Saturday, August 8, 2015

My Favorite (Y-linked) Pedigree...Part 1

This is my favorite pedigree to use in class because it requires student to develop an explanation based on evidence and their understanding of sex chromosome inheritance EVEN in the face of expert knowledge (i.e. textbooks and/or instructors) that contradicts their interpretation.  (See Part 2 of this post for ideas about how to incorporate bioinformatics and chromosome biology.)

Most Genetics textbooks indicate that there are no Y-linked diseases or disorders in humans.  I present my students with this pedigree.  I tell them that the affected individuals in the family (shaded shapes) are deaf.  I then ask the students to work individually or in groups to explain how deafness is inherited.

This pedigree is adapted from Wang, et al, (2013), American Journal of Human Genetics, 92 (2), pg. 301-306.  I reduced the number of generations and family members and altered the shading on one shape to make the pedigree a little easier for students to interpret.  Shapes with slashes are deceased family members.  The two family members indicated by black arrows were candidates for genome sequencing (see Part 2 if this post).

There is clear evidence for deafness being Y-linked in this family (deafness is only found in males and, most importantly, it is only passed from fathers to sons.  Also, with only two exception (see below) all sons of affected fathers are affected).  However, students are reluctant to suggest this explanation possibly because they have prior knowledge from other classes or textbooks indicating that there are no Y-linked diseases or disorders in humans.  In my experience students typically suggest a few alternative explanations (X-linkage, autosomal dominant, etc.) before someone sticks their neck out and suggests Y-linkage.

At this point I reveal the title for the paper:

The abstract indicates that Y-linked deafness results in part from a duplicated region of chromosome 1 that has incorporated into Y.  This interesting observation provides an engaging way to discuss chromosomal rearrangements, the importance of gene dosage, and even add an element of bioinformatics into class (see part II of this post).

Some Follow-Up Questions:

X-linked disorders tend to affect males more than females (as does deafness in this family)…how can we eliminate the possibility that deafness is X-linked?
X-linked disorders have several characteristics:
1) They are more common in males
2) They are passed from mothers to sons
We can’t eliminate X-linkage based only on characteristic 1.  However, there are no cases in which characteristic 2 is observed.  In my teaching experience students often latch on to characteristic #1 when analyzing inheritance patterns for X-linkage and fail to confirm X-linkage using (the more powerful) characteristic #2.

What is the evidence for the disorder being Y-linked?
Only males are affected.  Passed from fathers to sons.  All sons of affected fathers are affected (There appear to be two exceptions…see bellow.)

Deafness is only found in one branch of the family.  Suggest an explanation for the lack of deafness in the other two branches.
All three sons in generation IV all inherited a Y chromosome from their father.  The father was not deaf and therefore, is expected to have an unaffected Y chromosome.  This ‘normal’ Y was passed to two of the sons (IV-3 and IV-5).  The other son (IV-1…the first person on the pedigree with deafness) has inherited an affected Y chromosome.  The affected Y chromosome is likely to have originated from an error during meiosis in the father (I-1) (see Part II of this post for a more detailed explanation.)

There are two males in on the affected branch of the pedigree who have affected fathers but do not have deafness.  They are marked with an asterisk.  The authors of the study include this note about these individuals: “Asterisks indicate individuals who are on the affected branch but who were below the age of onset of symptoms at the time of examination.” Interpret this statement.
From this statement we infer that individuals are typically not deaf at birth but develop deafness later in life.  “Age of onset” refers to the age at which symptoms typically become apparent.  It is likely that these two individuals will become deaf when they are older.

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