ISAG 2010

Title: The power of comparative genetics and genomics for finding genes of medical relevance

Abstract: After the sequencing of the human genome, over 40 vertebrate genomes have been added to the sequencing pipeline. These include model organisms such as mouse, dog and horse to be used for comparative genetics and representatives for different vertebrate lineages such as the opossum, platypus, chicken, anolis lizard and various fish as well as 24 additional mammals selected specifically to annotate the human genome through comparative genomics.

The first realization that sequencing the human genome was not enough came when the first mammalian model organism, the mouse, was sequenced and compared to the human genome. These analyses showed that ~ 5% of the human genome is under selective constraint and therefore likely to be functional. However, only 1.5 % is protein coding, suggesting that regulatory signals take up perhaps 3.5% of the human genome. Computational analysis of the human, mouse and dog genomes has been used to determine that the human genome has only ~20,000 genes, to find transcription factor binding sites, miRNA binding site, enhancers and insulators. However, the resolution with only a few mammals is low, finding only large elements genome-wide or small features in targeted regions. The 24 mammals project is therefore currently ongoing to generate enough evolutionary power to identify elements 10 bp or larger. The analysis of this data set is now producing a detailed annotation of the human genome that helps to determine which polymorphisms within a genomic region associated with disease have the highest likelihood of being functional.

Many model organisms have also been developed for their ability to identify disease mutations. The dog is an outstanding disease model, sharing many of man’s diseases and having a population history that results in a haplotype structure that makes gene mapping very efficient. We have therefore developed the tools and strategies for trait mapping in the dog and show that many mutations, even for monogenic traits, are more complex than simple base pair substitutions. Progress has now been made on mapping traits as diverse as multiple cancers, inflammatory diseases, cardiomyopathy and neurological and psychiatric disease. Often the role of strong artificial selection or even natural selection can be seen in the disease genes identified.

I will review the annotation of the human genome and give several examples of canine trait mapping with the particular aim of showing how crucial it will be to annotate the human genome to allow the dissection of complex traits in both animal and human medicine.
 

Bio: Kerstin Lindblad-Toh is a professor in comparative genomics and the Director of Science for Life Laboratory Uppsala and the Scientific Director of Vertebrate Genome Biology at the Broad Institute.

At the Broad Institute Kerstin is responsible for the 29 mammals project to annotate the human genome for functional constraint as well as for a large number of vertebrate genome projects several of which emphasize the detection of selective sweeps. She also leads the dog disease-mapping group. Her group has developed several SNP chips that have been used to identify canine disease genes.

In Uppsala, Kerstin’s research emphasizes the dog as a comparative model for human diseases. Her group is mapping over 20 diseases including cancer, autoimmune, cardiac and neurological diseases. Many of the findings are now being translated to human patients cohorts. She is an active participant in and on the Steering Committee of the LUPA consortium an FP7 project aiming to map human complex traits using dog a as a model.

Kerstin is also the Director Science for Life Laboratory Uppsala, a novel strategic research center with the vision of being an internationally leading center that develops, applies, and provides access to large-scale technologies for molecular biosciences with a focus on translational medicine and on evolutionary and systems biology.

An author on over 100 papers, Kerstin has received several scholarships and awards from the Svenska Institutet Scholarship for Research Abroad and the Swedish Medical Research Council and the prestigious European Young Investigator award (EURYI) and Fernström’s price.

Kerstin received her Ph.D. from the Department of Molecular Medicine, Karolinska Institute, Sweden, in 1998 studying trinucleotide repeat disorders.

Contact Details: Kerstin Lindblad-Toh, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden & Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge MA 02141 USA
Email: kersli@broadinstitute.org

Abstract: Quantitative genetics based on large, outbred populations has had a long history in both animal breeding and human disease studies. It is one of the few techniques which one can apply to understand a complex phenotype when nothing else is known about the phenotype. A traditional downside of quantitative genetics has been the need for both reasonably large numbers of individuals studied and a large number of markers which needed to be typed. To reduce the required marker density often populations with reasonably long linkage disequilibrium were used, preventing the use of quantitative genetics in a number of scenarios. The logistics therefore prevented quantitative genetics being widely used outside of complex phenotypes.

However, the economics of quantitative genetics has been completely changed by the advent of ultra-high throughput sequencing. Now very higher marker density, 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 structure and function in Humans and oogenesis in Drosophila using quantitative genetics, and explore the similarities and differences in using quantitative genetics for basic biology compared to complex phenotype exploration.

