Introductory genetics for veterinary students

Transcription

1 Introductory genetics for veterinary students Michel Georges Introduction 1

2 References Genetics Analysis of Genes and Genomes 7 th edition. Hartl & Jones Molecular Biology of the Cell 5 th edition. Alberts et al. Table of contents Genes in cells Genes in pedigrees Genes in populations Evolutionary genetics Genome analysis Veterinary genetics 2

3 Veterinary genetics Identification and parentage control Managing recessive defects defects From empirical to genomic selection of complex traits of agronomic and medical importance Genomic information helps inventorize and preserve domestic animal biodiversity Genetic engineering of livestock Gene therapy Individual identification ( tracability ) Identification and parentage control is common practice in developed countries Microchipped dogs/horses Eartagged livestock ( tracability ) Herd/Studbook requirements 3

4 Individual identification ( tracability ) DNA fingerprinting is the ultimate identification tool = multilocus genotype at a sample of DSP Blood groups > microsatellites > SNPs In vitro cloning DNA fingerprinting 4

5 In vitro cloning DNA fingerprinting SNP chips 5

6 Individual identification ( tracability ) DNA fingerprinting is the ultimate identification tool = multilocus genotype at a sample of DSP Blood groups > microsatellites > SNPs Quality is measured by matching probability (identification) and exclusion power (parentage) Individual identification ( tracability ) Future DNA fingerprinting systems will include DSP dtermining visible phenotypes (f.i. coat color, fur type, horns, ) With sufficient DSP, animals can be assigned to specific breeds or in the case of admixture their breed composition estimated. 6

7 Breed assignment/composition Veterinary genetics Identification and parentage control Managing recessive defects defects From empirical to genomic selection of complex traits of agronomic and medical importance Genomic information helps inventorize and preserve domestic animal biodiversity Genetic engineering of livestock Gene therapy 7

8 Managing recessive defects Breeding programs cause reduction in effective population size (i.e. increase the rate of inbreeding) causing regular outbursts of recessive defects (particularly with AI) Demonstrating the inherited nature of a novel defects is not trivial Managing recessive defects Autozygosity mapping of the causative gene has become the most effective way to prove the genetic determinism 8

9 Autozygosity mapping Managing recessive defects Autozygosity mapping of the causative gene has become the most effective way to prove the genetic determinism Identifying the causative mutations is straightforward when it affects protein structure (i.e. 50% of the time). 9

10 Autozygosity mapping Managing recessive defects Diagnostic tests can be direct or indirect 10

11 Developing genetic tests: direct vs indirect Developing genetic tests: direct vs indirect? porteur non porteur 11

12 Developing genetic tests: direct vs indirect Managing recessive defects Diagnostic tests can be direct or indirect Avoiding at risk matings with or without diagnostic tests may be more effective than systematic culling of carriers. 12

13 Managing recessive defects Heterozygous advantage (due to pleiotropy or hitchiking) account for the high incidence of some genetic defects Inherited defects may cause early embryonic lethality Managing recessive defects Not all inherited defects have a simple monogenic determinism (f.i. White Heifer s disease, hip dysplasia,...) 13

14 OMIA: On-line Mendelian Inheritance in Animals Veterinary genetics Identification and parentage control Managing recessive defects defects From empirical to genomic selection of complex traits of agronomic and medical importance Genomic information helps inventorize and preserve domestic animal biodiversity Genetic engineering of livestock Gene therapy 14

15 From empirical to genomic selection: empirical selection Domestication has had a major impact on the genome of domestic species From empirical to genomic selection: empirical selection 15

16 From empirical to genomic selection: biometrical selection AI and biometrical selection have dramatically accelerated genetic progress From empirical to genomic selection: biometrical selection. without knowledge of the genes! 16

17 From empirical to genomic selection: biometrical selection Fisher, Wright, Henderson Breeders equation Genetic variation Accuracy of selection Environment Relatives (<-> infinitesimal model) Selection intensity (AI) 1/generation interval From empirical to genomic selection: biometrical selection The animal model 17

18 From empirical to genomic selection: QTL & MAS Advances in positional cloning of disease genes in humans in the 80- ies spurred efforts to map QTL in livestock QTL influencing nearly all economically important traits have been mapped in experimental or extant pedigrees. Experimental crosses: line cross model 18

19 Extant pedigrees: f.i. the grand-daughter design Extant pedigrees: f.i. the grand-daughter design 19

20 QTL example Mb 8 -> 56 BTA14 microsatellites From empirical to genomic selection: QTL & MAS Advances in positional cloning of disease genes in humans in the 80- ies spurred efforts to map QTL in livestock QTL influencing nearly all economically important traits have been mapped in experimental or extant pedigrees. 20

21 From empirical to genomic selection: QTL & MAS Haplotype sharing of progeny tested chromosomes has allowed finemapping of some QTL Identifying the causative QTN is very difficult and has only been achieved a handful of cases. QTL-based Marker Assisted Selection has had limited applicability Haplotype sharing of progenytested chromosomes 21

