Take-out # 6
A. Chakravarti and A. Kapoor. Mendelian Puzzles.. Science. 2012. 335:930-931.
An essential first step for this assignment is, given a citation, is to be able to obtain
the article. Pdfs are not always there for the picking.
1. How can a recessive allele be “sheltered in carriers for hundreds of
generations”?
A recessive mutation in the heterozygous state would not be manifested by
phenotype because it would be masked by the dominant allele. The phenotype
conferred by the recessive mutation will only be observed in the homozygous
condition. This statement is made, but not expanded upon, in the article.
Therefore, some speculation/integration/outside research was necessary.
2. What is an exome and how is one characterized?
The exome is the protein-coding fraction of the genome. It can be
characterized by sequencing the protein coding portions of the genome (exons).
Current technology does not allow for efficient direct sequencing of just exons
in a sample of total genomic DNA. Therefore, the products of expressed genes
that reflect the information in exons – mRNAs will be sequenced. The actual
sequencing may be performed on DNA complementary to the RNA. This term
was defined in the article, but the way an exome is characterized was not
defined. Therefore, some speculation/integration/outside research was
necessary.
3. How can mutations in two adjacent genes lead to the same phenotype?
The same phenotype can occur when two adjacent genes are controlled by the
same regulatory system – even if the genes are not duplicates of each other.
See highlighted section of pdf.
4. Describe three different ways that individuals with the same specific
phenotype do not have identifiable mutations in the coding region of the
same gene.
The same phenotype can be caused by different genes; the same phenotype may
be caused by alternative regulation of the same gene; the environment may
induce the same phenotype in individuals with different forms of the same gene.
See highlighted section of pdf.
5. What is the meaning of “penetrance”, as used in genetics?
Penetrance is the proportion of individuals in a population that have the same
allele and show the same phenotype. This term was defined as “phenotypic
discordance” - see highlighted section of pdf. But the meaning of “phenotypic
discordance” may not be intuitively obvious.
6. According to the article, what is the most likely cause of incomplete
penetrance?
Interactions of a primary gene with other modifier genes. Epistasis anyone? See
highlighted section of pdf.
7. Assuming the “noncoding” DNA referred to in the article is the same as the
“dark matter” referred to in an earlier assigned reading, explain how
individuals with the same mutation in the same gene could have different
phenotypes.
Two individuals could have the same mutation, but differ in the elements that
regulate the gene – e.g. enhancers, slicers, insulators and splice site controllers.
These elements (DNA sequences) are located in the dark matter. See
highlighted section of pdf.
8. Explain how it possible for a regulatory element to be (i) linked with gene
that is regulated, (ii) unlinked but on the same chromosome with gene that
is regulated, or (iii) on a different chromosome from the gene that is
regulated.
The regulatory elements may be a binding site for transcription factors – DNA
binding proteins - that can have effects on the expression of target genes at a
great distance. Or the regulatory elements themselves could be encoding
transcription factors or regulatory RNAs. This statement is made, but not
expanded upon, in the article. Therefore, some speculation/integration/outside
research will be necessary.
9. Why would natural selection against regulatory elements be weaker than
selection for deleterious mutations in the coding regions of genes?
Mutations in regulatory elements are less apparent than mutations in coding
regions; therefore they can exist undetected until paired with a disease
mutation. See highlighted section of pdf.
10. According to the article, simple Mendelian inheritance - based on mutations
in coding regions of genes - is more of an exception than the rule. Why, then,
have you just spent a quarter studying the exception, rather than the rule?
New genetic characteristics that arise through mutation can be crucial for
evolution. Mutations selected by humans are the basis of agriculture. Mutations
are the only “new” source of genetic material, everything else is a predictable
product of recombination. Genetics is complex – simple Mendelian models
provide a framework for starting to understand this complexity. This question
is not addressed in the article. Therefore, an opinion, based on material
presented in this class and/or outside reading, is required.