What is Whole Genome Sequencing (WGS)?

Whole Genome Sequencing (WGS) is the most comprehensive method for analyzing an individual’s complete DNA sequence. It decodes 100% of the genome, including coding (exons), non-coding (introns, promoters, enhancers), repetitive regions, and regulatory elements, enabling a full view of genetic variation.

WGS captures single nucleotide variants (SNVs), insertions/deletions (indels), copy number variations (CNVs), structural variants (SVs), and even mitochondrial DNA mutations — making it a powerful tool for both clinical diagnostics and research discovery.

Overview

• Purpose: Decode the entire genome to identify all types of genetic variation

• Target Area: Entire nuclear and mitochondrial genome (~3.2 billion base pairs)

• Applications: Rare disease diagnosis, cancer genomics, population genetics, infectious disease tracking, pharmacogenomics

• Output: High-resolution map of all known and novel genomic variants

How WGS Works

1. Sample Collection & DNA Extraction
   Genomic DNA is extracted from biological samples like blood, saliva, or tissue.

2. Library Preparation
   DNA is fragmented and sequencing adapters are ligated to both ends.

3. Sequencing
   Libraries are sequenced using high-throughput platforms such as Illumina, MGI, Oxford Nanopore (ONT), or PacBio.

4. Data Processing & Alignment
   Raw reads are aligned to a reference genome (e.g., GRCh38) using tools like BWA or Minimap2.

5. Variant Calling & Annotation
   Software pipelines detect SNPs, indels, CNVs, and structural variants. These are annotated using databases such as ClinVar, gnomAD, OMIM, etc.

Applications of Whole Genome Sequencing

• Rare Disease Diagnosis
  Detects causative variants even outside coding regions when other methods fail.

• Cancer Genomics
  Identifies somatic mutations, structural rearrangements, and tumor mutational burden.

• Prenatal & Neonatal Screening
  Non-invasive or early detection of genetic abnormalities.

• Infectious Disease Genomics
  Tracks viral evolution (e.g., SARS-CoV-2), antimicrobial resistance, or pathogen outbreaks.

• Population & Evolutionary Genomics
  Studies human variation, ancestry, and natural selection patterns.

• Pharmacogenomics
  Evaluates how genes affect drug response and metabolism.

• Gene Discovery & Functional Genomics
  Links phenotype to genotype across regulatory and structural regions.

Advantages of WGS

• Complete Coverage
  Captures coding, non-coding, regulatory, and repetitive DNA.

• High Resolution
  Detects rare, common, and novel variants with base-pair accuracy.

• Unbiased
  Does not rely on gene panels or capture probes; ideal for discovering unknown variants.

• Structural Variation Detection
  Identifies large deletions, duplications, inversions, and translocations.

• Mitochondrial Sequencing
  Captures both nuclear and mitochondrial genomes in one workflow.

• Future-Proof
  Once sequenced, the data can be reanalyzed as new knowledge or tools emerge.

Key Features of WGS

Limitations and Challenges

• Cost
  Though decreasing, WGS is more expensive than targeted methods.

• Data Analysis Complexity
  Requires high computational power and expert bioinformatics.

• Variant Interpretation
  Many variants are of uncertain significance, especially in non-coding regions.

• Incidental Findings
  May reveal unexpected or unrelated genetic information (e.g., predisposition to disease).

• Ethical and Privacy Concerns
  WGS data is sensitive and must be stored and handled with strict confidentiality.