Further studies of the genes in the region around the MHC locus identified C4 as a likely causative gene. A particular allele of C4 was significantly associated with schizophrenia. In addition, it was found that individuals with high expression of this allele of C4 had elevated risk of developing schizophrenia. Which of the following variants would be most likely to increase risk of schizophrenia from this allele? a. a variant that decreases binding of an activating transcription factor to the C4 promoter
b. a 5’ UTR variant that destabilizes the C4 mRNA
c. a duplication of the C4 gene
d. a nonsense coding variant

c. a duplication of the C4 gene

Explanation:

Schizophrenia is a disease that affects the brain, which is characterized by an imbalance of neurotransmitters and the presence of damaged brain tissues. In humans, the Complement component 4 (C4) protein is found at the neurons (i.e., cell bodies, dendrites and axons), which are the most common brain cells, and neuronal synapses. Moreover, gene duplication can increase gene expression when repressive mechanisms (e.g., DNA methylation at promoter sites) capable of silencing the expression of the duplicated gene are lacking. Recently, it has been discovered that a chromosome rearrangement associated with a tandem duplication of a genomic region that contains a C4 gene may contribute to schizophrenia risk by increasing the expression of this gene​. In this example, a, b and d options are associated with a decrease in expression of the C4 gene, either by decreasing its transcription (options a and d) or by posttranscriptional mechanisms (option c).

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