What is a founder effect? Give examples. Define penetrance, expressivity

1. What is a founder effect? Give examples. Define penetrance, expressivity Ana Terron-Kwiatkowski, MRCPath part I course, London 2010

2. Founder effect, penetrance and expressivity Founder effect definition Origin and prevalence of common mutations High mutational rate in hot-spots Heterozygote advantage Genetic drift Founder effect - examples - Penetrance - Expressivity Value of genetic studies in small isolated populations Linkage mapping - rare Mendelian disorders Association studies - complex common diseases

3. What is a founder effect A founder effect can account for the presence of an allele at an unusually high frequency in an isolated population if the allele is selectively neutral and all copies are identical by descent with a copy that either was carried by a founder individual or arose by a mutation later. Founder effect can result from: - establishment of a new population from individuals derived from a much larger population - extreme reduction in population size - bottleneck - Alleles present in one copy can expand to high frequencies - even higher if strong genetic drift -

4. Origin and prevalence of common mutations 1- High mutation rate in hot-spots (CpG) recurrent ‘de novo’ mutations may compensate loss of mutant alleles due to lethality or reduce fitness in severe phenotypes - negative selection - common mutation occur in different haplotypes mutation frequencies similar in different populations 2- Heterozygote selective advantage - mutations occur in all populations at similar rate some of them may become more frequent due to selective advantage in particular environment CFTR Phe508del occur in different haplotypes, 4 common in Europe possibly a common ancestral haplotype, spread throughout Europe in different expansions - ß-Thalassemia among Kurdish Jews -protection against malaria

5. Origin and prevalence of common mutations 3- Genetic drift - random transmission of genotypes - can change allele frequencies associated with founder effect e.g. Gaucher disease in Norrbotten country 4- Founder effect - Common mutation occurred in an ancestral haplotype The more recent the mutation is, the more conserved the genetic region surrounding the mutation - Mutation frequency higher in founder population than in others - Strong LD between mutation and surrounding markers length of disease haplotype decreases with successive generations due to meiotic recombination - No selective advantage for mutation carriers

6. Common mutations due to founder effect Haemochromatosis – HFE p.C282Y common mutation - ancestral ‘celtic’ haplotype D6S248-D6S265-HLA-A-HLA-F-D6S105 associated with HH (Australia) and in strong LD with population controls. - other less common haplotypes originated by recombination (Scandinavia). Prothrombin 20210G>A and Factor V Leiden - common prothrombotic mutations in whites (1.7-2% and 4-5% respectively) - more frequent in Middle East - common ancestral haplotype - widespread distribution due to selective advantage: hemostasis, hemorrhage, protection against infection? (Factor V) Deafness- GJB2 c.35delG - major mutation for A.R. deafness in Caucasoids - mutation also detected in Jews of north-African or Middle East origin - carrier frequency 1:51 in overall European populations - founder effect + carrier advantage (in tissues other than than cochlea)

7. Common mutations due to founder effect LDLR G197del is most prevalent mutation causing FH in Ashkenazi Jews. highly conserved haplotype (chromosome 19) haplotypes differing from ancestral one LD decay over generations recurrent mutations on different haplotypes high penetrance mutation - 94% associated with severe hypercholesterolemia phenotypic expression not affected by known environmental factors or or modifying genes no evidence of selective metabolic advantage founder effect in rapidly expanding population

8. Founder mutations in BRCA genes BRCA1 and BRCA2 In some populations - wide spectrum of mutations Other populations - high frequency of specific BRCA1 and/or BRCA2 mutations  Founder effect Hereditary proportion of BRCA higher in Ashkenazi Jews due to 3 founder mutations rate 2.6% (0.2% mutation carriers in general population) Norway - 4 founder mutations account for 68% of BRCA1 mutations- high penetrance Finland - 11 founder mutations - 84% of BRCA1/2 mutations Iceland- BRCA2 c.999del5 mutation in 0.6% of population, 7.7% female BrCa, 40% male BrCa. Common haplotype. Strongly associated with age onset < 50 years. Penetrance and expression varies  environmental factors. Frequent mutation, not limited to those having a strong FH of BrCa  low penetrance

9. Founder mutations in BRCA genes

10. Founder mutations, penetrance and expressivity Founder mutations - might provide information regarding their penetrance and expressivity - apparent ‘de novo’ mutations may be due to low penetrance - carriers of founder mutation among the population controls Penetrance of a character for a given genotype is the probability that a person who has that genotype will manifest the character Expressivity of a particular genotype are the variable clinical feature(s) how the genotype can be manifested phenotypically

11. Genetic studies in small isolated populations ‘Population isolates’ proved useful for identification rare recessive disease genes - Limited number of founders - Disease alleles are enriched - Often one founder mutation In ‘population isolates’ genetic drift acts to randomly raise some alleles to fixation and send others to extinction, thus reducing heterogeneity: - enrichment of Tay-Sachs diasease in Ashkenazi Jews - low prevalence of CF in Finns Mapping genes underlying complex disorders may benefit from homogeneous populations with limited number of founders –‘founder populations’

12. Genetic studies of complex diseases in small isolated populations

13. Genetic studies of complex diseases in small isolated populations Genetic variants identified within isolates seemingly segregating a common disease in a near-Mendelian fashion are being replicated in large-scale population samples GWAS - hypothesis-free approach - in isolated populations require 30% fewer markers than in outbred populations - greater value when lower frequent variants are considered Problem of GWAS in genetic isolates: - Strong LD that initially help to identify disease locus may hamper to distinguish the biologically relevant variants from insignificant polymorphisms in complete LD - Comparing GWA data of different or heterogeneous populations will help to identify the causative variant/ gene

14. Genetic studies of complex diseases in small isolated populations Susceptibility to common complex diseases: - several common variants likely to explain a substantial fraction of heritable variation in complex traits - rare variants (or combination of) probably greater effects on phenotype increased frequencies in population isolates Each genetic isolate has unique profile of rare disease alleles → use multiple isolates to get a full picture Incidence and prevalence of many common diseases may vary between founder populations due to genetic background or environmental factors - environmental and phenotypic homogeneity can facilitate disease-gene identification

15. Genetic studies in small isolated populations: power of LD mapping in isolated populations LD mapping in isolated population of Newfoundland 6 affected individuals in 5 BBS families from Newfoundland (Canada) located Bardet-Biedl syndrome I (BBS1) locus within 1cM region around PYGM gene on chromosome 11q13 In European families BBS linked to 26cM region on 11q13 BBS genetic heterogeneity, 5 distinct loci on different chromosomes