Contact details: Ewan Birney, EMBL Outstation - Hinxton, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom. Email: birney@ebi.ac.uk

Abstract: Human epidemiological and animal experimental data indicate that the risk of developing adult onset chronic diseases such as cardiovascular disease, diabetes, obesity, and cancer is influenced by persistent adaptations to prenatal and early postnatal nutrition. Two epigenomic targets that potentially link environmental exposures to chemical and physical agents early in development to adult disease susceptibility are imprinted genes and those with metastable epialleles. Genes with 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.

Bio: Randy L. Jirtle is a professor of radiation oncology at Duke University, Durham, NC. Jirtle’s research interests are in epigenetics, genomic imprinting, and the fetal origins of disease susceptibility. He has published over 170 peer-reviewed articles, and was a featured scientist on the NOVA and ScienceNow television programs on epigenetics, He was invited to speak at the 2004 Nobel Symposium on Epigenetics. He was honored in 2006 with the Distinguished Achievement Award from the College of Engineering at the University of Wisconsin-Madison. In 2007, Jirtle received an Esther B. O'Keeffe Charitable Foundation Award and was nominated for Time Magazine’s “Person of the Year.” He was the inaugural recipient of the Epigenetic Medicine Award in 2008, and received the STARS Lecture Award in Nutrition and Cancer from the National Cancer Institute in 2009.

Contact details: Randy L. Jirtle, Duke University Medical Center, Department of Radiation Oncology, Durham, NC 27710 USA Email: jirtle@radonc.duke.edu

Title: Finding the causal variant in selective sweep

Abstract: The human genome contains hundreds of regions with patterns of genetic variation that reflect recent, positive natural selection, yet for most the underlying gene and the advantageous mutation remain unknown. We have developed a method, the 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 region for each to just ~50-100kb. In many cases, we can identify the precise gene and polymorphism targeted by selection. This includes genes involved in infectious disease susceptibility, skin pigment, metabolism, and hair and sweat. Nearly half of the ~200 regions we localized contain no genes at all, and 13 contain long, non-coding RNAs, which can regulate nearby genes. In several regions we significantly associate variants under selection with the expression of nearby genes.

We are now applying CMS to preliminary data available from the 1000 Genomes Project, a full sequence dataset which should contain the actual functional mutation in most cases, and are identifying new, intriguing coding and regulatory variants. With the cost of sequencing falling dramatically, full sequence data for many individuals will soon be available not just for more human populations, but for many other species as well. Although the current version of CMS is tailored to the population history of humans, the remarkable power of the composite approach suggests it can help elucidate the evolutionary history of a wide range of species.

Bio: Elinor Karlsson (Ph.D., Bioinformatics, Boston University, 2008) is a post-doctoral research fellow in Systems Biology at Harvard University and at the Broad Institute in Cambridge, Massachusetts, USA. Elinor's research has focused on using dog breeds to find the genes and mutations causing diseases shared between dogs and humans, including cancer, diabetes, epilepsy, and anxiety/compulsive disorders. She also has worked on developing genomic tests for natural and artificial selection, and on integrating them into trait association studies, to help pinpoint genetic variants influencing phenotypes which have historically conferred a selective advantage. In addition to her work in canine genomics, she studies human populations selected for resistance to infectious diseases like cholera in Bangladesh and viral hemorrhagic fevers in Africa.

Contact Details: Elinor Karlsson, Broad Institute, Cambridge, MA, USA.

Abstract: Investigating the patterns and processes of animal domestication from a genetics perspective has thus far been carried out primarily (though though not exclusively) by analyses of mitchondrial sequences. The greater resolution offered by DNA as compared with more traditional morphological approaches to within species questions has led to a great deal of novel results including the recognition that many more discrete populations have been involved in domestication across the Old World than previously suspected. Still, the maternal inheritance pattern of mtDNA has necessarily limited the DNA perspective. With the advent of high throughput sequencing technology (including the developement of large-scale SNP arrays), the nuclear genome is becoming increasingly available. This paper offers a brief summary of early results in this vein and in so doing, describes both the new narratives emerging from domestication studies, and a new hybridization hypothesis across numerous domestic animal taxa.

