Genetic Variation and Genome Examination

Genetic Variation

• Human genome comprises approximately 3 billion base pairs coding for around 20,000 genes.
• Typical genomic difference between individuals is estimated at 20 million base pairs.
• Genetic variants are essential for individuality (polymorphisms) and contribute to evolutionary processes.
• Pathogenic variants are a significant factor in disease development.

Genome Examination Advancements

• Dramatic improvements in sequencing technology have made genome examination more accessible and affordable.
• Next generation sequencing (NGS) has transformed cancer research and diagnostics.
• The 100,000 Genomes Project has normalized whole genome sequencing in the NHS.

DNA Replication

• Human DNA can replicate at about 1,000 nucleotides per second, with processes taking only a few hours per cell division.
• Error rates during replication are extremely low: 1 per 100,000 base pairs, improved to 1 per 10 million by proofreading, and further to ~10 errors per cell division through mismatch repair (MMR).

Content of the Human Genome

• Genes make up 1.5% of the genome, while 40% includes related sequences like introns and regulatory regions.
• Repetitive DNA constitutes 45% of the genome, including interspersed repeats and telomeres.

Somatic Mutations

• Somatic mutations can lead to cell death, but most often impact non-coding or inactive DNA, causing limited consequences.
• Mutations affecting genes that regulate cell growth can have significant implications.
• Inactive tumor suppressor genes and active oncogenes can enhance cell division, leading to cancer.

Cancer Mechanisms

• Cancer arises from the accumulation of mutations that disrupt the regulation of the cell cycle.
• Tumors originate as clonal expansions of genetically abnormal cells.
• Intrinsic cellular mechanisms typically ensure genomic integrity, which can fail, leading to cancer.

Cancer Risk Factors

• Major factors influencing cancer risk include age, environmental factors (e.g., smoking, diet), obesity, exercise, and infections (e.g., HPV).
• Genetic predisposition and family history also play critical roles.

Targeted Therapies

• Bevacizumab is used for glioblastoma by binding to VEGF to reduce blood vessel formation.
• Imatinib is used in chronic myeloid leukemia (CML) to block tyrosine kinase activity.

Genes Associated with Cancer

• Tumor suppressor genes, like APC, are crucial for regulating cell growth; their loss can lead to sporadic cancers.
• Oncogenes, such as KRAS and BRAF, facilitate rapid cell division when mutated.
• DNA repair genes like BRCA1 and BRCA2 are vital for maintaining genomic integrity.

DNA Repair Mechanisms

• Mismatch repair deficiencies lead to Lynch syndrome, increasing colorectal, ovarian, and endometrial cancer risks.
• BRCA genes are involved in double-strand DNA break repair.

Inherited Cancer Features

• Early onset of cancer, multiple primary cancers, and familial patterns may indicate inherited susceptibility.

High Penetrance Cancer Syndromes

• Examples include BRCA1/BRCA2, Lynch syndrome, Li-Fraumeni syndrome, and hereditary leiomyomatosis.

Hereditary Cancer Syndromes and Proportions

• Breast and ovarian cancers often linked to BRCA1/2, with 5-20% hereditary contribution.
• Retinoblastoma shows a 40% hereditary correlation with mutations in the RB1 gene.

Ovarian and Breast Cancer Specifics

• 15-20% of epithelial ovarian cancers are due to germline BRCA1/2 mutations.
• Triple-negative breast cancer (TNBC) diagnosis occurs in 10-15% of cases, with varying hereditary implications.

Explore the fundamental aspects of genetic variation, including the significance of polymorphisms and pathogenic variants in human health and disease. Additionally, learn about advancements in genome sequencing technologies that have revolutionized genetic research and examination. This quiz delves into how these developments impact our understanding of individuality and evolution.