Pedigree Analysis Assignment Help
Why do Pedigrees?
Punnett squares and chi-square tests work well for organisms that have large numbers of offspring and controlled matings, but humans are quite different:
- small families. Even large human families have 20 or fewer children.
- Uncontrolled matings, often with heterozygotes.
- Failure to truthfully identify parentage.
Goals of Pedigree Analysis
- Determine the mode of inheritance: dominant, recessive, partial dominance, sex-linked, autosomal, mitochondrial, maternal effect.
- Determine the probability of an affected offspring for a given cross.
- We will now look at how various kinds of traits are inherited from a pedigree point of view.
- Traits on the Y chromosome are only found in males, never in females.
- The father’s traits are passed to all sons.
- Dominance is irrelevant: there is only 1 copy of each Y-linked gene (hemizygous).
- Mitochondria are only inherited from the mother.
- If a female has a mitochondrial trait, all of her offspring inherit it.
- If a male has a mitochondrial trait, none of his offspring inherit it.
- Note that only 1 allele is present in each individual, so dominance is not an issue.
- In any pedigree there are people whose parents are unknown. These people are called “outsiders”, and we need to make some assumptions about their genotypes.
- Sometimes the assumptions are proved wrong when the outsiders have children. Also, a given problem might specify the genotype of an outsider.
- Outsider rule for dominant pedigrees: affected outsiders are assumed to be heterozygotes.
- Outsider rule for recessive pedigrees: unaffected (normal) outsiders are assumed to be homozygotes.
- Both of these rules are derived from the observation that mutant alleles are rare.
Maternal Effect Genes
- The maternal effect rule: “Mother’s genotype determines offspring’s phenotype.”
- Assume that the trait is recessive, in a complete dominance situation.
- Also assume all “outsiders” (people with unknown parents) are homozygous for the allele they are expressing : the dominant allele if they are unaffected, and the recessive allele if they are affected.
- Assume that the trait is dominant in males but recessive in females.
- Assume all outsiders are homozygotes.
- DD is always affected
- dd is always normal
- Dd is affected in males, but normal in females
- There are several possibilities for dominance, but for this problem assume the trait is dominant but only expressed in males.
- Affected outsider males are heterozygous; unaffected males are homozygous normal
- Assume that outsider females are homozygous normal.
- Mothers pass their X’s to both sons and daughters
- Fathers pass their X to daughters only.
- Normal outsider rule for dominant pedigrees for females, but for sex-linked traits remember that males are hemizygous and express whichever gene is on their X.
- XD = dominant mutant allele
- Xd = recessive normal allele
- males get their X from their mother
- fathers pass their X to daughters only
- females express it only if they get a copy from both parents.
- expressed in males if present
- recessive in females
- Outsider rule for recessives (only affects females in sex-linked situations): normal outsiders are assumed to be homozygous.
- Assume affected outsiders are assumed to be heterozygotes.
- All unaffected individuals are homozygous for the normal recessive allele.
- All affected are homozygotes.
- Unaffected outsiders are assumed to be homozygous normal
- Consanguineous matings are often (but not always) involved.
- We are now going to look at detailed analysis of dominant and recessive autosomal pedigrees.
- To simplify things, we are going to only use these two types.
- The main problems:
- determining inheritance type
- determining genotypes for various individuals
- determining the probability of an affected offspring between two members of the chart.
Dominant vs. Recessive
Is it a dominant pedigree or a recessive pedigree?
- If two affected people have an unaffected child, it must be a dominant pedigree: D is the dominant mutant allele and d is the recessive wild type allele. Both parents are Dd and the normal child is dd.
- If two unaffected people have an affected child, it is a recessive pedigree: R is the dominant wild type allele and r is the recessive mutant allele. Both parents are Rr and the affected child is rr.
- If every affected person has an affected parent it is a dominant pedigree.
Assigning Genotypes for Dominant Pedigrees
- All unaffected are dd.
- Affected children of an affected parent and an unaffected parent must be heterozygous Dd, because they inherited a d allele from the unaffected parent.
- The affected parents of an unaffected child must be heterozygotes Dd, since they both passed a d allele to their child.
- Outsider rule for dominant autosomal pedigrees: An affected outsider (a person with no known parents) is assumed to be heterozygous (Dd).
- If both parents are heterozygous Dd x Dd, their affected offspring have a 2/3 chance of being Dd and a 1/3 chance of being DD.
Assigning Genotypes for Recessive Pedigrees
- all affected are rr.
- If an affected person (rr) mates with an unaffected person, any unaffected offspring must be Rr heterozygotes, because they got a r allele from their affected parent.
- If two unaffected mate and have an affected child, both parents must be Rr heterozygotes.
- Recessive outsider rule: outsiders are those whose parents are unknown. In a recessive autosomal pedigree, unaffected outsiders are assumed to be RR, homozygous normal.
- Children of RR x Rr have a 1/2 chance of being RR and a 1/2 chance of being Rr. Note that any siblings who have an rr child must be Rr.
- Unaffected children of Rr x Rr have a 2/3 chance of being Rr and a 1/3 chance of being RR.
- Determining the probability of an affected offspring for most crosses is quite simple: just determine the parents’ genotypes and follow Mendelian rules to determine the frequency of the mutant phenotype.
- In some cases, one or both parents has a genotype that is not completely determined. For instance, one parent has a 1/2 chance of being DD and a 1/2 of being Dd.
- If the other parent is dd and this is a dominant autosomal pedigree, here is how to determine the overall probability of an affected phenotype:
- determine the probability of an affected offspring for each possible set of parental genotypes.
- Combine them using the AND and OR rules of probability
Conditional Probability, Pt. 2
- In our example, one parent has a 1/2 chance of being Dd and a 1/2 chance of being DD, and the other parent is dd.
- There are thus 2 possibilities for the cross: it could be DD x dd, or it could be Dd x dd. We have no way of knowing for sure.
- If the cross is DD x dd, all the offspring as Dd, and since the trait is dominant, all are affected.
- On the other hand, if the cross is Dd x dd, ½ the offspring are Dd (affected) and ½ are dd (normal).
- So, there is a ½ chance that the mating is DD x dd, with all offspring affected, and a ½ chance that the mating is Dd x dd, with ½ the offspring affected.
- Or: (1/2 * 1) + (1/2 * 1/2) = overall probability
- = 1/2 + 1/4 =3/4
- More complicated: in a recessive pedigree, one parent has a ½ chance of being RR and a ½ chance of being Rr, while the other parent has a 1/3 chance of being RR and a 2/3 chance of being Rr.
- In this case there are 4 possible matings:
- There is a 1/2 * 1/3 = 1/6 chance that the mating is RR x RR. In this case, 0 offspring will be affected (rr).
- There is a 1/2 * 2/3 = 2/6 = 1/3 chance that the mating is RR x Rr. In this case, none of the offspring are affected.
- There is a 1/2 * 1/3 = 1/6 chance that the mating is Rr x RR. In this case, no offspring will be affected (rr).
- There is a 1/2 * 2/3 = 1/3 chance that the mating is Rr x Rr. In this case, 1/4 of the offspring will be affected (rr).
- Combining all possibilities:
- (1/6 * 0 ) + (1/3 * 0) + (1/6 * 0) + (1/3 *1/4) = 0 + 0 + 0 + 1/12 = 1/12