Bio: GREGER LARSON (PhD 2006 University of Oxford) is an RCUK Research Fellow at Durham University, Durham, UK. Greger's research has focused primarily on the use of animal domestication both as an evoultionary model and as a means to understand the origins of agriculture, civilization, and human dispersals. His primary means of pursuing these questions is through a molecular genetic approach, and he is involved in projects that seek to leverage the newly developing sequencing technologies to address questions related to the timing, locations, and process of domestication, as well as how changes at the level of the genome influence the physical and behavioral characteristics of domesticated animals. He is also expanding his interests to include issues of feralization, hybridization, and to non-domestication related topics such as historical biogeography and island evolution.

Abstract: 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 susceptibility to disease or drug response variation. The identification of the underlying genes to these traits has the potential to revolutionize the way medicine is practiced. On the one hand, this may enhance drug discovery and on the other hand help developing personalized medicine, "the right drug for the right patient". In recent years, the development of novel technologies has brought about large scale genome-wide association studies (GWAS). Hundreds of GWAS have been reported so far, revolutionizing the landscape of the genetics of complex traits through the identification of associated genes. Nevertheless, in most instances, the proportion of variance explained by the detected genes is relatively modest. Furthermore, most polymorphisms identified do not necessarily have a functional effect. Whole genome sequencing is yet another technology which may further close the gap to the delineation of the genetic basis of complex traits. This technology has already been successfully applied at a relatively small scale, its full utilization still requires a cost- reduction of at least an order of magnitude. Revolutions are spotted as such usually only after they have occurred. It seems too pretentious to state that the genetic revolution is here, but I find it safe to say that it has begun.

Bio: Prof. Darvasi received his PhD from the Hebrew University in 1994 and subsequently did a post doctorate at Universite de Paris V. Following that, Prof. Darvasi held a visiting position at the Jackson Laboratory. Prior to his return to Israel, Prof. Darvasi served as Associate Director of Human Genetics and Head of Statistical Genetics at SmithKline Beecham in the UK. Upon his return to Israel in 1999 he founded IDgene Pharmaceuticals Ltd. and joined The Hebrew University as a Faculty member. During the past decade Prof. Darvasi developed leading experimental strategies for the identification of genes affecting complex traits in model organisms and humans. These strategies were successfully implemented by Prof. Darvasi to study the genetic basis of a wide range of traits such as chronic pain, schizophrenia and diabetes.

Contact Details: Prof. Ariel Darvasi, Department of Genetics
The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904
Email: arield@cc.huji.ac.il

Abstract: Genome wide association (GWA) studies in humans have identified several hundred variants associated with common human traits. These traits include diseases and continuous measures, including diabetes, autoimmune diseases, bone disorders and inflammatory conditions. Many of these traits are relevant to animal studies including, height, body mass index and fat mass. Here I will give some brief background to GWA studies in humans before focusing on a “model” trait – adult height. This trait has proven to be a model trait in that genome wide genetic and phenotypic data is available from >200,000 individuals, it is strongly heritable and highly polygenic. Recent studies by the Genetic Investigation of Anthropometric Traits (GIANT) consortium, have identified 180 loci associated with human height. These loci are non-randomly distributed across the genome, being enriched for genes known to be involved in mammalian growth. I will conclude with where human genetic studies are likely to go next, a step which is likely to involve whole genome and exome sequence data as well as genotype data.

Biography: I have been working as a molecular geneticist for fourteen years, the majority of that time on common human traits and diseases, particularly type 2 diabetes and related conditions. I obtained a personal chair as Professor of Human Genetics at the Peninsula Medical School in Exeter in 2007 and head a team of 12 that has become internationally recognized as a world leader in the genetics of common traits and conditions. Most recently, our team jointly led the type 2 diabetes component to the WTCCC efforts alongside Prof Mark McCarthy and his team in Oxford. This work, alongside that of other groups, resulted in an unprecedented leap in the understanding of the genetic component to type 2 diabetes and related anthropometric traits. In addition to new type 2 diabetes loci we, with collaborators, have identified the first robustly associated loci that influence adiposity (FTO, Science 2007) and height (HMGA2, Nature Genetics 2007) in the general population.

We are now members of several consortia that are continuing to identify more variants in the human genome that influence important human traits. We are translating these genetic associations into an improved understanding of the biological basis of disease and normal physiology. Examples include Mendelian Randomization studies that provide evidence for a role of sex-hormones in type 2 diabetes and links between fetal growth and type 2 diabetes.

