INHERITANCE OF TRAITS PEDIGREE ANALYSIS ASSIGNMENT 4

The aim of this set of exercises (pages 8-14) is to familiarize with Mendelian inheritance + pedigree analysis + probabilistic inference. In case you want to know more about the disease genes appearing in the exercises: http://www.ncbi.nlm.nih.gov/omim A suggested way to perform this set: two students together Submission: At the beginning of III teaching period (deadline for all assignments).

Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

INHERITANCE - PEDIGREES

A member of a family who first comes to the attention is called the propositus. Usually the phenotype of the propositus is exceptional in some way (for example, the propositus might suffer from some type of disorder). The investigator then traces the history of the phenotype in the propositus back through the history of the family and draws a family tree, or pedigree, by using the standard symbols. Many variant phenotypes of humans are determined by the alleles of single autosomal genes (like Mendels pea phenotypes). The patterns in the pedigree have to be interpreted differently, depending on whether one of the contrasting phenotypes is a rare disorder or whether both phenotypes of a pair are common morphs of a polymorphism. Most pedigrees are drawn up for medical reasons and hence inherently concern medical disorders that are almost by definition rare.
Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

INHERITANCE - PEDIGREES

PEDIGREE ANALYSIS OF AUTOSOMAL RECESSIVE DISORDERS The corresponding unaffected phenotype must be determined by the corresponding dominant allele. For example, the human disease phenylketonuria (PKU) is inherited in a simple Mendelian manner as a recessive phenotype, with PKU determined by the allele p and the normal condition by P. Therefore, sufferers from this disease are of genotype p/p, and people who do not have the disease are either P/P or P/p. What patterns in a pedigree would reveal such an inheritance? The two key points are that (1) generally the disease appears in the progeny of unaffected parents and (2) the affected progeny include both males and females. If it is known that both male and female progeny are affected, a reasonbale assumption is a simple Mendelian inheritance of a gene on an autosome, rather than a gene on a sex chromosome. The following typical pedigree illustrates the key point that affected children are born to unaffected parents Both parents must be heterozygotes, say A/a; both must have an a allele because each contributed an a allele to each affected child, and both must have an A allele because they are normal. We can identify the genotypes of the children (in the order shown) as A/, a/a, a/a, and A/
Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

INHERITANCE - PEDIGREES

The pedigrees of autosomal recessive disorders tend to look rather bare, with few black symbols. A recessive condition shows up in groups of affected siblings, and the people in earlier and later generations tend not to be affected. To understand why this is so, it is important to have some understanding of the genetic structure of populations underlying such rare conditions. By definition, if the condition is rare, most people do not carry the abnormal allele The formation of an affected person usually depends on the chance union of unrelated heterozygotes. Inbreeding (mating between relatives) increases the chance that two heterozygotes will mate, like cousins in the pedigree. An ancestor who is a Heterozygote may produce many descendants who also are heterozygotes. In general: the smaller the population, the higher the probability that mating individuals are relatives.

Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

INHERITANCE - PEDIGREES

PEDIGREE ANALYSIS OF AUTOSOMAL DOMINANT DISORDERS Here the normal allele is recessive, and the abnormal allele is dominant. It may seem paradoxical that a rare disorder can be dominant, but remember that dominance and recessiveness are simply properties of how alleles act and are not defined in terms of how common they are in the population. In pedigree analysis, the main clues for identifying an autosomal dominant disorder with Mendelian inheritance are that the phenotype tends to appear in every generation of the pedigree and that affected fathers and mothers transmit the phenotype to both sons and daughters. Abnormal alleles can also arise de novo by the process of mutation.

Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

INHERITANCE - PEDIGREES

PEDIGREE ANALYSIS OF X-LINKED RECESSIVE DISORDERS Typical features in pedigrees: Many more males than females show the rare phenotype under study. This is because of the product law: a female will show the phenotype only if both her mother and her father bear the allele (for example, XA Xa Xa Y), whereas a male can show the phenotype when only the mother carries the allele. If the recessive allele is very rare, almost all persons showing the phenotype are male. None of the offspring of an affected male show the phenotype, but all his daughters are carriers, who bear the recessive allele masked in the heterozygous condition. Half the sons of these carrier daughters show the phenotype. None of the sons of an affected male show the phenotype under study, nor will they pass the condition to their offspring. The reason behind this lack of male-tomale transmission is that a son obtains his Y chromosome from his father, so he cannot normally inherit the fathers X chromosome, too.
Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

INHERITANCE - PEDIGREES An example problem Phenylketonuria (PKU) is a human hereditary disease resulting from the inability of the body to process the chemical phenylalanine, which is contained in the protein that we eat. PKU is manifested in early infancy and, if it remains untreated, generally leads to mental retardation. PKU is caused by a recessive allele with simple Mendelian inheritance. A couple intends to have children but consults a genetic counselor because the man has a sister with PKU and the woman has a brother with PKU. There are no other known cases in their families. They ask the genetic counselor to determine the probability that their first child will have PKU. What is this probability? The only way in which the man and woman can have a PKU child is if both of them are heterozygotes (it is obvious that they themselves do not have the disease). Both the grandparental matings are simple Mendelian monohybrid crosses expected to produce progeny in the following proportions: normal and PKU . It is known that the man and the woman are normal, so the probability of their being a heterozygote is 2/3, because within the P/ class, 2/3 are P/p and , 1/3 are P/P. The probability of both the man and the woman being heterozygotes is 2/3 x 2/3 = 4/9. If they are both heterozygous, then one-quarter of their children would have PKU, so the probability that their first child will have PKU is and the probability of their being heterozygous and of their first child having PKU is 4/9 x = 4/36 = 1/9, which is the answer.
Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

ASSIGNMENT SET 4

4.1. A rare human disease afflicted a family as shown in the pedigree. What is the most likely mode of inheritance? What would be the outcomes of the cousin marriages 1 x 9, 1 x 4, 2 x 3, 2 x 8 ?

