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Mapping Mendelian and Complex Diseases: Genetics, Linkage and Association

This article discusses the genetic mapping of Mendelian and complex diseases, including linkage mapping in pedigrees and association mapping in populations. It explores topics such as natural mutants, heritability, twin studies, and the role of genes and the environment in disease development. The article also delves into various diseases such as snakebite, osteoporosis, schizophrenia, cystic fibrosis, and asthma, and explains the use of polymorphic markers for disease mapping.

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Mapping Mendelian and Complex Diseases: Genetics, Linkage and Association

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  1. Human Genetics, part I Liisa Kauppi (Keeney lab) Mapping Mendelian and complex diseases - Linkage mapping in pedigrees - Association mapping in populations

  2. Genes and Environment “Natural” mutants only Heritability: first degree relatives of a patient at greater risk For type I diabetes, l = 15 (6%/0.4%) Twin studies: Adopted (separated in infancy) Fraternal vs. identical twins Biological vs. non-biological siblings

  3. COMPLEX/MULTIFACTORIAL DISEASE MENDELIAN High penetrance, Single gene Polygenic, Reduced penetrance Pure environment Snakebite Osteoporosis Schizophrenia Cystic fibrosis Asthma Infectious disease “Common disease” Language Body weight Blood type Height HARD EASY Genes and Human Disease

  4. Polymorphic markers are needed for disease mapping Microsatellites Tandem arrays of simple repeats, for example (CA)n, n=15…27 MULTI-ALLELIC A Single nucleotide polymorphisms (SNPs) Abundant, perhaps 1 every 300 bp - RFLPs G BI-ALLELIC Mostly non-coding

  5. Genotype frequencies: Hardy-Weinberg equation B allele has frequency pb allele has frequency qp + q = 1 p2 (BB) + 2pq (Bb) + q2 (bb) = 1 Hardy-Weinberg equilibrium

  6. How are recessive traits maintained in a population? HWE of allele frequencies:p2 + 2pq+ q2= 1 Hypothetical example: in Sardinia, 1 in 5 individuals have straight hair This trait is determined by a single gene and it is recessive. S allele = curly hair, s allele = straight hair Frequency of s/s homozygotes is 0.2 Frequency of s allele is 0.45 (0.2) Frequency of S allele is 1 - 0.45 = 0.55 Gametes for next generation: Frequencies of genotypes and alleles remain unchanged from one generation to the next.

  7. HWE allows calculations of carrier frequencies for recessive traits (with caution) Example: Cystic fibrosis, alleles CF and cf Incidence 1/2000 births p2 + 2pq+ q2= 1 Frequency of cf/cf homozygotes is 0.0005 Frequency of cf allele is 0.022 (0.0005) Frequency of CF allele is 1- 0.022 = 0.978 Frequency of CF/cf heterozygotes is 2 x 0.978 x 0.022 = 0.043

  8. So what if genotypes at a locus are not in HWE? p2 + 2pq+ q2= 1 Suggests that assumptions are not met Example: heterozygote deficit could arise from recent admixture Population 1 Population 2 B freq 0.9 b freq 0.1 B freq 0.1 b freq 0.9 n=1000 n=1000 0.81+0.18+0.01 0.01+0.18+0.81 810+180+10 10+180+810 HWE B freq 0.5 b freq 0.5 0.25+0.5+0.25 n=2000 expected 500+1000+500 observed 820+360+820

  9. Departure from HWE (heterozygote excess): the Prion protein gene and human disease • PRNP gene linked to prion diseases e.g. CJD, kuru • A common polymorphism, M129V, influences the course of these diseases: the MV heterozygous genotype is protective • Kuru acquired from ritual cannibalism was reported (1950s) in the Fore people of Papua New Guinea, where it caused up to 1% annual mortality • Departure from Hardy-Weinberg equilibrium for the M129V polymorphism is seen in Fore women over 50 (23/30heterozygotes, P = 0.01)

  10. NR R NR NR NR R Linkage studies - recombination in a familyhow often are 2 loci separated by meiotic recombination? I 2 loci on same chromosome II Informative and uninformative meioses III Recombination fraction  is 2/6=0.33

  11. 2 5 16 2 1 34 3 1 32 4 1 4 1 4 2 32 NR NR NR NR NR R Recombination fraction  is 1/6=0.167 Recognizing recombinantsdoes the disease segregate with this marker? 1 I II 6 III

  12. 2 1 34 3 1 32 4 1 4 1 4 2 32 NR NR NR NR NR R OR R R R R R NR Recognizing recombinantsOften samples are missing I II III Recombination fraction  is 1/6=0.167 or 5/6=0.833

  13. 56 2 1 34 1 5 1 6 3 1 32 4 1 4 1 4 2 32 NR NR NR NR NR R But are these identical by descent? Recognizing recombinantsTracing additional family members can help I II III