Previously, I trained as a diagnostic molecular geneticist with the Oxford Regional health Authority at the Churchill hospital where I learnt the basics of linkage analysis and Bayesian calculations for risk prediction in families with cystic fibrosis and muscular dystrophy, amongst other conditions.

I began me research career in 1996 in Exeter in the field of monogenic forms of diabetes. My work, as a PhD student with Prof Andrew hattersley, played a key role in the characterization of the genes for maturity onset diabetes of the young. I completed my PhD in 1998 and now have over 100 publications. Key work prior to the genome wide association efforts includes some of the first use of meta-analyses and multiple replication studies to determine the role of common variants in disease. These include the assessment of common variants in the KCNJ11 (E23K variant) and Calpain10 genes in type 2 diabetes risk and the identification of the first robust associations between common variants and birth weight (TCF7L2 and Glucokinase, AJHG 2006 & 2007).

In 2003 I won the European Association for diabetes (EASD) Albert Renold award that enabled me to work at the Centre National de genotypage (CNG) with Prof Mark Lathrop throughout 2004. In 2006 I was awarded the Diabetes UK R.D. Lawrence Award for the best UK diabetes researcher under 40 years of age and in 2007 I was one of four recipients of the EASD “Rising Star” award.

Contact: Tim Frayling, Peninsula College of Medicine and Dentistry, University of Exeter, UK. Email: Tim.frayling@pms.ac.uk

Title: Identifying regulatory QTN in livestock

Bio: Michel Georges got his DVM and PhD degree from the ULg in 1983 and 1991, respectively. He worked for Genmark Inc in Salt Lake City from 1989 to 1993. He has been Professor in Genetics at the University of Liège since 1994. His team is using genomic tools to analyze the genetic architecture of medically and agronomically important complex traits in mammals. In 2007 he was awarded the Wolf Prize in Agriculture together with Ronald Phillips for “for groundbreaking discoveries in genetics and genomics, laying the foundations for improvements in crop and livestock breeding, and sparking important advances in plant and animal sciences”.

Contact Details: Michel Georges, GIGA Tower (B34), 1 avenue de l'Hôpital, 4000-Liège, Belgium. Email:-michel.georges@ulg.ac.be

Abstract: Strong directional selection in domestic animals leads to dramatic changes in allele frequencies, selective sweeps, of genetic variants with notable effects on the trait under selection. The identification and molecular characterization of the causative mutations underlying such sweeps can generate new basic knowledge of biomedical importance. The characterization of the paternally expressed IGF2 QTL in pigs affecting muscle growth and fat deposition is a prime example of this. First we used QTL mapping and haplotype sharing analysis and showed that the causative mutation is a single nucleotide substitution at an evolutionary conserved site in intron 3 of IGF2. Now we have demonstrated that this mutation disrupts the binding of a previously unknown transcription factor that we named ZBED6. ZBED6 has evolved from a domesticated DNA transposase and is an innovation in the placental mammals. Our further characterization of ZBED6 has revealed that it is widely expressed both during development and in adult tissue. ChIP-sequencing has revealed more than a thousand potential downstream targets besides IGF2. Major topics for ongoing research include studies how ZBED6 regulates transcription of IGF2 and other target genes and whether mutations in ZBED6 or ZBED6 binding sites are associated with human disease.

Bio: Leif Andersson is today professor in Functional Genomics at Uppsala University and guest professor in Molecular Animal Genetics at the Swedish University of Agricultural Sciences in Uppsala. Leif Andersson and his group have successfully used molecular genetics and genomics to unravel the molecular basis for phenotypic diversity in domestic animals, from coat colour to metabolic traits. His group has generated highly informative intercrosses between the wild boar and domestic pigs as well as between the red junglefowl and domestic chicken. The overall aim is to identify functionally important mutations that provide new insight into basic biology and that lead to practical applications in agriculture and human medicine.

Contact details: Leif Andersson. Department of Medical Biochemistry and Microbiology, Uppsala University & Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden. Email: Leif.andersson@imbim.uu.se

Abstract: Natural Killer cells are lymphocytes of the innate immune system that have been known for their roles in cancer and transplant immunology. During the last ten years it has been found that they contribute to the onset and shaping of adaptive cellular responses through interplay with dendritic cells and T-cells. These possible roles in resistance to infections and vaccine development have lead to new interest for NK cells in veterinary infection biology.

