Genetics - Mapping Rare Variants

Front 1

Mendelian disease pattern

Back 1

Presence of some allele at ONE LOCUS sufficient to cause AD, AR, or XLR disease

Front 2

Locus heterogeneity exception

Back 2

Same gene/protein is defective in all sub-families of disease

Front 3

Allelic hetergeneity exception

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Each disease sub-family has problematic variants of same gene

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Predictive testing

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If defective gene is known, but particular variants are not
- Helps establish risk

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Allelic hetergeneity examples

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- Autosomal dominant = Achondroplastic dwarfism (FGFR3)
- Autosomal recessive = Cystic fibrosis (CFTR)
- X-linked recessive = Duchenne muscular dystrophy (DMD)

Front 6

Molecular markers

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Common DNA sequence variations
- Have at least 2 or more distinct possible sequences

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Markers physically close together

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Tend to be inherited together

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Markers far apart

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More likely to have cross-over event occur b/w them

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Markers on different chromosomes

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Always segregate independently of one another (kinda obvious...)

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Recombination fraction (θ)

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Probability of recombination occuring b/w marker and target loci
- From 0-0.5, or 0-50%

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centiMorgans (cM)

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= θ x 100
- Thus, if θ = 0.05, 0.05 x 100 = 5 cM

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Molecular markers close to target loci

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θ = 0, 0 cM, no possibility of crossover in b/w

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Phase

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Designation of which allele (normal or mutant) is on same chromosome with which molecular marker (A or B)

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Linkage in risk assessment

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Use pedigree and phase information to determine risk of disease

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Recombination probability if marker and loci are 1cM apart

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θ x 100 = cM, thus 1cM = 0.01 or 1%
- If recombination probability = 1%, chance against recombination = 99%

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Finding phase of fetus

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Examine disesae loci and marker pairs for pedigree
- Phases of parents matter most!

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Autosomal dominant risk

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If child gets disease allele, get disease
- If they inherit marker of same phase with disease, probably got disease...
- Only possibility is recombination
- If 1cM, recombination prob = 1%
- Chance of NOT having disease = 1%

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Autsomal recessive risk - CF

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2 brothers have, sister doesn't
- If new fetus has markers of NON-disease alleles (again 1cM), chance of getting disease = 0.01 x 0.01 = 0.01%

Front 19

Linkage mapping

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For locating unknown loci of Mendelian disease allele
- Req. ~400 markers
- ID allele/marker relationships in disease sub-families
- Screen genes for mutations
- Basically, narrow down options to find culprit

Front 20

Whole exome sequencing (WES)

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- Less costly way of searching for Mendelian disease-causing alleles
- Most diseases related to exons, protein product, abundance of such

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WES challenges

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- Sooo much information - 10's of 1000's variants in single person
- Prioritizing which variants are important
- Quality of library data still needs improving...

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WES & AR disease

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Began WES with AR because required 2 mutant alleles
- Consanguinous will have EXACT same 2 mutant alleles
- Non-consanguinous will have 2 mutants, prolly not the same

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WES & Miller syndrome

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Miller is AD, similar facial/limb deformities to teratogen Methotrexate
- Walked through the sequence of eliminating potential causative alleles by common genes in family