Question

You have found several families exhibiting a non-Alzheimer’s dementia and have shown that this disorder appears to be due to a Mendelian recessive allele.  Outline the protocol that you would use to successfully locate the chromosomal region for the disorder, to identify candidate genes, and to determine the probable candidate gene for causing the disorder.

Answer 1

Candidate genes are type of a genes that directly or indirectly regulating the developmental processes of the investigated traits, that could be confirmed by evaluating the effects of the gene variants during analysis. Candidate gene approach is mainly applied for gene-disease research and for genetic association studies.

Alzheimer's disease is a type of  disorder that causes brain cells to degenerate and die.

The first strategy employs a phenotype to genotype approach. Researchers examine polymorphic genomic markers such as short tandem repeats found commonly in families with a high burden of AD (two or more cases of AD among first–degree relatives) across multiple generations to identify broad genomic regions co-transmitted with the disease. This method, used to determine linkage or tendency of genes to be inherited together because of their spatial proximity, is known as linkage analysis. The technique is typically followed by positional cloning of candidate genes to test their contribution to AD. Linkage analyses were instrumental in the identification of genes associated with familial or early-onset AD, which is described in more detail below.

The second strategy for identifying the genetic risks of AD employs a genotype to phenotype approach. Researchers compare allele frequencies of available polymorphic markers such as single nucleotide polymorphisms (SNPs) between healthy (control) and sick (case) people to identify genes associated with AD. These studies are known as genome-wide association studies and represent modern genetic tools for studying complex or sporadic forms of AD or other parameters such as the concentration of soluble TREM2 in cerebrospinal fluid.