The activation of NK cells is regulated by the interplay of activating and inhibitory receptor signals as well as cytokine stimulation. NK cell receptors fall into two structural categories; the killer cell lectin-like receptors and the leukocyte immunoglobulin-like receptors. Both categories include activating and inhibitory variants, however different categories of genes have expanded to become gene families that bind to MHC class I ligands in different species. These NK cell receptor multigene families may show polymorphism; different individuals may have haplotypes with varying gene contents as well as allelic variants of individual genes.

The main roles of NK cells in infections and the most important NK cell receptors will be discussed with focus on the knowledge achieved in rodents and humans and will be extended to data generated in veterinary relevant species where information exists. The aim of the talk will be to raise interest about NK cells and their receptors among listeners with a genetic approach to disease susceptibility.

Bio: Anne K. Storset is a veterinarian and professor in Immunology at the Norwegian School of Veterinary Science in Oslo. The main aim of her research is to increase the basic knowledge on ruminant NK cells both from a comparative point of view and with regard to ruminant disease resistance and development of vaccines. She has characterized bovine NK cells and the genes for several bovine NK cell receptors and is currently involved in the characterization of NK cells in small ruminants and swine. Her group focuses on basal functions of ruminant NK cells with special emphasis on their role in infections, their role in secondary lymphoid organs and in diagnosis of bovine tuberculosis.

Contact Details: Anne K. Storset, Norwegian School of Veterinary Science, P.O. Box 8146 Dep, 0033 Oslo, Norway Email: Anne.Storset@nvh.no

Title: How manipulation of resistance and tolerance to infections can alter animal health and disease transmission

Abstract: Evolution provides two main routes a host can use to reduce the costs of infection. The first route is “resistance” and is the ability to reduce pathogen levels. We know much about resistance - most of immunology focuses on these killing mechanisms. The second route is “tolerance”, which is defined as the ability of the host to maintain its health in the presence of pathogens. For example, a tolerant host would not get very sick as pathogen levels increase. We’ve found that it is simple to manipulate both resistance and tolerance mechanisms in our model system and this provides hope for new therapies. Tolerance is not a panacea, however, as it can result in hosts carrying high levels of pathogens and therefore we need to think carefully about how resistance and tolerance can be manipulated together to increase animal health during an immune response.

Bio: David Schneider is interested in the pathogenesis of infectious disease and uses the fruit fly as a model host for viral, parasite and bacterial infections. David was raised in Ottawa Canada and attended the University of Toronto as an undergraduate. He received his Ph.D. in Molecular Biology at the University of California at Berkeley, in Kathryn Anderson’s lab. There he studied the role of Toll signaling in Drosophila development. David followed this with a postdoc at UCSF and a position as a Whitehead Fellow where he started to look at the immune system of the fly, using the fly as a model mosquito to study vector borne diseases. Once at Stanford, he started to use the fly more generally, as a model animal to study infections. David tries to integrate all of the physiological changes occurring in a host during an infection to understand what it means to be sick and not just how a host kills a microbe.

Contact Details: David Schneider, Department of Microbiology and Immunology, Stanford University, Stanford, CA. Email: david.schneider@stanford.edu

Title: Mapping resistance to chicken gut bacterial pathogens – Salmonella and Campylobacter

Abstract:

Pete Kaiser¹,², Mark S Fife², Joanna Howell², Nigel Salmon², Pauline M van Diemen², Paul M Hocking¹, Michael A Jones²,³ and Mark P Stevens²

¹The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9PS, UK
²Institute for Animal Health, Compton, Berkshire RG20 7NN, UK
³Current address: School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Leicestershire LE12 5RD, UK
Corresponding author: pete.kaiser@roslin.ed.ac.uk

