mtDNA & PEDIGREES Notes

CG VII
Dr Colin McClure
c.mcclure@ic.ac.uk

mtDNA & Y-DNA inheritance patterns
Identify the inheritance patterns of various genetic diseases
Interpret family pedigrees and determine how genetic information transfers between generations
Apply knowledge of inheritance laws to understand how disease alleles can affect phenotypes

Nuclear DNA is inherited from both parents / from all ancestors
mtDNA is only passed down from mother’s lineage
- Only egg supplies mitochondria to fertilised zygote

Mitochondrial genome extremely small compared to the nuclear genome
Despite small size, mitochondrial DNA mutations important cause for inherited disease
Several mtDNA copies in each individual cell
Acquired mtDNA mutations implicated in ageing & age-related disease, e.g. diabetes

Generations have Roman numerals
Individuals numbered from left so each individual has their own unique reference
Males = square, females = round, affected = filled (solid)
Diamond = sex unknown
Carriers might be dotted

With mtDNA analysis, scientists have been able to trace the migration routes of humans over the last 150,000 years or so

Similar to what has been done with mtDNA, scientists have also developed Y-DNA analysis and have traced it's migration routes

FOUR examples of Family trees and inheritance patterns
- Li-Fraumeni syndrome
- Cystic Fibrosis
- Duchenne Muscular Dystrophy
- Myoclonic Epilepsy with Ragged-Red Fibers (MERRF)

Questions:
1. Is the inheritance pattern autosomal dominant, autosomal recessive, X-linked recessive, or none of these?
2. Can there be any carriers of the disease?
3. What information is key to telling you about the inheritance pattern?
4. What can you say about the genotype of individuals 1 & 2 in generation I?
5. What is the likelihood of the children of cross I,1&2 to inherit Li-Fraumeni syndrome?
Answers:
1. Autosomal dominant
2. No
3. All children with the disorder have one affected parent, both M & F get the disorder, not all children are necessarily affected
4. 1 is normal, 2 must be heterozygous as has 1 normal child
5. 50%
Observations:
- Autosomal dominant: Each affected child has at least one affected parent
- There can be no carriers
- All affected individuals in this family tree have to be heterozygous, as all have one affected and one normal parent.
- Individual I,2 also has to be heterozygous as has one healthy child
- All non-affected individuals in the family tree have to be homozygous recessive
Punnett Square:
- 2 unaffected parents, Mother is carrier:
  - 50% children normal
  - 50% of daughters & sons affected
    
    \begin{array}{c|cc} & L & l \ \hline l & Ll & ll \ l & Ll & ll \ \end{array}

Questions:
1. Is the inheritance pattern autosomal dominant, autosomal recessive, X-linked recessive, or none of these?
2. Can there be any carriers of the disease?
3. What information is key to telling you about the inheritance pattern?
4. What can you say about the genotype of individuals 1&2 and 3&4 in generation I?
5. What can you say about the genotype of individuals 3&4 in generation II?
Answers:
1. Autosomal recessive
2. Yes
3. Skips generations, girls and boys are affected
4. at least one in each couple must be a carrier
5. Carriers
Observations:
- Autosomal recessive: Each affected child does not have at least one affected parent, skips generations, both F & M are affected
- There can be carriers
- All affected individuals in this family tree have to be homozygous, as the disease allele is recessive
- At least one individual in each set of grandparents has to be a carrier
- As both parents 3&4 (i.e. II,3&4) in generation II have to be carriers to be able to pass this condition to some of their children
Punnett Squares:
- Gen I Crosses (1&2, 3&4)
  - 2 unaffected parents, 1 must be carrier
  - 50% carriers of disease allele
    
    \begin{array}{c|cc} & F & f \ \hline F & FF & Ff \ F & FF & Ff \ \end{array}
    
    \begin{array}{c|cc} & F & f \ \hline F & FF & Ff \ f & Ff & ff \ \end{array}
- Gen II Cross (3&4)
  - 2 unaffected parents, both carriers
  - 50% of offspring carriers, 25% affected, 25% genotypically normal

Questions:
1. Is the inheritance pattern autosomal dominant, autosomal recessive, X-linked recessive, or none of these?
2. Can there be any carriers of the disease?
3. What information is key to telling you about the inheritance pattern?
4. What can you say about the genotype of individuals I,1&2?
5. What can you say about the genotype of individuals II,2&3?
Answers:
1. X-linked recessive
2. Yes, only F
3. Sons of carrier F affected or normal, while daughters carriers or normal
4. F must be a carrier, as M is normal
5. F must be a carrier, as M is normal
Punnett Square:
- 1 unaffected father & 1 carrier mother (heterozygous):
  - 50% daughter carriers
  - 50% sons affected
    
    \begin{array}{c|cc} & XC & Y \ \hline X & XCX & XCY \ X & XX & XY \ \end{array}

Questions:
1. Is the inheritance pattern autosomal dominant, autosomal recessive, X-linked recessive, or none of these?
2. What information is key to telling you about the inheritance pattern?
3. How is MERRF inherited?
Answers:
1. None of these
2. F pass it to all children, while M do not pass it on
3. Mitochondrial inheritance pattern, mitochondria in cytoplasm of egg, mothers pass to all of their children, fathers cannot pass it on as the mitochondria are in the sperm tail and are therefore not passed on
Observations:
- Mitochondrial inheritance
- Mothers pass the condition on to all of their children, as all inherit their mitochondrial DNA
- Only F can pass it on to the next generation
- Can not be explained with Punnett squares as is not carried on chromosomes

FOUR examples of Family trees and inheritance patterns
- Li-Fraumeni syndrome – Autosomal dominant
- Cystic Fibrosis – Autosomal recessive
- Duchenne Muscular Dystrophy – X-linked recessive
- MERRF – Mitochondrial inheritance