCD)

A fundamental question in biology is how cell fate decisions are regulated in embryonic and adult stem cells. This question has major implications for both regenerative medicine and our understanding of the early events that lead to cancer. In the Bracken lab we study the function of transcription factors and chromatin remodelers involved in stem cell differentiation and cancer progression. To do this we use modern transcriptomic methodoligies such as ChIP-SEQ, expression microarray profiling and RNA-SEQ. The goal is to provide important molecular insights into normal development and differentiation events while also identifying novel molecular targets for cancer therapy.

HRB Doctoral Programme in Molecular Medicine Keynote Lecture: Rare and Common Variants in Human Disease
Prof B. David Goldstein (Duke Institute for Genome Sciences & Policy)