Salmonella and Campylobacter are major zoonotic bacterial pathogens. Around 10,000–30 000 cases of human salmonellosis and 40,000-60,000 cases of human camylobacteriosis were reported per annum in England and Wales alone in the past decade (Health Protection Agency, 2008; http://www.hpa.org.uk). The vast majority of human cases arise from the consumption of infected poultry. One sustainable solution would therefore be to reduce contamination of poultry by identifying disease resistance genes. In contrast, intravenous challenge with S. Typhimurium provides a valuable model for systemic infection, often causing a typhoid-like infection, with bacterial replication resulting in the destruction of the spleen and liver of infected animals.
Resistance to systemic salmonellosis, and to colonisation with either Salmonella or Campylobacter, is partly genetically determined. For systemic salmonellosis, we have confirmed and refined a resistance locus, SAL1, to a region of Chromosome 5 spanning 14 genes, including two very striking functional candidates; CD27-binding protein (Siva) and the RAC-alpha serine/threonine protein kinase homolog, AKT1 (protein kinase B, PKB).
Two inbred lines of chickens, 61 and N, are respectively resistant and susceptible to colonisation with either Salmonella or Campylobacter. Using a backcross experimental design and a high density genome-wide SNP panel, we have identified 4 resistance QTL for each colonisation model. Interestingly and perhaps surprisingly, none of the QTL regions are in common for the two colonisation models.

Bio: I have recently moved to the Roslin Institute, R(D)SVS, University of Edinburgh to a Chair in Animal Infectious Diseases, after 18 years at the Institute for Animal Health where I was recently Head of the Avian Infectious Diseases Programme and Acting Head of the Division of Immunology.

As primarily an immunologist, the focus of my group is on maximising the utility of avian genomes, through their exploitation, to improve understanding of host/pathogen interactions and disease resistance mechanisms. My group therefore has these main aims: 1) to clone and characterise avian cytokines, comparing their numbers and functions to those of their mammalian orthologues; 2) to understand the role of cytokines in driving avian innate and adaptive immune responses; 3) to identify cytokines with the potential to act as vaccine adjuvants and/or immunomodulators, and to investigate that potential; 4) to develop a comprehensive understanding of the molecules and cells of the avian innate immune response, particularly the function of heterophils (the avian equivalent of the neutrophil) and dendritic cells; 5) to use this understanding to identify disease resistance genes.

I am chairman of the Comparative and Veterinary Immunology Affinity Group of the British Society for Immunology, Avian Co-Chair of the Toolbox Committee of the Veterinary Immunology Committee (International Veterinary Immunology Society) and an Editorial Advisory Board member of Developmental and Comparative Immunology, Immunogenetics and Veterinary Immunology and Immunopathology. I am also a member of the Houghton Trust, a member of the Peer Review Panel of the Danish Council for Strategic Research and a member of the BBSRC Tools and Resources Strategy Panel.

Abstract: There has been a wide range among species and countries in the effectiveness with which modern livestock breeding methods have been employed. Most of the improvement has been made in quantitative traits using selection methods based on phenotype of individuals and their relatives for these traits, despite effort put into, for example, using genetic markers to identify QTL. Questions to address are: (1) What are current rates of response and are they sustainable? (2) To what extent will new concerns such as greenhouse gas emissions and pressure on limited natural resources influence opportunities, and how might these be met? (3) What opportunities are offered by new technologies to enhance rates of improvement both by utilizing genomics and other ‘omics in conventional programmes and by more radical means?

Bio: I am Emeritus Professor of Animal Genetics at the University of Edinburgh, having been on the academic staff since 1965. My areas of interest have continued to be centred on population and quantitative genetics, covering both theory and application, in particular to livestock improvement. Theoretical research has included developments in predicting selection response, particularly in the long term, from variation both initially present and from mutation; developments of methods for predicting effective population size and its influence on population dynamics; and more recently on factors maintaining and changing both genetic and environmental variation over evolutionary and shorter time scales. I have undertaken applied work in several species, often with industry partners, which has focussed on genetic parameter estimation and breeding programme design and evaluation. My current interests include analysis of relationship from genomic data.

Contact details: William G. Hill, Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JT, UK. E-mail: w.g.hill@ed.ac.uk

Title: Improving efficiency of animal protein production with genomic selection

Abstract: Production of sufficient protein to satisfy demand given projected population growth will be a major challenge in coming decades, particularly if climate change predictions are considered. Animal breeding has met the challenge of improving efficiency of protein production in the past, and will continue to do so. However rates of genetic gain for efficiency can be improved using a new technology called genomic selection. Results from genome wide association studies in livestock, and humans, has lead to the conclusion that the effect of individual quantitative trait loci (QTL) on complex traits, such as yield, are likely to be small, and that a large number of QTL are necessary to explain the genetic variation in these traits. Genomic selection overcomes this problem by estimating breeding values as the sum of the effect of all of the dense DNA markers across the genome. In dairy cattle breeding, the accuracy of estimated breeding values which can be achieved and the fact that these are available early in life has lead to rapid adoption of the technology. Genomic selection allows for increased rates of gain for traits which have been hard to select for in the past: the example is given here of reduced sensitivity of milk production to heat stress.

