Introduction to Genomics

Genomics is the study of the complete genetic material (genome) of an organism - every DNA sequence including protein-coding genes, regulatory elements, non-coding RNA, and repetitive regions. It integrates molecular biology, genetics, statistics, and computer science to answer one fundamental question: how does the sequence of DNA give rise to the biology of a living organism?

Unlike classical genetics which studies one gene at a time, genomics looks at the entire genome simultaneously. This systems-level view allows us to discover disease genes, understand evolution, predict drug responses, and diagnose rare conditions that were previously undiagnosable.

Core Branches of Genomics

• Structural genomics - sequencing, assembling, and physically mapping genomes; the foundation for everything else
• Functional genomics - determining what genes do: RNA-seq (expression), ChIP-seq (binding), ATAC-seq (accessibility)
• Comparative genomics - aligning genomes across species to identify conserved (important) regions and study evolution
• Clinical genomics - translating sequencing findings into diagnosis, prognosis, and treatment decisions
• Metagenomics - sequencing microbial communities (gut microbiome, environmental samples) without culturing
• Pharmacogenomics - predicting drug response from genetic variation (e.g., CYP2D6 variants affect codeine metabolism)
• Cancer genomics - identifying somatic driver mutations, fusions, and copy number changes in tumours

• ~3.2 billion base pairs (3.2 Gb) per haploid genome - if stretched, DNA from one cell would be ~2 metres long
• ~20,000–25,000 protein-coding genes - only ~1.5% of total DNA; the rest is regulatory, repetitive, or non-coding RNA
• 46 chromosomes (22 autosome pairs + XX or XY sex chromosomes) in diploid somatic cells
• ~99.9% identical between any two humans - variants in the remaining 0.1% (~3 million sites) drive most heritable disease
• Human Genome Project completed April 2003 after 13 years and $3 billion; first time any genome was sequenced
• T2T-CHM13 (2022) filled the remaining 8% gaps including centromeres; first truly complete human genome
• Average gene spans ~27 kb genomic space but encodes only ~1.3 kb of protein-coding sequence

The clinical impact of genomics has shifted from research curiosity to routine medical practice. Whole exome sequencing now provides diagnoses for 25–35% of patients with rare undiagnosed diseases who had previously exhausted all other investigations.

• Rare disease diagnosis: 1 in 17 people affected worldwide; 80% have a genetic origin; WES/WGS is now first-line for undiagnosed patients
• Cancer genomics: somatic driver mutations guide targeted therapy - EGFR in lung cancer, HER2 in breast, BRAF in melanoma
• Pharmacogenomics: CYP2D6 poor metabolisers accumulate codeine toxicity; HLA-B*57:01 causes abacavir hypersensitivity
• Newborn screening: 35+ conditions including PKU, congenital hypothyroidism, and SMA detectable from a heel-prick blood spot
• Infectious disease: Nanopore sequencing identified SARS-CoV-2 variants in real time; metagenomics diagnoses encephalitis in hours
• Hereditary risk: BRCA1/2 carriers have 70% lifetime breast cancer risk; Lynch syndrome confers 50% colorectal cancer risk
• Preimplantation genetic testing (PGT): embryo selection before IVF for families with known genetic conditions

A 4-year-old boy presented to a genetics clinic in Mumbai with severe hypotonia (low muscle tone), developmental delay, seizures, and elevated lactate. Over 3 years, he had undergone 47 investigations including MRI, muscle biopsy, metabolic panels, and chromosomal microarray - all inconclusive. His family had spent ₹18 lakhs on diagnostics.

Whole exome sequencing of the trio (child + both parents) was performed. Within 6 weeks, a de novo pathogenic variant was identified: NM_004249.3(HSD17B10):c.388A>G p.(Lys130Glu) in the HSD10 gene on the X chromosome, causing HSD10 mitochondrial disease (also known as 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency). This is an ultra-rare X-linked disorder with fewer than 50 reported cases globally.

• Time to diagnosis: 6 weeks by WES vs 3 years without it
• Variant type: de novo missense - required trio sequencing to identify
• Clinical impact: family counselled on recurrence risk (<1% for de novo), genetic testing of mother confirmed carrier status
• Management changed: started thiamine supplementation and mitochondrial cofactors; seizure medications optimised
• This case demonstrates why clinical genomics is transformative for undiagnosed disease