30 S0001 – S0016 Invited Speaker Abstracts INVITED SPEAKERS S0001–S0016 31 S0001 The power of comparative genetics and genomics S0004 Finding the causal variant in selective sweeps Kerstin Linbald-Toh. Elinor Karlsson. Broad Institute, USA; Uppsala University, Sweden. Broad Institute, Cambridge, MA, USA. The human genome contains hundreds of regions with patterns of genetic variation that refl ect recent, positive natural selection, yet for most the underlying gene and S0002 Using intra-species variation to understanding basic the advantageous mutation remain unknown. We have developed a method, the biology Composite of Multiple Signals (CMS), that, by combining multiple different tests for natural selection, increases our resolution by up to 100-fold. By applying CMS to the International Haplotype Map, we localize hundred signals, reducing the candidate Ewan Birney. region for each to just ~50-100kb. In many cases, we can identify the precise gene EMBL Outstation – Hinxton, European Bioinformatics Institute, Welcome Trust Genome and polymorphism targeted by selection. This includes genes involved in infectious Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom. disease susceptibility, skin pigment, metabolism, and hair and sweat. Nearly half Quantitative genetics based on large, outbred populations has had a long history in of the ~200 regions we localized contain no genes at all, and 13 contain long, non- both animal breeding and human disease studies. It is one of the few techniques coding RNAs, which can regulate nearby genes. In several regions we signifi cantly which one can apply to understand a complex phenotype when nothing else is known associate variants under selection with the expression of nearby genes. about the phenotype. A traditional downside of quantitative genetics has been the We are now applying CMS to preliminary data available from the 1000 Genomes need for both reasonably large numbers of individuals studied and a large number Project, a full sequence dataset which should contain the actual functional of markers which needed to be typed. To reduce the required marker density often mutation in most cases, and are identifying new, intriguing coding and regulatory populations with reasonably long linkage disequilibrium were used, preventing variants. With the cost of sequencing falling dramatically, full sequence data for the use of quantitative genetics in a number of scenarios. The logistics therefore many individuals will soon be available not just for more human populations, but prevented quantitative genetics being widely used outside of complex phenotypes. for many other species as well. Although the current version of CMS is tailored to However, the economics of quantitative genetics has been completely changed the population history of humans, the remarkable power of the composite approach by the advent of ultra-high throughput sequencing. Now very higher marker density, suggests it can help elucidate the evolutionary history of a wide range of species. include the ultimate full resequencing is achievable at reasonable cost. This is a huge boon to “traditional” complex phenotype quantitative genetics, but also opens up this tool for basic molecular biologists studying fundamental processes in biology. I will describe some recent success in exploring the interaction of chromatin S0005 Domestication, dispersal and hybridisation: The next structure and function in Humans and oogenesis in Drosophila using quantitative generation of emerging narratives genetics, and explore the similarities and differences in using quantitative genetics for basic biology compared to complex phenotype exploration. Greger Larson. Department of Archaeology, Durham University, South Road, Durham DH1 3LE, UK. Investigating the patterns and processes of animal domestication from a genetics perspective has thus far been carried out primarily (though though not exclusively) S0003 Epigenetics, Imprinting and Disease Susceptibility by analyses of mitchondrial sequences. The greater resolution offered by DNA as compared with more traditional morphological approaches to within species Randy Jirtle. questions has led to a great deal of novel results including the recognition that Duke University Medical Center, Department of Radiation Oncology, Durham, NC 27710 USA. many more discrete populations have been involved in domestication across the Old World than previously suspected. Still, the maternal inheritance pattern of Human epidemiological and animal experimental data indicate that the risk of mtDNA has necessarily limited the DNA perspective. With the advent of high developing adult onset chronic diseases such as cardiovascular disease, diabetes, throughput sequencing technology (including the development of large-scale SNP obesity, and cancer is infl uenced by persistent adaptations to prenatal and early arrays), the nuclear genome is becoming increasingly available. This paper offers postnatal nutrition. Two epigenomic targets that potentially link environmental a brief summary of early results in this vein and in so doing, describes both the exposures to chemical and physical agents early in development to adult disease new narratives emerging from domestication studies, and a new hybridization susceptibility are imprinted genes and those with metastable epialleles. Genes with hypothesis across numerous domestic animal taxa. metastable epialleles have highly variable functions because of stochastic allelic changes in the epigenome rather than mutations in the genome. Genomic imprinting is an unusual epigenetic form of gene regulation that evolved 150 million years ago in mammals with the development of the placenta and the advent of viviparity. It results in monoallelic, parent-of-origin dependent gene silencing. Thus, only a single genetic or epigenetic event is required to alter the function of an imprinted gene. The potential importance of these two novel subsets of epigenetically labile genes in normal human variation, and the etiology of environmentally-induced diseases will be discussed. ISAG 2010 32 INVITED SPEAKERS S0001–S0016 S0006 Genome-wide association studies (GWAS) in humans: Is S0009 How selective sweeps in domestic animals can teach the genetic revolution fi nally here? human medicine Ariel Darvasi. Leif Andersson. Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Department of Medical Biochemistry and Microbiology, Uppsala University & Givat Ram, Jerusalem 91904. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden. Identifying the genetic basis of complex traits is considered one of the major challenges science is facing today. Complex traits in humans include for example Strong directional selection in domestic animals leads to dramatic changes in susceptibility to disease or drug response variation. The identifi cation of the allele frequencies, selective sweeps, of genetic variants with notable effects on underlying genes to these traits has the potential to revolutionize the way medicine the trait under selection. The identifi cation and molecular characterization of the is practiced. On the one hand, this may enhance drug discovery and on the other causative mutations underlying such sweeps can generate new basic knowledge hand help developing personalized medicine, “the right drug for the right patient”. of biomedical importance. The characterization of the paternally expressed IGF2 In recent years, the development of novel technologies has brought about large scale QTL in pigs affecting muscle growth and fat deposition is a prime example of this. genome-wide association studies (GWAS). Hundreds of GWAS have been reported First we used QTL mapping and haplotype sharing analysis and showed that the so far, revolutionizing the landscape of the genetics of complex traits through the causative mutation is a single nucleotide substitution at an evolutionary conserved identifi cation of associated genes. Nevertheless, in most instances, the proportion site in intron 3 of IGF2. Now we have demonstrated that this mutation disrupts the of variance explained by the detected genes is relatively modest. Furthermore, binding of a previously unknown transcription factor that we named ZBED6. ZBED6 most polymorphisms identifi ed do not necessarily have a functional effect. Whole has evolved from a domesticated DNA transposase and is an innovation in the genome sequencing is yet another technology which may further close the gap to placental mammals. Our further characterization of ZBED6 has revealed that it is the delineation of the genetic basis of complex traits. This technology has already widely expressed both during development and in adult tissue. ChIP-sequencing has been successfully applied at a relatively small scale, its full utilization still requires revealed more than a thousand potential downstream targets besides IGF2. Major a cost- reduction of at least an order of magnitude. Revolutions are spotted as such topics for ongoing research include studies how ZBED6 regulates transcription of usually only after they have occurred. It seems too pretentious to state that the IGF2 and other target genes and whether mutations in ZBED6 or ZBED6 binding genetic revolution is here, but I fi nd it safe to say that it has begun. sites are associated with human disease. S0007 Identifying regulatory QTN in livestock S0010 The role of NK cells in health and disease Michel Georges. Anne K. Storset. GIGA Tower (B34), 1 avenue