Wednesday, October 08, 2014

Best introduction to human genomics

Puzzled by your 23andMe/Promethease results? Having trouble figuring out what SNPs are and what they're good, or bad for? Time to learn some human genetics and genomics.

"Human Genetics and Genomics" (4th Edition) by Bruce R. Korf and Mira B. Irons is a bird's eye view of the basics of molecular biology through to the technologies of genome analysis to the medical implications of DNA and chromosome variation. It's aimed at medical students, so there are case studies to keep it real.

Chapter 1 starts us off with a tour round human DNA. We look at how it's structured, how it's replicated in cells and how DNA is transcribed into proteins. We take a quick look at epigenetics (the way some genes can be chemically silenced - switched off).

Chapter 2 looks at genetic variation. This covers single nucleotide polymorphisms (SNPs), DNA repair mechanisms, gene duplication and its role in evolution. PCR (Polymerase Chain Reaction) as used for forensic analysis of DNA samples amongst other things is also described.

Chapter 3 is 'Patterns of Inheritance'. Here you'll learn how to take a family history looking for dominant or recessive patterns of Mendelian inheritance. We also look at sex-linked inheritance (X or Y chromosome location of the gene in question), mosaicism and genomic imprinting.

Chapter 4 describes the Human Genome Project and the history of attempts to find out where on the human chromosome set a gene of interest (often disease-causing) actually resides. You'll meet some common terms such as linkage disequilibrium, which is carefully explained. The working example in this chapter is cystic fibrosis.

Chapter 5 discusses 'Multifactorial Inheritance'. Most 'quantitative traits' such as height, personality and intelligence are under the control of hundreds or thousands of alleles of small effect. The same is true of many diseases. So in this chapter we learn about heritability, additive and threshold models of multi-allele effects and that very latest thing: genome-wide association studies (GWAS) which are shedding light on .. almost everything.

Chapter 6 raises its gaze to the organisation of genes into chromosomes. Sadly, this is another level where errors can occur (e.g. chromosome 21 trisomy leading to Down Syndrome) and there are plenty of more subtle things which can go wrong (deletions, duplications, inversions, rings, translocations). Characteristic diseases and syndromes duly follow.

Chapter 7 looks at Population Genetics. We learn about the Hardy-Weinberg equation (very clear explanation) and how it is used to work out the carrier frequency of a recessive disease in various populations. The working example here is Sickle Cell Anaemia.

Chapter 8 focuses on Cancer Genetics. Cancer is a genetic disease, emerging from a cascade of errors in those genes which regulate cell development and division. We now have a causal narrative of the mechanisms behind many cancers, as this chapter explains in good detail.

Chapter 9 looks at chromosome translocation with specific application to Down Syndrome.

The remaining chapters (10-17) are shorter and look in detail at:
  • Molecular diagnosis of conditions based on genetic testing
  • Newborn screening (e.g. for PKU) 
  • Developmental genetics (CHARGE syndrome is the example) 
  • Carrier screening (Tay-Sachs in an Ashkenazi context is the example in this chapter)
  • Genetic risk assessment (companies like 23andMe are discussed in some detail)
  • Genetic testing for risks of cancer (BRCA1 and 2 is the example)
  • The genetics of drug response - Pharmacogenetics (example: malignant hyperthermia)
  • Emerging treatment for genetic disorders such as gene therapy.

This book was published in 2013 so it's pretty much up-to-date. If you're not a medical student with good recall, have Google/Wikipedia next to you as you read it: most terms are explained - and then you come to something like Epistasis!