4.2. In the accompanying pedigree, the black symbols represent individuals with a very rare blood disease. If you had no other information to go on, would you think it most likely that the disease was dominant or recessive? Give your reasons.
Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

ASSIGNMENT SET 4 4.3. The ability to taste the chemical phenylthiocarbamide is an autosomal dominant phenotype, and the inability to taste it is recessive. If a taster woman with a nontaster father marries a taster man who in a previous marriage had a nontaster daughter, what is the probability that their first child will be A nontaster girl A taster girl A taster boy What is the probability that their first two children will be tasters of either sex. 4.4. Bill and Mary are contemplating having children, but Bills brother has galactosemia (an autosomal recessive disease) and Marys great-grandmother also had galactosemia. Mary has a sister who has three children, none of whom have galactosemia. What is the probability that Bills and Marys s first child will have galactosemia? 4.5. Suppose that a husband and wife are both heterozygous for a recessive allele for albinism. If they have dizygotic (two-egg) twins, what is the probability that both the twins will have the same phenotype for pigmentation?
Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

ASSIGNMENT SET 4 4.6. The pedigree is for a rare, but relatively mild, hereditary disorder. Is the disorder inherited as a recessive or a dominant phenotype? Give genotypes for as many individuals in the pedigree as possible. Invent your own defined allele symbols. Consider the four unaffected children of parents III-4 and III-5. In all four-child progenies from parents of these genotypes, what proportion is expected to contain all unaffected children? 4.7. Tay-Sachs disease is a rare human disease in which toxic substances accumulate in nerve cells. The recessive allele responsible for the disease is inherited in a simple Mendelian manner. A woman is planning to marry her first cousin, but the couple discovers that their shared grandfathers sister died in infancy of Tay-Sachs disease. What is the probability that the cousins first child will have Tay-Sachs disease, assuming that all people who marry into the family are homozygous normal?
Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

10

ASSIGNMENT SET 4 4.8. The accompanying pedigree was obtained for a rare kidney disease. Deduce the the inheritance of this disease. If individuals 1 and 2 marry, what is the probability that their first child will have the kidney disease?

4.9 Consider the accompanying pedigree of a rare autosomal recessive disease, phenylketonuria (PKU). Assume that all people marrying into the pedigree lack the disease allele. If individuals A and B marry, what is the probability that their first child will have PKU? If their first child is normal, what is the probability that their second child will have PKU? If their first child has the disease, what is the probability that their second child will be unaffected 11

Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

ASSIGNMENT SET 4

4.10. A rare, recessive allele inherited in a Mendelian manner causes the disease cystic fibrosis. A phenotypically normal man whose father had cystic fibrosis marries a phenotypically normal woman from outside the family, and the couple consider having a child. Draw the pedigree as far as described. If the frequency in the population of heterozygotes for cystic fibrosis is 1 in 50, what is the chance that the couples first child will have cystic fibrosis? If the first child does have cystic fibrosis, what is the probability that the second child will be normal? 4.11. An X-linked dominant allele causes hypophosphatemia in humans. A man with hypophosphatemia marries a normal woman. What proportion of their sons will have hypophosphatemia?

Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

12

ASSIGNMENT SET 4 4.12. Duchenne muscular dystrophy is sex-linked and usually affects only males. Victims of the disease become progressively weaker, starting early in life. What is the probability that a woman whose brother has Duchennes disease will have an affected child? If your mothers brother (your uncle) had Duchennes disease, what is the probability that you have received the allele? If your fathers brother had the disease, what is the probability that you have received the allele? 4.13. A sex-linked recessive allele c produces a red-green colorblindness in humans. A normal woman whose father was colorblind marries a colorblind man. What genotypes are possible for the mother of the colorblind man? What are the chances that the first child from this marriage will be a colorblind boy? Of the girls produced by these parents, what proportion can be expected to be colorblind? Of all the children (sex unspecified) of these parents, what proportion can be expected to have normal color vision?

Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

13

ASSIGNMENT SET 4

4.14. A mans grandfather has galactosemia. This is a rare autosomal recessive disease caused by inability to process galactose, leading to muscle, nerve, and kidney malfunction. The man married a woman whose sister had galactosemia. The woman is now pregnant with their first child. Draw the pedigree as described. What is the probability that this child will have galactosemia? If the first child does have galactosemia, what is the probability a second child will have it. 4.15. In humans, color vision depends on genes encoding three pigments. The R (red pigment) and G (green pigment) genes are on the X chromosome, whereas the B (blue pigment) gene is autosomal. A mutation in any one of these genes can cause colorblindness. Suppose that a colorblind man married a woman with normal color vision. All their sons were colorblind, and all their daughters were normal. Specify the genotypes of both parents and all possible children, explaining your reasoning.

Inheritance - Pedigree analysis - ASSIGNMENT 4 / Evol disease genes 2010 / SVarvio

14