There are many different types of genetic tests that are used for a range of applications, from ancestry analysis to diagnosing clinical conditions like Alzheimer’s. The type of genetic test to be performed is based on your reason for testing. Each type of test differs in the information it can provide, the amount of data obtained from it, its cost, accuracy, and even the sample used for the test (saliva, blood, hair, etc.).
Genetic testing is used to identify the changes in your DNA sequences, also known as mutations or variations.
As a simple example- if the word “APPLE” were a gene sequence, it will be spelled correctly in the majority of people; however, you may carry a “variation” of this gene that is spelled as “APBLE.”
Biologically speaking, many of these changes are harmless, meaning small spelling variations do not alter the individual’s health. However, some variations are harmful or advantageous to varying degrees.
The analysis of your DNA data reveals what variations are present in your DNA and their effects on your health.
Genotyping test
The genotyping test is one of the most inexpensive tests available in the market. This test is also very popular among consumers since it is widely marketed by many direct to consumer (DTC) genetic companies like 23andme and AncestryDNA to perform ancestry and health analysis.
Genotyping reveals the differences in a sample DNA sequence by comparing it with the reference DNA sequence.
As a simple example, if A-P-P-L-E is the reference gene sequence, and the sample sequence is A-P-B-L-E, genotyping tests will be able to detect the P→ B change. This kind of change in a single letter is called a single nucleotide polymorphism (SNP). Your genome contains around 4-5 million SNPs that may be unique to you.
Most SNPs do not have any significant health implications; however, some of these differences may be indicative of the development of certain health conditions or certain unique traits related to your health and wellness. They can be advantageous or disadvantageous to various degrees. These DNA variants or genotypes may act alone or in concert with a few to several hundred other DNA variants to create a health impact.
Genotyping has a broad range of applications, including ancestry, pharmacogenomics (ADME), fingerprinting, clinical and health conditions, and lifestyle and wellness traits. Though generally, genotyping is not the test of choice for health or clinical applications.
A note on genotyping:
Genetic tests based on the genotyping chip method have an accuracy of more than 99% when performed using standardized protocols in certified labs. However, even the less than 1% inaccuracy amounts to a few hundred variants, some of which can be important. Typically, genotyping tests are not used for clinical or diagnostic purposes.
Targeted sequencing
The full human genome is 3 GB in size. You can imagine a book with chapters, pages, paras, and sentences which is 3 GB in size. Your clinician may only be interested in para two on page 100 in chapter 3 because it is relevant to the condition he/she is treating you for. He will order a test for your known as targeted sequencing, which is designed to read specific segments of the DNA. This test is much cheaper than reading the whole genome and has a significantly shorter turnaround time.
Targeted sequencing is typically used for:
- Diagnosing monogenic diseases: Monogenic diseases result from modifications in a single gene. Though relatively rare, they affect a number of people worldwide. Scientists currently estimate that over 10,000 human diseases are known to be monogenic. In cases of a strong clinical indication of such monogenic disorders, targeting sequencing can be done instead of examining the entire genome.
- Testing for specific variants among family members: If there’s a family history of a particular disorder, only the variant associated with the disorder can be tested in the other family members.
- To confirm the results from another genetic test: Targeted sequencing also helps confirm the presence of a mutation/variation before the results are given out.
Whole-Exome Sequencing (WES)
Though the genome is 3 GB in size, much of it is filled with pages that scientists don’t yet understand the meaning of. Approximately 98% of the genome is not yet understood. The 2% that scientists do understand is known as the exome. Many people prefer to go for a test that reveals the information in their entire exome- this is known as Whole-Exome Sequencing (WES).
Exome sequencing is typically used for:
- Clinical diagnostics: Exome sequencing can be used to identify the genetic change that causes a disease. Detecting disease-causing mutations can heavily influence the diagnostic and therapeutic approaches, can guide prediction of disease natural history, and makes it possible to test at-risk family members.
- Direct-to-consumer (DTC) tests: Some DTC genetic companies offer WES, which can be taken up by individuals who want to be proactive towards their health. Early diagnosis of clinical conditions (if present) can help with effective management through lifestyle modifications and early interventions.
- Identification of less reported variants: Many disease-association studies focus on the common variations present across the larger population. However, some disease-causing variants within the exome found in lesser frequencies may remain undetected in other genetic tests. The identification of such rare variants is one of the most important applications of WES.
Whole-genome sequencing test
If you prefer to have your whole genome analyzed, a Whole-Genome Sequencing (WGS) test is what would be performed for this purpose.
Whole-genome sequencing is typically used for:
- Research studies: WGS may be used in a Genome-Wide Association Studies (GWAS) – they aim to associate specific genetic variants to a particular disease. This involves scanning the entire genome of many different people to identify genetic markers that could contribute to the development of a disease or other traits.
- Clinical trials: One of the rapidly evolving fields of genomic research is personalized medicine: tailoring disease treatments according to the individual’s genes. Whole-genome sequencing captures a much broader set of variations that might contribute to the response.
- Diagnostic purposes: Exome sequencing is not the most popular choice for copy number variations detection. Some diseases like Huntington’s disease are caused due to such mutations. Since WGS sequences all of the genes, it can diagnose many more conditions compared to WES.
- If the cause of a medical condition is not specifically known, then WGS can help in broadly analyzing the Genome for disease-causing genetic features.
The accuracy of sequencing tests depends on what is known as ‘Coverage.’ Coverage, also termed as ‘sequencing depth,’ refers to the number of times the DNA sample gets sequenced. Essentially, the higher the number, the higher the accuracy.
| Technique | Cost | Site | Coverage | Data Size(depends on coverage) |
| Targeted sequencing | $300-$1000 | The specific region of interest | 200-1000x | 100 MB–5 GB |
| WES | $500 – $2000 | Exome | 150-200x | 5 GB–20 GB |
| WGS | $1000 – $3000 | Genome | 30-60x | 60 GB–350 GB |
Before choosing a genetic test, it’s important to keep in mind a few points:
- No one genetic test can predict/detect all diseases. There are genetic and non-genetic factors of diseases and all factors need to be considered as a whole to arrive at a diagnosis. In addition, not all genetic factors are known to science yet, so, even if the whole genome is sequenced, there will be many “variants of unknown significance” in the genome.
- The effects of a lot of mutations are still unknown.
- The results might be inconclusive. In some cases, the results may not provide any useful information about the gene of interest or may identify a variant whose effects are unknown at large.
- You may receive some unexpected results which may not be relevant to the condition being investigated. This often happens with whole-genome sequencing.