Contact Details: Ben J. Hayes, Biosciences Research Division, Department of Primary Industries Victoria, Melbourne, Victoria, Australia. Email: ben.hayes@dpi.vic.gov.au

HELEN SANG

Abstract: Genetic modification technologies for the major livestock species were developed in the 1980s, although methods for use in poultry have been slower in becoming available. The technologies have become more sophisticated and more efficient, with the use of nuclear transfer in mammals and the use of lentiviral vectors in birds and mammals. The advantages and limitations of these methods will be discussed. Methods that have been developed for genome modification in the chicken, for example primordial germ cell culture, will also be described. Transgenic technologies continue to be improved by adopting advances from other fields, particularly the gene therapy field. The potential for use of site-specific zinc finger nucleases for direct manipulation of the genome, by inducing site-specific mutations and with the potential for promoting high frequency homologous recombination is an exciting new area in transgenic technologies. The potential for generating ES cells from livestock species, a goal that has not been achieved by adapting the mouse ES cell derivation methods, by using the induced pluripotential stem cell approach, also has the potential to increase the efficiency and sophistication of transgenic technologies in farmed animal species.
Now that increasingly efficient and more sophisticated genome modification technologies are available, it is possible to consider the potential for their use in modification of production animals. Many potential applications have been discussed over the last 20 years but few have been extensively tested. The possible areas of applications will be discussed, with the example of avian influenza resistance by transgenesis in the chicken, and the issues of public acceptance considered.

Bio: Helen Sang has a background in genetics and molecular biology. She was a Principal Investigator at The Roslin Institute and has been appointed to a personal chair at the University of Edinburgh, following the merger of Roslin with the Royal (Dick) School of Veterinary Sciences. Her research has been focused on the development of technologies for genetic modification of the chicken. Genetic modification of the chicken using lentiviral vectors is being utilised in a number of projects, from basic developmental biology to the production of therapeutic proteins in hens’ eggs and disease resistance by transgenesis.

Contact details: Helen Sang, The Roslin Institute, Roslin, Midlothian EH25 9PS, U.K. Tel:5274200. Email: helen.sang@roslin.ed.ac.uk

Title: Trypanosomiasis resistant cattle

Abstract: Jayne Raper, Russell Thomson, Aris Economides, Jose Cibelli, Alan Archibald, Bruce Whitelaw, Harry Noyes, Stephen Kemp.

Bovine African Trypanosomiasis is prevalent in 36 countries of sub-Saharan Africa. It is caused by Trypanosoma congolense, T. vivax, and T. brucei brucei and is transmitted by tsetse flies. Humans are protected from these parasites due to an innate immune complex called trypanosome lytic factor (TLF), a subtype of high-density lipoprotein. TLF is a primate specific immune factor ONLY found in humans, some Great Apes and Old World Monkeys. Within the lipid/protein complex apoL-I is the component that is necessary for the lethal action of TLF. We have shown that expression of exogenous human APOL1 in mice, which are susceptible to trypanosomiasis, protects them against infection by T. congolense, T. b. brucei and T. evansi.
Two other species, T. b. rhodesiense and T. b. gambiense, are resistant to human TLF and therefore infect humans and cause sleeping sickness. Cattle are also infected by T. b. rhodesiense and due to their close proximity with humans act as reservoirs that facilitate the transmission of Human African Trypanosomiasis.

Some Old World Monkeys including baboons are naturally resistant to all African trypanosomes. We have recently isolated the baboon APOL1 orthologue, which is 60% similar to human APOL1. Mice transiently transfected with this gene are protected against human infective species T. b. rhodesiense as well as the cattle pathogens T. congolense and T. b. brucei. Due to this discovery we are developing transgenic cattle that carry baboon APOL1 and will evaluate their ability to resist infection. If successful this could lead to improved sustainability of livestock in a broad region of the developing world.

Contact Details: Jayne Raper, New York University School of Medicine, New York, USA  Email: jayne.raper@med.nyu.edu