  14. For the example pedigree with 1/6 recombinants: (1 - 0.167)5 x 0.167 Z = log = 0.632 (0.5)6 Which marker is the disease locus closest to?Lod scores Logarithm of odds (Lod) score Z Likelihood of loci being linked Likelihood of loci not being linked Z = log Lod scores between -2 and +3 are inconclusive Below -2  exclusion Above +3  linkage Requires a precise genetic model

  15. Which marker is the disease locus closest to?Multi-point lod scores chr 3p12-14 Waardenburg syndrome type 2 After Hughes et al. (1994) Nature Genet 7, 509-512

  16. 2 1 34 Number of shared parental alleles probability 32 32 1/4 2 3 1 1 1/2 4 2 1 4 1 0 1/4 Multifactorial diseases (no simple Mendelian inheritance pattern) Sib-pair analysis

  17. Affected sib-pairs Which loci do the affected sibs share more often than expected by chance? 2 1 34 2 1 34 Number of shared parental alleles Number of shared parental alleles 32 32 32 32 2 2 3 1 1

  18. Detecting linkage in pedigrees can be complicated…

  19. … and you need lots of meioses!

  20. Cases vs. controls HLA-DR4 allele (UK) General population 36% Rheumatoid arthritis patients 78% Seek correlation between genotype and phenotype Allele B is associated with disease D if people who have D also have B more often than predicted from B’s frequency To test every polymorphism is too expensive Association mapping in a population

  21. Linkage disequilibrium (LD) measures association between two alleles Mutation creates new variants A A G A A T G A Recombination reshuffles existing variation A T X LD diminishes G A If enough crossovers take place, the loci are in “free association” A A G T Commonly used LD measures: D’ and r2 Initially, the new allele is in LD with nearby alleles LD value = 1

  22. meiotic recombination creates novel haplotypes Markers form haplotype blocks in the population Haplotypes are sets of markers inherited as a “package”

  23. C T G A C A T G < 4 combinations -> LD Conversely: all 4 combinations -> low or no LD But also: population history, drift, selection… LD is a measure of allelic association in a population 2 SNP loci on the same chromosome C/G A/T

  24. Disease haplotypes shorten from one generation to the next

  25. Recombination hotspots are key in shaping haplotype blocks Perhaps at least 90% of crossovers take place at highly localized hotspots HLA class II Recombination activity Haplotype blocks Kauppi et al. (2004) Nat Rev Genet 5, 413-424

  26. A C T G or A G T C ? Other individuals in population A C A C T G T G How do you extract haplotypes from genotype data? A/T C/G Blood DNA Other family members

  27. Data just released: • A haplotype map of the human genome, Nature 437, 1299-1320 • HapMap project • Examines haplotypes in four populations • DNA samples: 270 people in total • Yoruba (Nigeria): 30 parent-child trios • Whites with North and West European ancestry (USA): 30 trios • Japan: 45 unrelated individuals • China: 45 unrelated individuals • Identify “haplotype tag SNPs” to minimize genotyping effort • >3,500,000 SNPs typed in total

  28. Limited within-block diversity Example: a 8.5-kb long block on chr 2, 36 SNPs typed In principle, could give rise to 236 different haplotypes Only seven different haplotypes found among 120 European chromosomes

  29. Recombination hotspots are widespreadand account for LD structure 7q21 The International HapMap Consortium

  30. G/C 3 G/A 2 T/C 4 G/C 5 A/T 1 A/C 6 G G A A G G G T T G G A C C C C C C C C C C C C A A A A T T G G G C C C high r2 high r2 high r2 Pairwise tagging Tags: SNP 1 SNP 3 SNP 6 3 in total Test for association: SNP 1 SNP 3 SNP 6 After Carlson et al. (2004) AJHG 74:106

  31. The Common-Disease Common-Variant Hypothesis • Says • disease-predisposing variants will exist at relatively high frequency (i.e. >1%) in the population. • are ancient alleles occurring on specific haplotypes. • detectable in a case-control study using tagging SNPs. • Alternative hypothesis says • disease-predisposing alleles are sporadic new mutations, perhaps around the same genes, on different haplotypes. • families with history of the same disease owe their condition to different mutations events.

  32. Does same phenotype mean same genotype? Coding SNPs, nonsynonymous or synonymous “Regulatory” SNPs

  33. Common Gene Variation in Complex Disease • Case-control studies, comparing the frequencies of common gene variants can identify susceptibility and protective alleles • Some have multiple identified genes (*) Phenotype IDDM* Alzheimer dementia Deep venous thrombosis Colorectal cancer NIDDM Gene HLA APOE F5 APC PPAR Variant DR3,4 E4 Leiden 3920A 12A

  34. Other types of variation may also have a role in complex disease common copy number polymorphisms large scale rearrangements, deletions and insertions microsatellite expansions, small insertion/deletions etc.

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