22 Haplotype sharing of progenytested chromosomes Haplotype sharing of progenytested chromosomes 22

23 From empirical to genomic selection: QTL & MAS Haplotype sharing of progeny tested chromosomes has allowed finemapping of some QTL Identifying the causative QTN is very difficult and has only been achieved a handful of cases. QTL-based Marker Assisted Selection has had limited applicability QTN identification has been achieved in a handful of cases 23

24 QTN identification has been achieved in a handful of cases From empirical to genomic selection: QTL & MAS Haplotype sharing of progeny tested chromosomes has allowed finemapping of some QTL Identifying the causative QTN is very difficult and has only been achieved a handful of cases. QTL-based Marker Assisted Selection has had limited applicability 24

25 From empirical to genomic selection: genomic selection Genomic selection emerged from: A conceptual breakthrough (Meuwissen & Goddard, 2001) Imagine HD SNP chips and LD Estimate all SNP effects in large training set Compute molecular breeding values in test set as sum of indivdiual SNP effects. A technological breakthrough High density SNP chips The GS revolution without knowing the genes 25

26 From empirical to genomic selection: the dog system Genes underlying common complex diseases are effectively identified in dogs to the benefit of human. The haplotype structure of the domestic dog 26

27 Across breed fine-mapping The LUPA project 27

28 Veterinary genetics Identification and parentage control Managing recessive defects defects From empirical to genomic selection of complex traits of agronomic and medical importance Genomic information helps inventorise and preserve domestic animal biodiversity Genetic engineering of livestock Gene therapy Genomics & domestic biodiversity Using genomic information to limit genetic erosion with breeds Using genomic information to inventorize and organize the world heritage of domestic breeds (f.i. FAO) 28

29 Veterinary genetics Identification and parentage control Managing recessive defects defects From empirical to genomic selection of complex traits of agronomic and medical importance Genomic information helps inventorise and preserve domestic animal biodiversity Genetic engineering of livestock Gene therapy Genetic engineering of livestock Gene augmentation, knock-out and targetting are feasible in livestock Gene pharming has been the primary driving force behind genetic engineering of livestock Contrary to plants, genetic engineering of production traits in livestock is in its infancy Is there a need/demand for engineered livestock? 29

30 Gene augmentation, knock-out and targetting are feasible in livestock Gene augmentation is achieved by pronuclear microinjection of transgenes The use of zing finger nucleases will allow gene KO in livestock Cloning by nuclear transfer paves the way for gene targeting in livestock Pronuclear microinjection 30

31 Using zinc finger nucleases to generate KO Nuclear transfer paves the way for gene targeting in livestock 31

32 Genetic engineering of livestock Gene augmentation, knock-out and targetting are feasible in livestock Gene pharming has been the primary driving force behind genetic engineering of livestock Contrary to plants, genetic engineering of production traits in livestock is in its infancy Is there a need/demand for engineered livestock? Gene pharming = using transgenic livestock as bioreactors for the production of highvalue proteins Examples: Pharma proteins Antibodies Xenotransplantation 32

33 Phraming: examples Gene pharming = using transgenic livestock as bioreactors for the production of highvalue proteins Examples: Pharma proteins Antibodies Xenotransplantation 33

34 Gene pharming = using transgenic livestock as bioreactors for the production of highvalue proteins Examples: Pharma proteins Antibodies Xenotransplantation 34

35 Xenotransplantation Genetic engineering of livestock Gene augmentation, knock-out and targetting are feasible in livestock Gene pharming has been the primary driving force behind genetic engineering of livestock Contrary to plants, genetic engineering of production traits in livestock is in its infancy Is there a need/demand for engineered livestock? 35

36 Gene pharming = using transgenic livestock as bioreactors for the production of highvalue proteins Examples: Pharma proteins Antibodies Xenotransplantation Engineering production traits: pilot experiments Enhanced ( designer ) food products Increased casein content Modified fatty acid content Lactose-free milk Disease resistance Mastitis resistance Prion disease resistance Enviro-pigs 36

37 Designer food products Engineering production traits: pilot experiments Enhanced ( designer ) food products Increased casein content Modified fatty acid content Lactose-free milk Disease resistance Mastitis resistance Prion disease resistance Enviro pigs 37

38 Disease resistance Engineering production traits: pilot experiments Enhanced ( designer ) food products Increased casein content Modified fatty acid content Lactose-free milk Disease resistance Mastitis resistance Prion disease resistance Enviro pigs 38

39 Enviro pigs Genetic engineering of livestock Gene augmentation, knock-out and targetting are feasible in livestock Gene pharming has been the primary driving force behind genetic engineering of livestock Contrary to plants, genetic engineering of production traits in livestock is in its infancy Is there a need/demand for engineered livestock? 39