In exomic sequencing, affected the DNA of affected individuals and of related un
ID: 260422 • Letter: I
Question
In exomic sequencing, affected the DNA of affected individuals and of related unaffected individuals is sequenced and compared to search for the mutation responsible for the trait being studied.
A. What is exomic sequencing?
B. Why does this approach only work for rare, highly penetrant traits?
C. Why are variants that are present in common polymorphism databases ruled out?
D. If you were using this approach to search for the mutation responsible for a recessive trait, why must the affected individuals be homozygous for the mutation?
Explanation / Answer
A. Exomic sequencing is a genomic technique for sequencing all of the entire protein-coding genes in a genome also known as the exome.
B. False positive and false negative findings are associated with genomic resequencing approaches and is a critical issueGenetic heterogeneity and population ethnicity are also major limitations as they may increase the number of false positive and false negative findings which will make the identification of candidate genes more difficult.
Exome sequencing provides high coverage variant calls across coding regions, which are needed to separate true variants from noise. A few strategies have been developed to improve the quality of exome data such as:
C. Rare recessive disorders would not have single nucleotide polymorphisms (SNPs) in public databases such as dbSNP. More common recessive phenotypes may have disease-causing variants reported in dbSNP. Strategies in exome sequencing identifies genes with rare, potentially pathogenic variants in all or most sequenced individuals with a given disease. This approach narrows down the candidate set of genes by removing variants also found in databases of common polymorphisms such as dbSNP and also removing variants that are deemed to be unlikely to cause disease, such as synonymous or intergenic nucleotide substitutions, as this approach work only in rare specific traits that are highly penetrating.
D. A recessive mutation is one in which both alleles must be mutant in order for the mutant phenotype to be observed; that is, the individual must be homozygous for the mutant allele to show the mutant phenotype.
Recessive mutations inactivate the affected gene and lead to a loss of function. For instance, recessive mutations may remove part of or all the gene from the chromosome, disrupt expression of the gene, or alter the structure of the encoded protein, thereby altering its function.
Genes for recessive disorders are usually easier to identify than dominant disorders because the genes are less likely to have more than one rare nonsynonymous variant. Hence ,here the affected individuals must be homozygous.